HCQ for COVID-19: real-time analysis of all 368 studies

Covid Analysis (Preprint) (meta analysis)

HCQ for COVID-19: real-time meta analysis of 302 studies

• 32 of the 33 early treatment studies report a positive effect. 19 show statistically significant improvements in isolation (14 for the most serious outcome).

• 45 of the 59 pre-exposure prophylaxis studies report a positive effect. 18 show statistically significant improvements in isolation (16 for the most serious outcome). 12 of the 14 negative effects are from studies where all or most patients were autoimmune disorder patients.

• Late treatment is less successful, with only 67% of the 203 studies reporting a positive effect. Very late stage treatment is not effective and may be harmful, especially when using excessive dosages.

• 83% of Randomized Controlled Trials (RCTs) for early, PrEP, or PEP treatment report positive effects, the probability of results as good or better for an ineffective treatment is 0.0038.

• Meta analysis using the most serious outcome reported shows 64% [54‑72%] improvement for the 33 early treatment studies. Results are similar after exclusion based sensitivity analysis and after restriction to peer-reviewed studies. Restricting to the 8 RCTs shows 46% [16‑65%] improvement, and restricting to the 13 mortality results shows 75% [60‑84%] lower mortality.

• There is evidence of bias towards publishing negative results. 77% of prospective studies report positive effects, compared to 71% of retrospective studies. Studies from North America are 2.8 times more likely to report negative results than studies from the rest of the world combined, p = 0.0000000160. The probability that an ineffective treatment generated results as positive as the 302 studies is estimated to be 1 in 751 trillion.

• Negative meta analyses of HCQ generally choose a subset of trials, focusing on late treatment, especially trials with very late treatment and excessive dosages.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 5% of HCQ studies show zero events in the treatment arm.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. All practical, effective, and safe means should be used. Not doing so increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

• All data to reproduce this paper and the sources are in the appendix. See [Ladapo, Prodromos, Risch, Risch (B)] for other meta analyses showing efficacy when HCQ is used early.

Total	302 studies	4,805 authors	415,386 patients
Positive effects	219 studies	3,401 authors	292,860 patients

Early treatment	64% improvement	RR 0.36 [0.28-0.46]
Late treatment	19% improvement	RR 0.81 [0.76-0.86]

Rao et al., Expert Review of Anti-infective Therapy, doi:10.1080/14787210.2022.2015326 (Peer Reviewed)

Hydroxychloroquine as pre-exposure prophylaxis against COVID-19 infection among healthcare workers: a prospective cohort study

Prospective PrEP study with low risk healthcare workers in India showing RR=0.89 [0.53-1.52]. There were no significant adverse effects. Only mean age and gender distribution are provided for baseline characteristics, no severity information is provided, and no adjustments were made. Authors analyze HCQ use for <8 vs. ≥8 weeks, noting a lack of statistical significance, but not providing the results.

risk of case, 11.0% lower, RR 0.89, p = 0.68, treatment 16 of 273 (5.9%), control 67 of 1,021 (6.6%).

Excluded in after exclusion results of meta analysis: unadjusted results with minimal group details.

Rao et al., 12/4/2021, prospective, India, South Asia, peer-reviewed, 8 authors.

Ferreira et al., Revista da Associação Médica Brasileira, doi:10.1590/1806-9282.20210661 (Peer Reviewed)

Outcomes associated with Hydroxychloroquine and Ivermectin in hospitalized patients with COVID-19: a single-center experience

Retrospective 230 hospitalized patients in Brazil showing higher mortality with HCQ treatment. Authors note that the treatments were more likely to be offered to sicker patients. Authors indicate that they do not know when medication was started, which in some cases could have been after ICU admission or intubation. Dosage is unknown.

risk of death, 151.5% higher, RR 2.51, p = 0.03, treatment 17 of 111 (15.3%), control 11 of 81 (13.6%), OR converted to RR, multivariate.

risk of death/intubation, 45.9% higher, RR 1.46, p = 0.23, treatment 30 of 111 (27.0%), control 15 of 81 (18.5%).

risk of death/intubation/ICU, 61.3% higher, RR 1.61, p = 0.04, treatment 42 of 111 (37.8%), control 19 of 81 (23.5%).

Ferreira et al., 11/26/2021, retrospective, Brazil, South America, peer-reviewed, 5 authors, 12 March, 2020 - 8 July, 2020, dosage not specified.

Calderón et al., PAMJ - Clinical Medicine, doi:10.11604/pamj-cm.2021.7.15.30981 (Peer Reviewed)

Treatment with hydroxychloroquine vs nitazoxanide in patients with COVID-19: brief report

Planned RCT of HCQ vs. HCQ+nitazoxanide which was aborted due to the retracted Surgisphere paper. Authors retrospectively analyze a small set of HCQ vs. nitazoxanide patients (which were protocol deviations in the planned RCT), showing reduced hospitalization time and ICU admission with nitazoxanide.

risk of death, 214.8% higher, RR 3.15, p = 0.38, treatment 5 of 27 (18.5%), control 1 of 17 (5.9%).

risk of mechanical ventilation, 651.9% higher, RR 7.52, p = 0.15, treatment 4 of 27 (14.8%), control 0 of 17 (0.0%), continuity correction due to zero event.

risk of ICU admission, 145.5% higher, RR 2.45, p < 0.001, treatment 16 of 27 (59.3%), control 0 of 17 (0.0%), adjusted, continuity correction due to zero event.

hospitalization time, 107.4% higher, relative time 2.07, p = 0.006, treatment 27, control 17.

Calderón et al., 11/23/2021, retrospective, Mexico, North America, peer-reviewed, 7 authors, dosage 200mg bid days 1-7.

Ahmed et al., BioMed Research International, doi:10.1155/2021/1676914 (Peer Reviewed)

Factors Affecting the Incidence, Progression, and Severity of COVID-19 in Type 1 Diabetes Mellitus

Retrospective type 1 diabetes patients in Saudi Arabia showing reduced risk of cases with HCQ prophylaxis.

risk of case, 99.3% lower, RR 0.007, p = 0.08, treatment 0 of 50 (0.0%) cases, 13 of 50 (26.0%) controls, case control OR.

Ahmed et al., 11/23/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 7 authors.

Samajdar et al., Journal of the Association of Physicians India, 69:11 (Peer Reviewed)

Ivermectin and Hydroxychloroquine for Chemo-Prophylaxis of COVID-19: A Questionnaire Survey of Perception and Prescribing Practice of Physicians vis-a-vis Outcomes

Physician survey in India with 164 ivermectin prophylaxis, 129 HCQ prophylaxis, and 81 control patients, showing significantly lower COVID-19 cases with treatment. Details of the treatment and control groups and the definition of cases are not provided, and the results are subject to survey bias. Authors also report on community prophylaxis but present only combined ivermectin/HCQ results.

risk of case, 74.5% lower, RR 0.25, p < 0.001, treatment 12 of 129 (9.3%), control 29 of 81 (35.8%), OR converted to RR, physician survey.

risk of case, 48.6% lower, RR 0.51, p = 0.03, treatment 11 of 109 (10.1%), control 39 of 200 (19.5%), OR converted to RR, combined ivermectin or HCQ in community.

Excluded in after exclusion results of meta analysis: minimal details provided, unadjusted results with no group details, results may be significantly affected by survey bias.

Samajdar et al., 11/17/2021, retrospective, India, South Asia, peer-reviewed, 9 authors, 1 September, 2020 - 31 December, 2020, dosage not specified.

Chechter et al., medRxiv, doi:10.1101/2021.11.05.21265569 (Preprint)

Evaluation of patients treated by telemedicine in the COVID-19 pandemic by a private clinic in Sao Paulo, Brazil: A non-randomized clinical trial preliminary study

Prospective study of 187 telemedicine patients in Brazil. 74 presenting with moderate symptoms were offered treatment with HCQ+AZ, 12 did not accept HCQ (taking AZ only), forming a control group. There was lower hospitalization and improved recovery with treatment. There appears to be different group sizes in the text and tables without explanation (maybe a typo). RBR-658khm.

risk of hospitalization, 94.7% lower, RR 0.05, p = 0.004, treatment 0 of 60 (0.0%), control 3 of 12 (25.0%), relative risk is not 0 because of continuity correction due to zero events.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Chechter et al., 11/5/2021, prospective, Brazil, South America, preprint, 13 authors, dosage 800mg day 1, 400mg days 2-5.

Sarhan et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.10.024 (Peer Reviewed)

Efficacy of the early treatment with tocilizumab-hydroxychloroquine and tocilizumab-remdesivir in severe COVID-19 Patients

Small 108 patient RCT comparing HCQ vs. remdesivir in very late stage treatment. All patients received tocilizumab. There were significant unadjusted baseline differences in ventilation and ICU admission. NCT04779047. REC-H-PhBSU-21011.

risk of death, 25.7% lower, RR 0.74, p = 0.39, treatment 12 of 56 (21.4%), control 15 of 52 (28.8%).

risk of no hospital discharge, 25.7% lower, RR 0.74, p = 0.39, treatment 12 of 56 (21.4%), control 15 of 52 (28.8%).

hospitalization time, 25.0% higher, relative time 1.25, p = 0.06, treatment 56, control 52.

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline, significant unadjusted differences between groups.

Sarhan et al., 11/2/2021, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 8 authors, 1 October, 2020 - 10 March, 2021, this trial compares with another treatment - results may be better when compared to placebo.

Guglielmetti et al., Scientific Reports, doi:10.1038/s41598-021-00243-4 (Peer Reviewed)

Treatment for COVID-19—a cohort study from Northern Italy

Retrospective 600 hospitalized patients in Italy, showing lower mortality with HCQ treatment, without reaching statistical significance (p = 0.1).

risk of death, 28.0% lower, RR 0.72, p = 0.10, treatment 474, control 126, multivariable Cox proportional hazards.

Guglielmetti et al., 10/25/2021, retrospective, Italy, Europe, peer-reviewed, 19 authors, 21 February, 2020 - 15 May, 2020.

Babalola et al., Research Square, doi:10.21203/rs.3.rs-950352/v1 (Preprint)

A Randomized Controlled Trial of Ivermectin Monotherapy Versus Hydroxychloroquine, Ivermectin, and Azithromycin Combination Therapy in Covid-19 Patients in Nigeria

Small RCT with 61 patients in Nigeria, all patients treated with ivermectin, zinc, and vitamin C, showing no significant improvements in recovery with the addition of HCQ+AZ. PACTR202108891693522.

risk of no hospital discharge, 54.5% higher, RR 1.55, p = 0.20, treatment 17 of 30 (56.7%), control 11 of 30 (36.7%), day 7.

risk of no virological cure, 9.5% lower, RR 0.90, p = 0.78, treatment 19 of 30 (63.3%), control 21 of 30 (70.0%), day 5 mid-recovery.

Babalola et al., 10/1/2021, Single Blind Randomized Controlled Trial, Nigeria, Africa, preprint, 6 authors, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary.

Fung et al., medRxiv, doi:10.1101/2021.09.28.21264186 (Preprint)

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients

Retrospective database analysis of 374,229 patients in the USA, showing no significant difference with HCQ use, however authors do not adjust for the very different baseline risk for systemic autoimmune disease patients. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

Authors compare with patients that never used HCQ and with patients that previously used HCQ. The comparison with patients previously using HCQ is more relevant because the matching of patients with systemic autoimmune disease is likely to be better.

[1] c19hcq.com/ferri.html

risk of death, 15.0% lower, RR 0.85, p = 0.10, vs. past use (better match for systemic autoimmune diseases).

risk of hospitalization, 5.0% lower, RR 0.95, p = 0.41, vs. past use (better match for systemic autoimmune diseases).

risk of case, 10.0% lower, RR 0.90, p = 0.004, vs. past use (better match for systemic autoimmune diseases).

risk of death, 6.0% higher, RR 1.06, p = 0.39, vs. never used.

risk of hospitalization, 4.0% higher, RR 1.04, p = 0.32, vs. never used.

risk of case, 5.0% lower, RR 0.95, p = 0.06, vs. never used.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Fung et al., 10/1/2021, retrospective, population-based cohort, USA, North America, preprint, 6 authors.

Menardi et al., PharmAdvances, doi:10.36118/pharmadvances.2021.15 (Peer Reviewed)

A retrospective analysis on pharmacological approaches to COVID-19 patients in an Italian hub hospital during the early phase of the pandemic

Retrospective 277 hospitalized patients in Italy, showing lower mortality with HCQ treatment, not reaching statistical significance, and subject to confounding by indication.

risk of death, 35.2% lower, RR 0.65, p = 0.12, treatment 32 of 200 (16.0%), control 19 of 77 (24.7%).

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups, substantial unadjusted confounding by indication likely.

Menardi et al., 9/30/2021, retrospective, Italy, Europe, peer-reviewed, 10 authors.

Uygen et al., Northern Clinics of Istanbul, doi:10.14744/nci.2021.65471 (Peer Reviewed)

Effect of Hydroxychloroquine Use on the Length Of Hospital Stay in Children Diagnosed With Covid 19

Retrospective 40 pediatric hospitalized patients, 15 treated with HCQ, showing 7.2 vs. 8.2 days until PCR-, not quite reaching statistical significance.

time to viral-, 12.2% lower, relative time 0.88, p = 0.05, treatment 15, control 25.

Uygen et al., 9/15/2021, retrospective, Turkey, Europe, peer-reviewed, 4 authors.

Çivriz Bozdağ et al., Turk. J. Haematol., doi:10.4274/tjh.galenos.2021.2021.0287 (Peer Reviewed)

Clinical Characteristics and Outcome of COVID-19 in Turkish Hematological Malignancy Patients

Retrospective 340 patients with hematological malignancy in Turkey, showing higher mortality with HCQ treatment. Confounding by time is likely because more HCQ patients were earlier in time when overall treatment protocols were significantly worse.

risk of death, 399.2% higher, RR 4.99, p = 0.003, treatment 35, control 140.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Çivriz Bozdağ et al., 9/15/2021, retrospective, Turkey, Europe, peer-reviewed, 62 authors.

Alotaibi et al., International Journal of General Medicine, 2021:14 (Peer Reviewed)

Effectiveness and Safety of Favipiravir Compared to Hydroxychloroquine for Management of Covid-19: A Retrospective Study

Retrospective hospitalized patients in Saudi Arabia, showing lower mortality with favipiravir compared to HCQ, not quite reaching statistical significance. Authors do not indicate the factors behind which therapy was chosen. Confounding by indication and time are possible.

risk of death, 133.5% higher, RR 2.33, p = 0.05, treatment 193, control 244, multivariate.

Alotaibi et al., 9/14/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 11 authors, this trial compares with another treatment - results may be better when compared to placebo.

Agarwal et al., medRxiv, doi:10.1101/2021.09.13.21262971 (Preprint)

Low dose hydroxychloroquine prophylaxis for COVID-19 - a prospective study

Small prophylaxis trial with 29 low dose HCQ and 455 control healthcare workers in India, showing no statistically significant differences.

risk of hospitalization, 94.8% lower, RR 0.05, p = 0.61, treatment 0 of 29 (0.0%), control 17 of 455 (3.7%), relative risk is not 0 because of continuity correction due to zero events.

relative severity, 26.9% lower, RR 0.73, p = 0.21, treatment 29, control 455.

risk of case, 4.6% higher, RR 1.05, p = 0.81, treatment 6 of 29 (20.7%), control 90 of 455 (19.8%).

Agarwal et al., 9/14/2021, prospective, India, South Asia, preprint, 1 author.

Accinelli et al., Travel Medicine and Infectious Disease, doi:10.1016/j.tmaid.2021.102163 (Peer Reviewed)

Hydroxychloroquine / azithromycin in COVID-19: The association between time to treatment and case fatality rate

Retrospective 1,265 outpatients in Peru treated with HCQ+AZ showing mortality associated with treatment delay. Mortality was six times lower than the national average.

Accinelli et al., 9/14/2021, peer-reviewed, 6 authors.

Sawanpanyalert et al., Southeast Asian Journal of Tropical Medicine and Public Health, 52:4 (Peer Reviewed)

Assessment of outcomes following implementation of antiviral treatment guidelines for COVID-19 during the first wave in Thailand

Retrospective 744 hospitalized patients in Thailand, showing lower risk of a poor outcome for favipiravir treatment within 4 days of symptom onset. Early treatment with CQ/HCQ and lopinavir/ritonavir or darunavir/ritonavir also showed lower risk, but without statistical significance. Sample sizes for the number of patients treated within 4 days of symptom onset are not provided.

risk of death, ICU, intubation, or high-flow oxygen, 42.0% lower, RR 0.58, p = 0.37, within 4 days of symptom onset, RR approximated with OR.

Sawanpanyalert et al., 9/9/2021, retrospective, Thailand, South Asia, peer-reviewed, 11 authors, dosage varies, this trial uses multiple treatments in the treatment arm (combined with lopinavir/ritonavir or darunavir/ritonavir) - results of individual treatments may vary.

Rodrigues et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2021.106428 (Peer Reviewed)

Hydroxychloroquine plus azithromycin early treatment of mild COVID-19 in outpatient setting: a randomized, double-blinded, placebo-controlled clinical trial evaluating viral clearance

RCT 84 low risk patients, 42 treated with HCQ/AZ, showing no significant differences. There was only one hospitalization which was in the treatment arm.

risk of hospitalization, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 42 (2.4%), control 0 of 42 (0.0%), continuity correction due to zero event.

risk of no virological cure, 14.4% lower, RR 0.86, p = 0.15, treatment 29 of 36 (80.6%), control 32 of 34 (94.1%), PP, day 3.

risk of no virological cure, 13.1% lower, RR 0.87, p = 0.45, treatment 23 of 36 (63.9%), control 25 of 34 (73.5%), PP, day 6.

risk of no virological cure, 23.3% lower, RR 0.77, p = 0.47, treatment 13 of 36 (36.1%), control 16 of 34 (47.1%), PP, day 9.

risk of no virological cure, 3.1% lower, RR 0.97, p = 1.00, treatment 31 of 42 (73.8%), control 32 of 42 (76.2%), ITT, day 3.

risk of no virological cure, no change, RR 1.00, p = 1.00, treatment 25 of 42 (59.5%), control 25 of 42 (59.5%), ITT, day 6.

risk of no virological cure, 6.2% lower, RR 0.94, p = 1.00, treatment 15 of 42 (35.7%), control 16 of 42 (38.1%), ITT, day 9.

time to viral-, 8.8% lower, relative time 0.91, p = 0.26, treatment 36, control 34, PP.

time to viral-, 1.4% lower, relative time 0.99, p = 0.85, treatment 42, control 42, ITT.

Rodrigues et al., 8/25/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 8 authors, dosage 400mg bid days 1-7.

Naggie et al., medRxiv, doi:10.1101/2021.08.19.21262275 (Preprint)

Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial (HERO-HCQ)

RCT 1,360 healthcare workers in the USA showing OR 0.75 [0.49-1.15] for confirmed or suspected COVID-19 clinical infection by day 30. There were no significant safety issues. Authors note that pooling the results with the COVID PREP study gives OR 0.74 [0.55-1.0] p = 0.046. NCT04334148.

risk of symptomatic case, 23.5% lower, RR 0.76, p = 0.18, treatment 41 of 683 (6.0%), control 53 of 676 (7.8%), OR converted to RR, logistic regression.

risk of symptomatic case, 29.3% lower, RR 0.71, p = 0.18, treatment 41 of 683 (6.0%), control 53 of 676 (7.8%), OR converted to RR, Mantel–Haenszel.

Naggie et al., 8/25/2021, Randomized Controlled Trial, USA, North America, preprint, 22 authors.

Patil et al., Research Square, doi:10.21203/rs.3.rs-805748/v1 (Preprint)

A Prospective Longitudinal Study Evaluating The Influence of Immunosuppressives and Other Factors On COVID-19 in Autoimmune Rheumatic Diseases

Prospective study of 9,212 autoimmune rheumatic disease patients showing lower mortality with HCQ, without reaching statistical significance. Authors incorrectly state "HCQ use did not influence occurrence of COVID-19 (RR = 0.909, CI (0.715,1.154), p = 0.432) or mortality (p = 0.097)" [1]. CFR for the autoimmune rheumatic disease patients was 4.6 times higher than in the general population from the same area.

[1] nature.com/articles/d41586-019-00857-9

risk of death, 65.9% lower, RR 0.34, p = 0.10, treatment 5,266, control 3,946.

risk of case, 9.1% lower, RR 0.91, p = 0.43, treatment 167 of 5,266 (3.2%), control 147 of 3,946 (3.7%), adjusted.

Patil et al., 8/24/2021, prospective, India, South Asia, preprint, 20 authors.

Eldeen et al., Microbes and Infectious Diseases, doi:10.21608/mid.2021.85877.1177 (Peer Reviewed)

Comparative study between the therapeutic effect of remdesivir versus hydroxychloroquine in COVID-19 hospitalized patients

Small study comparing 25 HCQ and 25 remdesivir hospitalized patients, reporting faster viral clearance with remdesivir. The article proof is missing the results for the HCQ group. Confounding by time is likely - remdesivir patients were after HCQ patients in time, and treatment protocols improved over the period of the study.

Eldeen et al., 8/16/2021, peer-reviewed, 5 authors.

Tai et al., Pharmaceutics, doi:10.3390/pharmaceutics13081260 (Peer Reviewed)

Nebulised Isotonic Hydroxychloroquine Aerosols for Potential Treatment of COVID-19

Analysis of HCQ solutions suitable for nebulization for COVID-19.

Tai et al., 8/14/2021, peer-reviewed, 8 authors.

Shabani et al., Pulmonary Pharmacology & Therapeutics, doi:10.1016/j.pupt.2021.102069 (Peer Reviewed)

Evaluation of the Prophylactic Effect of Hydroxychloroquine on People in Close-Contact with Patients with Covid-19

Small PEP trial with 51 HCQ patients, not showing a significant difference in cases. IRCT20130917014693N10.

risk of symptomatic case, 19.0% lower, RR 0.81, p = 1.00, treatment 2 of 51 (3.9%), control 3 of 62 (4.8%), day 7.

risk of case, 6.4% higher, RR 1.06, p = 1.00, treatment 7 of 51 (13.7%), control 8 of 62 (12.9%), day 7, PCR+ and symptomatic.

risk of case, 21.6% higher, RR 1.22, p = 0.78, treatment 7 of 51 (13.7%), control 7 of 62 (11.3%), day 7, PCR+ only.

Shabani et al., 8/10/2021, prospective, Iran, Middle East, peer-reviewed, 16 authors.

Stricker et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.001 (Peer Reviewed) (meta analysis)

Hydroxychloroquine Pre-Exposure Prophylaxis for COVID-19 in Healthcare Workers from India: A Meta-Analysis

Meta analysis of 11 HCQ PrEP studies in India covering 7,616 healthcare workers, showing significantly lower cases with treatment.

risk of death, 75.0% lower, RR 0.25, p < 0.001, treatment 1,273, control 4,127, >=6 doses.

risk of death, 44.0% lower, RR 0.56, p = 0.004, treatment 3,489, control 4,127, any number of doses.

Stricker et al., 8/5/2021, peer-reviewed, 2 authors.

Özuygur Ermiş et al., Turkish Journal of Medical Sciences, doi:10.3906/sag-2009-64 (Peer Reviewed)

The Efficacy of Hydroxychloroquine and Azithromycin Combination Therapy on Hospital Mortality in COVID 19 Pneumonia Patients

Retrospective 370 hospitalized patients, 222 receiving HCQ+AZ and 148 receiving HCQ, showing mortality OR 0.61 [0.23-1.59], p = 0.31 for the addition of AZ.

Özuygur Ermiş et al., 8/4/2021, peer-reviewed, 13 authors.

Bhatt et al., medRxiv, doi:10.1101/2021.08.02.21260750 (Preprint)

Hydroxychloroquine Prophylaxis against Coronavirus Disease-19: Practice Outcomes among Health-Care Workers

Observational study of 927 low-risk healthcare workers in India, 731 volunteering for weekly HCQ prophylaxis, showing higher cases with treatment in unadjusted results. Clinical outcome was in the protocol, however no information on which patients were symptomatic is provided. There were no adverse events and no hospitalizations or deaths. Adherence was very low, decreasing weekly, with almost all participants discontinuing by week 11. The majority of infections occurred in later weeks when adherence was very low, and there was no per protocol analysis. #ECR/206/Inst/GJ/2013/RR-20.

risk of case, 49.3% higher, RR 1.49, p = 0.02, treatment 167 of 731 (22.8%), control 30 of 196 (15.3%).

Bhatt et al., 8/4/2021, prospective, India, South Asia, preprint, 4 authors.

Alghamdi et al., Saudi Pharmaceutical Journal, doi:10.1016/j.jsps.2021.08.008 (Peer Reviewed)

Clinical characteristics and treatment outcomes of severe (ICU) COVID-19 patients in Saudi Arabia: A single centre study

Retrospective 171 ICU patients in Saudi Arabia showing no significant difference for HCQ treatment in unadjusted results.

risk of death, 39.2% higher, RR 1.39, p = 0.52, treatment 29 of 128 (22.7%), control 7 of 43 (16.3%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, very late stage, ICU patients.

Alghamdi et al., 8/4/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 1 author.

Barra et al., medRxiv, doi:10.1101/2021.07.30.21261220 (Preprint)

COVID-19 in hospitalized patients in 4 hospitals in San Isidro, Buenos Aires, Argentina

Retrospective 668 hospitalized patients in Argentina, 18 treated with HCQ, not showing a significant difference in unadjusted results.

risk of death, 10.8% lower, RR 0.89, p = 1.00, treatment 2 of 18 (11.1%), control 81 of 650 (12.5%), unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Barra et al., 7/31/2021, retrospective, Argentina, South America, preprint, 12 authors.

Sobngwi et al., medRxiv, doi:10.1101/2021.07.25.21260838 (Preprint)

Doxycycline is a safe alternative to Hydroxychloroquine + Azithromycin to prevent clinical worsening and hospitalization in mild COVID-19 patients: An open label randomized clinical trial (DOXYCOV)

RCT 194 mild/asymptomatic low-risk patients in Cameroon, 97 treated with HCQ+AZ and 97 treated with doxycycline, showing 2.1% symptomatic patients at day 10 with HCQ+AZ, versus 4.3% with doxycycline, but without statistical significance. There were only 6 patients with symtoms at day 10. There was no mortality or hospitalization, and no major adverse events.

risk of no recovery, 51.6% lower, RR 0.48, p = 0.44, treatment 2 of 95 (2.1%), control 4 of 92 (4.3%), day 10.

risk of no recovery, 3.2% lower, RR 0.97, p = 1.00, treatment 18 of 95 (18.9%), control 18 of 92 (19.6%), day 3.

risk of no virological cure, 3.2% lower, RR 0.97, p = 0.88, treatment 32 of 95 (33.7%), control 32 of 92 (34.8%), day 10.

Sobngwi et al., 7/29/2021, Randomized Controlled Trial, Cameroon, Africa, preprint, 16 authors, dosage 400mg days 1-5, this trial compares with another treatment - results may be better when compared to placebo.

Küçükakkaş et al., Research Square, doi:10.21203/rs.3.rs-43812/v1 (Preprint)

The effect of hydroxychloroquine against SARS-CoV-2 infection in rheumatoid arthritis patients

Retrospective 17 rheumatoid arthritis COVID-19+ patients, 7 on HCQ treatment, showing no significant differences. They study reports only including hospitalized patients, but the results include non-hospitalized patients. Results do not reflect potential difference in the probability that a case is serious enough to have been tested and identified. Few group details are provided (even the age of patients in each group is not specified).

risk of ICU admission, 42.9% higher, RR 1.43, p = 1.00, treatment 1 of 7 (14.3%), control 1 of 10 (10.0%).

Excluded in after exclusion results of meta analysis: minimal details of groups provided.

Küçükakkaş et al., 7/20/2021, retrospective, Turkey, Europe, preprint, 2 authors.

Alhamlan et al., medRxiv, doi:10.1101/2021.07.13.21260428 (Preprint)

Epidemiology and Clinical Characteristics in Individuals with Confirmed SARS-CoV-2 Infection During the Early COVID-19 Pandemic in Saudi Arabia

Retrospective hospitalized patients in Saudi Arabia showing higher mortality with most treatments although not reaching statistical significance. Confounding by indication, time, or other factors is likely (a 19x higher risk with lopinavir/ritonavir and 3.5x higher risk with azithromycin is not supported by other studies for example). The number of patients treated with HCQ is not provided.

risk of death, 52.0% higher, RR 1.52, p = 0.57.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Alhamlan et al., 7/16/2021, retrospective, database analysis, Saudi Arabia, Middle East, preprint, 10 authors.

Barrat-Due et al., Annals of Internal Medicine, doi:10.7326/M21-0653 (Peer Reviewed)

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19

Small RCT in Norway with 52 HCQ and 42 remdesivir patients, showing no significant differences with treatment. Add-on trial to WHO Solidarity. NCT04321616.

risk of death, 120.0% higher, RR 2.20, p = 0.35, treatment 4 of 45 (8.9%), control 2 of 48 (4.2%), adjusted.

Barrat-Due et al., 7/13/2021, Double Blind Randomized Controlled Trial, Norway, Europe, peer-reviewed, 41 authors.

Roger et al., Anaesthesia Critical Care & Pain Medicine, doi:10.1016/j.accpm.2021.100931 (Peer Reviewed)

French Multicentre Observational Study on SARS-CoV-2 infections Intensive care initial management: the FRENCH CORONA Study

Prospective study of 966 ICU patients in France, 289 treated with HCQ, showing no significant difference with treatment. Time based confounding is likely because HCQ became increasingly controversial and less used over the time covered, while overall treatment protocols during this period improved dramatically, i.e., more control patients likely come later in the period when treatment protocols were greatly improved.

risk of death, no change, RR 1.00, p = 0.94, treatment 53 of 289 (18.3%), control 120 of 677 (17.7%), OR converted to RR.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Roger et al., 7/10/2021, prospective, France, Europe, peer-reviewed, 34 authors.

Jacobs et al., The Annals of Thoracic Surgery, doi:10.1016/j.athoracsur.2021.06.026 (Peer Reviewed)

Multi-institutional Analysis of 200 COVID-19 Patients treated with ECMO:Outcomes and Trends

Prospective study of 200 ECMO patients showing no significant difference in unadjusted results for HCQ treatment. Time based confounding is likely because HCQ became increasingly controversial and less used over the time covered (as shown in figure 4), while overall treatment protocols during this period improved dramatically, i.e., more control patients likely come later in the period when treatment protocols were greatly improved.

risk of death, 6.6% lower, RR 0.93, p = 0.74, treatment 24 of 46 (52.2%), control 86 of 154 (55.8%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Jacobs et al., 7/6/2021, prospective, USA, North America, peer-reviewed, 14 authors.

Taieb et al., J. Clin. Med. 2021, doi:10.3390/jcm10132954 (Peer Reviewed)

Hydroxychloroquine and Azithromycin Treatment of Hospitalized Patients Infected with SARS-CoV-2 in Senegal from March to October 2020

Retrospective 926 patients in Senegal, 674 treated with HCQ+AZ, showing significantly higher hospital discharge at day 15 with treatment.

risk of no hospital discharge, 38.7% lower, RR 0.61, p = 0.02, treatment 674, control 252, multivariate, RR approximated with OR.

Taieb et al., 6/30/2021, retrospective, Senegal, Africa, peer-reviewed, 29 authors.

Gerlovin et al., American Journal of Epidemiology, doi:10.1093/aje/kwab183 (Peer Reviewed)

Pharmacoepidemiology, Machine Learning and COVID-19: An intent-to-treat analysis of hydroxychloroquine, with or without azithromycin, and COVID-19 outcomes amongst hospitalized US Veterans

Retrospective 1,769 hospitalized patients in the USA showing no significant differences for HCQ, and higher intubation for HCQ+AZ.

risk of death, 22.0% higher, RR 1.22, p = 0.18, treatment 90 of 429 (21.0%), control 141 of 770 (18.3%), adjusted, HCQ+AZ.

risk of death, 21.0% higher, RR 1.21, p = 0.33, treatment 49 of 228 (21.5%), control 141 of 770 (18.3%), adjusted, HCQ.

risk of mechanical ventilation, 55.0% higher, RR 1.55, p = 0.02, treatment 64 of 429 (14.9%), control 69 of 770 (9.0%), adjusted, HCQ+AZ.

risk of mechanical ventilation, 33.0% higher, RR 1.33, p = 0.25, treatment 32 of 228 (14.0%), control 69 of 770 (9.0%), adjusted, HCQ.

Gerlovin et al., 6/24/2021, retrospective, USA, North America, peer-reviewed, 21 authors.

Yadav et al., Research Square, doi:10.21203/rs.3.rs-628277/v1 (Preprint)

Repurposing the Combination Drug of Favipiravir, Hydroxychloroquine and Oseltamivir as a Potential Inhibitor Against SARS-CoV-2: A Computational Study

In Silico study showing stronger inhibition of SAR-CoV-2 for HCQ+favipiravir+oseltamivir compared to any of these alone or combinations of two of these drugs.

Yadav et al., 6/21/2021, preprint, 2 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Schwartz et al., CMAJ Open, doi:10.9778/cmajo.20210069 (Peer Reviewed)

Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial

Small early terminated late treatment RCT not showing significant differences. The HCQ group was a median of 7 days from symptom onset at baseline, which may not include the delay delivering the medication. From the 4 HCQ hospitalizations, only one is in the per-protocol analysis, and that patient was hospitalized one day after randomization (authors do not specify if the patient received and took any HCQ before the hospitalization). The trial was terminated early due to the fraudulent Lancet article (wording here is notably different between the submitted and published versions). Per-protocol analysis, the submitted version, and the peer-review comments (two reviewers, only one with substantial feedback) are in the supplementary material.

risk of ICU admission, 133.3% higher, RR 2.33, p = 1.00, treatment 1 of 111 (0.9%), control 0 of 37 (0.0%), continuity correction due to zero event.

risk of hospitalization, 533.3% higher, RR 6.33, p = 0.57, treatment 4 of 111 (3.6%), control 0 of 37 (0.0%), continuity correction due to zero event.

risk of ICU admission, 141.9% higher, RR 2.42, p = 1.00, treatment 1 of 74 (1.4%), control 0 of 31 (0.0%), continuity correction due to zero event, per-protocol.

risk of hospitalization, 141.9% higher, RR 2.42, p = 1.00, treatment 1 of 74 (1.4%), control 0 of 31 (0.0%), continuity correction due to zero event, per-protocol.

Schwartz et al., 6/18/2021, Double Blind Randomized Controlled Trial, Canada, North America, peer-reviewed, 20 authors, dosage 800mg day 1, 400mg days 2-5.

Purwati et al., PLOS One, doi:10.1371/journal.pone.0252302 (Peer Reviewed) (In Vitro)

An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia

In Vitro study of combinations of drugs showing antiviral efficacy of HCQ alone and in combination with AZ, favipiravir, and doxycycline. No high levels of cytotoxicity were observed, and authors conclude that using a combination of drugs can reduce the degree of cytotoxicity, increase antiviral activity, reduce the effect on pro-inflammatory markers, and increase anti-inflammatory response.

Purwati et al., 6/18/2021, peer-reviewed, 16 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Turrini et al., Vaccines, 10.3390/vaccines9060640 (Peer Reviewed)

Clinical Course and Risk Factors for In-Hospital Mortality of 205 Patients with SARS-CoV-2 Pneumonia in Como, Lombardy Region, Italy

Retrospective 205 patients in Italy, 160 treated with HCQ, showing lower mortality with treatment in multivariate analysis, but not reaching statistical significance.

risk of death, 9.8% lower, RR 0.90, p = 0.15, treatment 103 of 160 (64.4%), control 33 of 45 (73.3%), adjusted, OR converted to RR, multivariate.

Turrini et al., 6/11/2021, retrospective, Italy, Europe, peer-reviewed, 16 authors.

Saib et al., PLOS ONE, doi:10.1371/journal.pone.0252388 (Peer Reviewed)

Lack of efficacy of hydroxychloroquine and azithromycin in patients hospitalized for COVID-19 pneumonia: A retrospective study

203 hospitalized patients in France, not showing significant differences with treatment. Confounding by indication is likely. Authors do not discuss confounding.

risk of death/intubation, 125.0% higher, RR 2.25, p = 0.23, treatment 9 of 52 (17.3%), control 4 of 52 (7.7%), PSM.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Saib et al., 6/9/2021, prospective, propensity score matching, France, Europe, peer-reviewed, 9 authors.

Singh et al., medRxiv, doi:0.1101/2021.06.06.21258091 (Preprint)

Safety and efficacy of antiviral therapy alone or in combination in COVID-19 - a randomized controlled trial (SEV COVID Trial)

Very small early terminated RCT in India, showing lower mortality but without statistical significance with the very small sample size. Time since symptom onset is not provided. The recovery percentage for non-severe group B (86.7%) does not match any number of recoveries, we have used the closest number (15/17).

risk of death, 47.5% lower, RR 0.53, p = 0.45, treatment 3 of 20 (15.0%), control 6 of 21 (28.6%), severe.

risk of death, 50.0% lower, RR 0.50, p = 0.48, treatment 3 of 37 (8.1%), control 6 of 37 (16.2%), all patients.

risk of no recovery, 14.1% lower, RR 0.86, p = 0.76, treatment 9 of 20 (45.0%), control 11 of 21 (52.4%), severe.

risk of no recovery, 8.3% lower, RR 0.92, p = 1.00, treatment 11 of 37 (29.7%), control 12 of 37 (32.4%), all patients.

Singh et al., 6/8/2021, Randomized Controlled Trial, India, South Asia, preprint, 13 authors, this trial uses multiple treatments in the treatment arm (combined with ribavirin) - results of individual treatments may vary.

Badyal et al., Journal of the Association of Physicians of India, Volume 69, June 2021 (Peer Reviewed)

Hydroxychloroquine for SARS CoV2 Prophylaxis in Healthcare Workers – A Multicentric Cohort Study Assessing Effectiveness and Safety

Prophylaxis study with 12,089 Indian healthcare workers, showing lower risk of COVID-19 cases with treatment, and increasingly lower risk for longer durations of HCQ prophylaxis. The appendices are not currently available.

risk of case, 60.1% lower, RR 0.40, p < 0.001, treatment 247 of 617 (40.0%), control 611 of 1,473 (41.5%), adjusted, OR converted to RR, >=6 weeks, logistic regression.

risk of case, 35.1% lower, RR 0.65, p = 0.003, treatment 88 of 185 (47.6%), control 611 of 1,473 (41.5%), adjusted, OR converted to RR, 4-5 weeks, logistic regression.

risk of case, 23.2% lower, RR 0.77, p = 0.04, treatment 80 of 181 (44.2%), control 611 of 1,473 (41.5%), adjusted, OR converted to RR, 2-3 weeks, logistic regression.

Badyal et al., 6/7/2021, prospective, India, South Asia, peer-reviewed, 18 authors.

Lagier et al., Preprint (Preprint)

Outcomes of 2,111 COVID-19 hospitalised patients treated with 2 hydroxychloroquine/azithromycin and other regimens in Marseille, France: a 3 monocentric retrospective analysis

Retrospective 2,011 hospitalized patients in France, median age 67, showing lower mortality with HCQ+AZ, and further benefit with the addition of zinc.

risk of death, 32.0% lower, RR 0.68, p = 0.004, treatment 93 of 1,270 (7.3%), control 146 of 841 (17.4%), adjusted, weighted multivariate Cox proportional hazards model.

Lagier et al., 6/4/2021, retrospective, France, Europe, preprint, 32 authors.

Byakika-Kibwika et al., Research Square, doi:10.21203/rs.3.rs-506195/v1 (Preprint)

Safety and Efficacy of Hydroxychloroquine for Treatment of Non-Severe COVID-19 in Adults in Uganda: A Randomized Open Label Phase II Clinical Trial

Small 105 patient RCT in Uganda showing no significant differences. No mortality was reported. The patients were very young (median age 32), recovering in a median time of 3 days with standard of care, so there is little room for a treatment to make improvements. Time since symptom onset is not specified, but the distribution of symptoms at baseline suggests that the enrollment is relatively late within a cohort of low risk patients.

recovery time, no change, relative time 1.00, p = 0.91, treatment 36, control 29.

relative improvement in Ct value, 29.3% lower, RR 0.71, p = 0.47, treatment 15, control 15.

risk of no virological cure, 2.6% higher, RR 1.03, p = 1.00, treatment 35 of 55 (63.6%), control 31 of 50 (62.0%), day 6.

risk of no virological cure, 6.7% higher, RR 1.07, p = 0.85, treatment 27 of 55 (49.1%), control 23 of 50 (46.0%), day 10.

Byakika-Kibwika et al., 6/4/2021, Randomized Controlled Trial, Uganda, Africa, preprint, 17 authors.

Sivapalan et al., European Respiratory Journal, doi:10.1183/13993003.00752-2021 (Peer Reviewed)

Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19–a randomised double-blinded placebo-controlled trial

Early terminated late stage (8 days from onset, 59% on oxygen) RCT not showing statistically significant differences. NCT04322396 ProPAC-COVID. NNF20SA0062834.

risk of death, 92.0% lower, RR 0.08, p = 0.32, treatment 1 of 61 (1.6%), control 2 of 56 (3.6%), adjusted.

risk of ICU admission, 22.4% higher, RR 1.22, p = 1.00, treatment 4 of 61 (6.6%), control 3 of 56 (5.4%).

relative days alive and discharged from hospital within 14 days (inverse), 8.4% higher, RR 1.08, p = 0.36, treatment 61, control 56, adjusted.

Sivapalan et al., 6/3/2021, Double Blind Randomized Controlled Trial, Denmark, Europe, peer-reviewed, 32 authors.

Korkmaz et al., Authorea, doi:10.22541/au.162257516.68665404/v1 (Preprint)

The effect of Hydroxychloroquine use due to rheumatic disease on the risk of Covid-19 infection and its course

Retrospective 683 patients in a rheumatology department, 384 chronic HCQ users and 299 control patients, showing no mortality for HCQ users vs. 2 deaths in the control group, and significantly fewer cases for HCQ users.

risk of death, 82.1% lower, RR 0.18, p = 0.19, treatment 0 of 385 (0.0%), control 2 of 299 (0.7%), relative risk is not 0 because of continuity correction due to zero events.

risk of case, 93.7% lower, RR 0.06, p < 0.001, treatment 2 of 395 (0.5%), control 24 of 299 (8.0%).

Korkmaz et al., 6/1/2021, retrospective, Turkey, Europe, preprint, 4 authors.

Kamstrup et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.05.076 (Peer Reviewed)

Hydroxychloroquine as a primary prophylactic agent against sars-cov-2 infection: a cohort study

Retrospective HCQ users in Denmark, not showing a significant difference, however authors do not adjust for the very different baseline risk for systemic autoimmune disease patients.

Authors appear unaware of research in the area, for example saying that "currently, no obvious connection exists between a known rheumatological disorder and the risk of contracting SARS-CoV-2". Many papers show that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, e.g., Ferri et al. show OR 4.42, p<0.001 [1].

Supplementary data is not currently available.

[1] c19hcq.com/ferri.html

risk of hospitalization, 44.0% higher, RR 1.44, p = 0.25, treatment 5,488, control 54,846, RR approximated with OR.

risk of case, 10.0% lower, RR 0.90, p = 0.23, treatment 188 of 5,488 (3.4%), control 2,040 of 54,846 (3.7%), adjusted Cox proportional hazards regression.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Kamstrup et al., 6/1/2021, retrospective, population-based cohort, Denmark, Europe, peer-reviewed, 21 authors.

Ramírez-García et al., Archivos de Medicina Universitaria (Peer Reviewed)

Hydroxychloroquine and Tocilizumab in the Treatment of COVID-19: A Longitudinal Observational Study

Retrospective 403 hospitalized patients in Spain, showing lower mortality with treatment, however authors do not adjust for the differences between the groups. Confounding by indication is likely.

risk of death, 67.0% lower, RR 0.33, p < 0.001, treatment 48 of 350 (13.7%), control 22 of 53 (41.5%).

risk of ICU admission, 6.0% higher, RR 1.06, p = 1.00, treatment 35 of 350 (10.0%), control 5 of 53 (9.4%).

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups, substantial unadjusted confounding by indication likely.

Ramírez-García et al., 5/31/2021, retrospective, Spain, Europe, peer-reviewed, 5 authors.

Smith et al., medRxiv, doi:10.1101/2021.05.28.21258012 (Preprint)

Observational Study on 255 Mechanically Ventilated Covid Patients at the Beginning of the USA Pandemic

Retrospective 255 mechanical ventilation patients in USA, showing that weight-adjusted HCQ+AZ improved survival by over 100%. QTc prolongation did not correlate with cumulative HCQ dose or HCQ serum level.

Although authors mention immortal time bias, full details on the timing of HCQ administration is not provided and this is not fully addressed. Survival curves indicate immortal time bias will significantly change results, although the observed benefit appears to exceed the potential bias.

risk of death, 27.2% lower, RR 0.73, p = 0.002, treatment 19 of 37 (51.4%), control 182 of 218 (83.5%), OR converted to RR, >3g HCQ and >1g AZ, multivariable cox proportional hazard regression.

risk of death, 92.9% lower, RR 0.07, p < 0.001, ≥80mg/kg HCQ and >1g AZ, RR approximated with OR.

Excluded in after exclusion results of meta analysis: immortal time bias may significantly affect results.

Smith et al., 5/31/2021, retrospective, USA, North America, preprint, 4 authors.

Ali et al., Journal of Pharmaceutical Research International, doi:10.9734/jpri/2020/v32i830468 (Peer Reviewed) (Dosing)

Optimizing the Use of Hydroxychloroquine in the Management of COVID-19 Given Its Pharmacological Profile

Review of the mechanisms of action, pharmacokinetics and toxicity of HCQ, recommending use as early as possible with a loading dose in 3-4 divided doses to minimize toxicity, and daily maintenance divided into two doses, continued until remission.

Ali et al., 5/29/2021, peer-reviewed, 8 authors.

Million et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm2203116 (preprint 5/27/2021) (Peer Reviewed)

Early Treatment with Hydroxychloroquine and Azithromycin in 10,429 COVID-19 Outpatients: A Monocentric Retrospective Cohort Study

Retrospective 10,429 outpatients in France, 8,315 treated with HCQ+AZ a median of 4 days from symptom onset, showing significantly lower mortality with treatment.

risk of death, 83.0% lower, RR 0.17, p < 0.001, treatment 5 of 8,315 (0.1%), control 11 of 2,114 (0.5%), adjusted.

risk of ICU admission, 44.0% lower, RR 0.56, p = 0.18, treatment 17 of 8,315 (0.2%), control 7 of 2,114 (0.3%), adjusted.

risk of hospitalization, 4.0% lower, RR 0.96, p = 0.77, treatment 214 of 8,315 (2.6%), control 64 of 2,114 (3.0%), adjusted.

Million et al., 5/27/2021, retrospective, France, Europe, peer-reviewed, 28 authors, dosage 200mg tid days 1-10.

Syed et al., medRxiv, doi:10.1101/2021.05.17.21257012 (Preprint)

Pre-Exposure Prophylaxis with Various Doses of Hdroxychloroquine among high-risk COVID 19 Healthcare Personnel: CHEER randomized controlled trial

Small PrEP RCT of low risk patients, showing no significant differences. Authors report that there was no hospitalization, ICU care or death from COVID-19, however table 3 shows events marked "requiring hospitalization". NCT04359537.

risk of symptomatic case, 59.7% higher, RR 1.60, p = 0.41, treatment 10 of 48 (20.8%), control 6 of 46 (13.0%), group 1.

risk of symptomatic case, 110.5% higher, RR 2.10, p = 0.13, treatment 14 of 51 (27.5%), control 6 of 46 (13.0%), group 2.

risk of symptomatic case, 16.4% lower, RR 0.84, p = 0.77, treatment 6 of 55 (10.9%), control 6 of 46 (13.0%), group 3.

risk of case, 6.2% lower, RR 0.94, p = 1.00, treatment 3 of 48 (6.2%), control 3 of 45 (6.7%), group 1.

risk of case, 6.2% lower, RR 0.94, p = 1.00, treatment 3 of 48 (6.2%), control 3 of 45 (6.7%), group 2.

risk of case, 72.2% lower, RR 0.28, p = 0.33, treatment 1 of 54 (1.9%), control 3 of 45 (6.7%), group 3.

Syed et al., 5/17/2021, Randomized Controlled Trial, Pakistan, South Asia, preprint, 9 authors.

Rojas-Serrano et al., medRxiv, doi:10.1101/2021.05.14.21257059 (Preprint)

Hydroxychloroquine For Prophylaxis Of COVID-19 In Health Workers: A Randomized Clinical Trial

Early terminated HCQ PrEP RCT with 62 HCQ and 65 placebo patients, showing 82% lower cases with treatment, p = 0.12. NCT04318015.

If the trial is continued and the same event rate is observed, statistical significance will be reached after adding about 16 patients per arm.

risk of symptomatic case, 82.0% lower, RR 0.18, p = 0.12, treatment 1 of 62 (1.6%), control 6 of 65 (9.2%), adjusted.

Rojas-Serrano et al., 5/16/2021, Double Blind Randomized Controlled Trial, Mexico, North America, preprint, 8 authors.

Drancourt et al., Viruses, doi:10.3390/v13050890 (Peer Reviewed)

SARS-CoV-2 Persistent Viral Shedding in the Context of Hydroxychloroquine-Azithromycin Treatment

Retrospective 3,737 patients in France, showing lower risk of persistent viral shedding with HCQ+AZ treatment.

Drancourt et al., 5/12/2021, peer-reviewed, 11 authors.

Sammartino et al., PLOS One, doi:10.1371/journal.pone.0251262 (Peer Reviewed)

Predictors for inpatient mortality during the first wave of the SARS-CoV-2 pandemic: A retrospective analysis

Retrospective 1,108 hospitalized patients in New York showing significantly higher mortality with HCQ treatment.

Time based confounding is very likely because HCQ became increasingly controversial and less used over the time covered (Mar - Jun 2020), while overall treatment protocols during this period improved dramatically, i.e., more control patients likely come later in the period when treatment protocols were greatly improved. Authors note that for every week or month later that a person was admitted, their risk of death dropped by 16% and 49%, respectively, yet they do not consider time based confounding.

risk of death, 240.0% higher, RR 3.40, p = 0.002, treatment 137, control 191, PSM, model 1a, RR approximated with OR.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Sammartino et al., 5/10/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 7 authors.

Vigbedor et al., Journal of Applied Pharmaceutical Science, doi:10.7324/JAPS.2021.110825 (Review) (Peer Reviewed)

Review of four major biomolecular target sites for COVID-19 and possible inhibitors as treatment interventions

Review of major target sites in SARS-CoV-2 and the host organism along with potential inhibitors.

Vigbedor et al., 5/8/2021, peer-reviewed, 8 authors.

De Rosa et al., J. Clin. Med., doi:10.3390/jcm10091951 (Peer Reviewed)

Risk Factors for Mortality in COVID-19 Hospitalized Patients in Piedmont, Italy: Results from the Multicenter, Regional, CORACLE Registry

Retrospective 1,538 hospitalized patients in Italy, showing only HCQ associated with reduced mortality. Authors analyze mortality amongst those that were alive at day 7 to avoid survival time bias due to drug recording requiring a minimum of 5 days treatment.

risk of death, 35.0% lower, RR 0.65, p = 0.02, treatment 118 of 731 (16.1%), control 80 of 280 (28.6%), adjusted, OR converted to RR, multivariate logistic regression, patients alive at day 7.

risk of death, 36.0% lower, RR 0.64, p < 0.001, treatment 207 of 1,019 (20.3%), control 215 of 519 (41.4%), adjusted, OR converted to RR, multivariate logistic regression, all patients.

De Rosa et al., 5/1/2021, retrospective, Italy, Europe, peer-reviewed, 20 authors.

Çiyiltepe et al., South. Clin. Ist. Euras., doi:10.14744/scie.2021.89847 (Peer Reviewed)

The Effect of Pre-admission Hydroxychloroquine Treatment on COVID-19-Related Intensive Care Follow-up in Geriatric Patients

Retrospective 147 ICU patients in Turkey, showing no significant difference in outcomes based on HCQ treatment before ICU admission. This is not very informative, for example we do not know if HCQ treated patients were much less likely to be admitted to the ICU.

risk of death, 3.2% lower, RR 0.97, p = 0.85, treatment 69 of 95 (72.6%), control 39 of 52 (75.0%).

Excluded in after exclusion results of meta analysis: treatment group only includes patients where treatment failed resulting in ICU admission.

Çiyiltepe et al., 4/30/2021, retrospective, Turkey, Europe, peer-reviewed, 5 authors.

Bosaeed et al., Infect. Dis. Ther., doi:10.1007/s40121-021-00496-6 (Peer Reviewed)

Favipiravir and Hydroxychloroquine Combination Therapy in Patients with Moderate to Severe COVID19 (FACCT Trial): An Open-Label, Multicenter, Randomized, Controlled Trial

RCT 254 very late stage (93% on oxygen, 17% in ICU at baseline) hospitalized patients in Saudi Arabia not showing significant differences with HCQ+favipiravir treatment. Only SaO₂ < 94% patients were eligible, however the actual SaO₂ of enrolled patients is not provided.

risk of death, 3.7% lower, RR 0.96, p = 0.91, treatment 14 of 125 (11.2%), control 15 of 129 (11.6%), 90 days.

risk of death, 28.6% lower, RR 0.71, p = 0.45, treatment 9 of 125 (7.2%), control 13 of 129 (10.1%), 28 days.

risk of death, 65.1% higher, RR 1.65, p = 0.68, treatment 8 of 125 (6.4%), control 5 of 129 (3.9%), 14 days.

risk of mechanical ventilation, 8.4% higher, RR 1.08, p = 0.78, treatment 21 of 125 (16.8%), control 20 of 129 (15.5%).

risk of ICU admission, 31.0% higher, RR 1.31, p = 0.24, treatment 33 of 125 (26.4%), control 26 of 129 (20.2%).

recovery time, 28.6% higher, relative time 1.29, p = 0.29, treatment 125, control 129.

hospitalization time, 12.5% higher, relative time 1.12, p = 0.42, treatment 125, control 129.

risk of no virological cure, 2.6% lower, RR 0.97, p = 0.75, treatment 100 of 125 (80.0%), control 106 of 129 (82.2%).

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline.

Bosaeed et al., 4/30/2021, Randomized Controlled Trial, Saudi Arabia, Middle East, peer-reviewed, 30 authors.

Aghajani et al., Journal of Medical Virology, doi:10.1002/jmv.27053 (Peer Reviewed)

Decreased In-Hospital Mortality Associated with Aspirin Administration in Hospitalized Patients Due to Severe COVID-19

Retrospective 991 hospitalized patients in Iran focusing on aspirin use but also showing results for HCQ, remdesivir, and favipiravir.

risk of death, 19.5% lower, RR 0.81, p = 0.09, treatment 553, control 438, multivariate Cox proportional regression.

Aghajani et al., 4/29/2021, retrospective, Iran, Middle East, peer-reviewed, 7 authors.

Kokturk et al., Respiratory Medicine, doi:10.1016/j.rmed.2021.106433 (Peer Reviewed)

The predictors of COVID-19 mortality in a nationwide cohort of Turkish patients

Retrospective 1,500 hospitalized late stage (median SaO₂ 87.7) patients in Turkey, showing no significant difference with HCQ treatment.

risk of death, 3.8% higher, RR 1.04, p = 0.97, treatment 62 of 1,382 (4.5%), control 5 of 118 (4.2%), adjusted, OR converted to RR.

Kokturk et al., 4/28/2021, retrospective, database analysis, Turkey, Europe, peer-reviewed, 68 authors.

Réa-Neto et al., Scientific Reports, doi:10.1038/s41598-021-88509-9 (Peer Reviewed)

An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients

Early terminated very late stage (99% on oxygen, 81% in ICU, 18% on mechanical ventilation at baseline) RCT with 24 CQ patients, 29 HCQ, and 52 control patients, showing worse clinical outcomes with treatment. NCT04420247.

risk of death, 57.0% higher, RR 1.57, p = 0.20, treatment 16 of 53 (30.2%), control 10 of 52 (19.2%).

risk of mechanical ventilation, 115.0% higher, RR 2.15, p = 0.03, treatment 53, control 52.

9-point scale clinical status, 147.0% higher, RR 2.47, p = 0.02, treatment 53, control 52, RR approximated with OR.

Réa-Neto et al., 4/27/2021, Randomized Controlled Trial, Brazil, South America, peer-reviewed, 6 authors.

Mohandas et al., (Peer Reviewed)

Clinical review of COVID-19 patients presenting to a quaternary care private hospital in South India: A retrospective study

Retrospective 3,345 hospitalized patients in India, 11.5% treated with HCQ, showing unadjusted higher mortality with treatment. Confounding by indication and time based confounding (due to declining use over the period when overall treatment protocols improved dramatically) are likely.

risk of death, 81.0% higher, RR 1.81, p = 0.007, treatment 27 of 384 (7.0%), control 115 of 2,961 (3.9%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, unadjusted results with no group details, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Mohandas et al., 4/26/2021, retrospective, India, South Asia, peer-reviewed, 6 authors.

Toya et al., SSRN (Preprint)

A Cross-Country Analysis of the Determinants of COVID-19 Fatalities

Country based analysis finding lower mortality with the use of HCQ.

Toya et al., 4/23/2021, preprint, 2 authors.

Reis et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468 (Peer Reviewed)

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19 The TOGETHER Randomized Clinical Trial

Early terminated RCT in Brazil showing lower mortality and hospitalization with HCQ, but not reaching statistical significance. Although the title includes "early treatment", treatment was relatively late, with most patients being over 5 days from the onset of symptoms. Adverse events were lower in the HCQ group compared to the control group.

The paper indicates the placebo was talc, however the trial protocol shows the "placebo" as vitamin C, for which there are 7 COVID-19 treatment studies as of April 2021 that collectively show significant efficacy.

Results differ significantly from those reported prior to publication. Prior to publication, authors reported an RR for hospitalization or death of 1.0 [0.45-2.21] [1]. Hence the trial may have been accidently terminated due to a data error.

[1] ajtmh.org/view/journals/tpmd/104/1/article-p35.xml

risk of death, 66.0% lower, RR 0.34, p = 1.00, treatment 0 of 214 (0.0%), control 1 of 227 (0.4%), relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 24.0% lower, RR 0.76, p = 0.57, treatment 8 of 214 (3.7%), control 11 of 227 (4.8%), ITT, Cox proportional hazards.

risk of no virological cure, 4.1% lower, RR 0.96, p = 0.10, treatment 97 of 185 (52.4%), control 102 of 179 (57.0%), adjusted, OR converted to RR, ITT, mixed-effect logistic model.

Reis et al., 4/22/2021, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 18 authors, dosage 800mg day 1, 400mg days 2-10.

Alzahrani et al., Rheumatology International , doi:10.1007/s00296-021-04857-9 (Peer Reviewed)

Clinical characteristics and outcome of COVID-19 in patients with rheumatic diseases

Retrospective 47 rheumatic disease patients not finding significant differences with HCQ.

risk of death, 58.8% lower, RR 0.41, p = 1.00, treatment 0 of 14 (0.0%), control 1 of 33 (3.0%), relative risk is not 0 because of continuity correction due to zero events.

risk of mechanical ventilation, 81.0% lower, RR 0.19, p = 0.54, treatment 0 of 14 (0.0%), control 3 of 33 (9.1%), relative risk is not 0 because of continuity correction due to zero events.

risk of severe case, 32.7% lower, RR 0.67, p = 0.70, treatment 2 of 14 (14.3%), control 7 of 33 (21.2%).

Alzahrani et al., 4/15/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 3 authors.

Alegiani et al., Rheumatology, doi:10.1093/rheumatology/keab348 (Peer Reviewed)

Risk of COVID-19 hospitalization and mortality in rheumatic patients treated with hydroxychloroquine or other conventional DMARDs in Italy

Retrospective database analysis case control study of rheumatic patients. When compared with other cDMARDs, HCQ users had significantly lower hospitalization, however there was no significant difference in mortality. Results differ significantly from previous studies, for example showing mortality OR 0.94 [0.83-1.06] for patients with rheumatic disease and mortality OR 0.88 [0.74-1.05] for patients with RA/SLE. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall.

risk of death, 8.0% higher, RR 1.08, p = 0.64, HCQ vs. other cDMARDs, RR approximated with OR.

risk of hospitalization, 18.0% lower, RR 0.82, p = 0.03, HCQ vs. other cDMARDs, RR approximated with OR.

risk of death, 19.0% higher, RR 1.19, p = 0.32, HCQ vs. MTX, RR approximated with OR.

risk of hospitalization, 12.0% lower, RR 0.88, p = 0.17, HCQ vs. MTX, RR approximated with OR.

Alegiani et al., 4/15/2021, retrospective, case control, database analysis, Italy, Europe, peer-reviewed, 16 authors.

Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035 (Peer Reviewed)

Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial

Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin C.

Only 71.4% reported >70% adherence, limiting efficacy.

QTc did not statistically significantly differ between baseline and follow-up readings (mean 379 vs 378ms, paired t-test p=0.387).

Meta-analysis of vitamin C in 6 previous trials shows a benefit of 16%, so the actual benefit of ivermectin, HCQ, and PVP-I may be higher. Cluster RCT with 40 clusters.

There were no hospitalizations and no deaths. NCT04446104.

risk of severe case, 35.1% lower, RR 0.65, p = 0.14, treatment 29 of 432 (6.7%), control 64 of 619 (10.3%).

risk of case, 32.0% lower, RR 0.68, p = 0.009, treatment 212 of 432 (49.1%), control 433 of 619 (70.0%), adjusted, OR converted to RR, model 6.

Seet et al., 4/14/2021, Cluster Randomized Controlled Trial, Singapore, Asia, peer-reviewed, 15 authors, dosage 400mg day 1, 200mg days 2-42, this trial compares with another treatment - results may be better when compared to placebo.

Gadhiya et al., BMJ Open, doi:10.1136/bmjopen-2020-042549 (Peer Reviewed)

Clinical characteristics of hospitalised patients with COVID-19 and the impact on mortality: a single-network, retrospective cohort study from Pennsylvania state

Retrospective 283 patients in the USA showing higher mortality with all treatments (not statistically significant). Confounding by indication is likely. In the supplementary appendix, authors note that the treatments were usually given for patients that required oxygen therapy. Oxygen therapy and ICU admission (possibly, the paper includes ICU admission for model 2 in some places but not others) were the only variables indicating severity used in adjustments. Time based confounding is likely because HCQ became increasingly controversial and less used over the time covered (March 1 to May 31, 2020), while overall treatment protocols during this period improved dramatically, i.e., more control patients likely come later in the period when treatment protocols were greatly improved.

risk of death, 4.8% higher, RR 1.05, p = 0.89, treatment 22 of 55 (40.0%), control 33 of 216 (15.3%), adjusted, OR converted to RR, multivariate logistic regression.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, substantial unadjusted confounding by indication likely.

Gadhiya et al., 4/8/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

Mulhem et al., BMJ Open, doi:10.1136/bmjopen-2020-042042 (Peer Reviewed)

3219 hospitalised patients with COVID-19 in Southeast Michigan: a retrospective case cohort study

Retrospective database analysis of 3,219 hospitalized patients in the USA. Very different results in the time period analysis (Table S2), and results significantly different to other studies for the same medications (e.g., heparin OR 3.06 [2.44-3.83]) suggest significant confounding by indication and confounding by time.

risk of death, 28.3% higher, RR 1.28, p = 0.10, treatment 435 of 2,496 (17.4%), control 81 of 723 (11.2%), adjusted, OR converted to RR, logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Mulhem et al., 4/7/2021, retrospective, database analysis, USA, North America, peer-reviewed, 3 authors.

Mokhtari et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.107636 (Peer Reviewed)

Clinical outcomes of patients with mild COVID-19 following treatment with hydroxychloroquine in an outpatient setting

Retrospective 28,759 adult outpatients with mild COVID-19 in Iran, 7,295 treated with HCQ, showing significantly lower hospitalization and mortality with treatment.

risk of death, 69.7% lower, RR 0.30, p < 0.001, treatment 27 of 7,295 (0.4%), control 287 of 21,464 (1.3%), adjusted, OR converted to RR.

risk of hospitalization, 35.3% lower, RR 0.65, p < 0.001, treatment 523 of 7,295 (7.2%), control 2,382 of 21,464 (11.1%), adjusted, OR converted to RR.

Mokhtari et al., 4/6/2021, retrospective, Iran, Middle East, peer-reviewed, 11 authors, dosage 400mg bid day 1, 200mg bid days 2-5.

Edington et al., European Journal of Internal Medicine, doi:10.1016/j.ejim.2021.03.028 (Peer Reviewed)

Safety of treatment with chloroquine and hydroxychloroquine: A ten-year systematic review and meta-analysis

Safety analysis of CQ and HCQ covering 46 RCTs with 23,132 patients, showing no mortality attributed to CQ/HCQ. Authors conclude that the data reinforces that CQ and HCQ have a good safety profile though caution is advised when using higher than usual doses in hospitalized COVID-19 patients.

Edington et al., 4/5/2021, peer-reviewed, 3 authors.

Alghamdi et al., Antibiotics, doi:10.3390/antibiotics10040365 (Peer Reviewed)

Clinical Efficacy of Hydroxychloroquine in Patients with COVID-19: Findings from an Observational Comparative Study in Saudi Arabia

Retrospective 775 hospitalized patients in Saudi Arabia showing no significant difference. There was no adjustment for severity or comorbidities. Confounding by indication is likely.

risk of death, 6.9% higher, RR 1.07, p = 0.88, treatment 44 of 568 (7.7%), control 15 of 207 (7.2%).

Excluded in after exclusion results of meta analysis: confounding by indication is likely and adjustments do not consider COVID-19 severity.

Alghamdi et al., 3/31/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 10 authors.

Faruqui et al., Indian J. Med. Res., doi:10.4103/ijmr.IJMR_2294_20 (Peer Reviewed)

Safety of hydroxychloroquine in healthcare workers for COVID-19 prophylaxis

Retrospective 1303 health care workers finding that HCQ prophylaxis was well tolerated. 20% reported an adverse event, mostly gastrointestinal. 1.5% received treatment for adverse effects, with none requiring hospitalization.

Faruqui et al., 3/26/2021, peer-reviewed, 24 authors.

Dev et al., Transactions of The Royal Society of Tropical Medicine and Hygiene, doi:10.1093/trstmh/trab047 (Peer Reviewed)

Risk factors and frequency of COVID-19 among healthcare workers at a tertiary care centre in India: a case–control study

Retrospective case control study of 3,100 healthcare workers in India showing lower cases with HCQ prophylaxis, and an inverse association between the number of HCQ doses taken and the risk of COVID-19 cases. Low risk population with no mortality and no severe cases.

risk of case, 26.0% lower, RR 0.74, p = 0.003, treatment 260, control 499, any number of HCQ doses vs. no HCQ prophylaxis.

Dev et al., 3/24/2021, retrospective, India, South Asia, peer-reviewed, 5 authors.

Barry et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.03.058 (Peer Reviewed)

Clinical Characteristics and Outcomes of Hospitalized COVID-19 Patients in a MERS-CoV Referral Hospital during the Peak of the Pandemic

605 hospitalized patients in Saudi Arabia showing no mortality with HCQ (only 6 patients received HCQ).

risk of death, 98.9% lower, RR 0.01, p = 0.60, treatment 0 of 6 (0.0%), control 91 of 599 (15.2%), relative risk is not 0 because of continuity correction due to zero events.

Barry et al., 3/23/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 14 authors.

Stewart et al., PLoS ONE, doi:10.1371/journal.pone.0248128 (Peer Reviewed)

COVID-19 Evidence Accelerator: A parallel analysis to describe the use of Hydroxychloroquine with or without Azithromycin among hospitalized COVID-19 patients

Collection of seven retrospective database analyses in the USA, showing higher mortality with treatment (not statistically significant).

Results contradict strong evidence from the RECOVERY/SOLIDARITY trials, suggesting substantial confounding by indication.

Time based confounding is very likely because HCQ became highly controversial and usage dramatically declined over the time covered, while overall treatment protocols during this period improved dramatically, i.e., more control patients likely come later in the period when treatment protocols were greatly improved.

This study includes anyone PCR+ during or prior to their visit, and anyone with ICD-10 COVID-19 codes which includes asymptomatic PCR+ patients, therefore some patients in the control groups may be asymptomatic with regards to SARS-CoV-2, but in the hospital for another reason.

Authors do not mention the possibility of any of these likely confounding factors.

risk of death, 18.0% higher, RR 1.18, p = 0.27, treatment 90 of 429 (21.0%), control 141 of 737 (19.1%), adjusted, VA, HCQ+AZ.

risk of death, 1.0% lower, RR 0.99, p = 0.95, treatment 66 of 578 (11.4%), control 188 of 1,243 (15.1%), adjusted, TriNetX, HCQ+AZ.

risk of death, 129.9% higher, RR 2.30, p < 0.001, treatment 32 of 108 (29.6%), control 33 of 256 (12.9%), Synapse, HCQ+AZ.

risk of death, 9.0% higher, RR 1.09, p = 0.65, treatment 212 of 1,157 (18.3%), control 203 of 1,101 (18.4%), adjusted, Health Catalyst, HCQ+AZ.

risk of death, 90.0% higher, RR 1.90, p = 0.09, treatment 46 of 208 (22.1%), control 47 of 1,334 (3.5%), adjusted, Dascena, HCQ+AZ.

risk of death, 16.0% higher, RR 1.16, p = 0.26, treatment 428 of 1,711 (25.0%), control 123 of 688 (17.9%), adjusted, COTA/HMH, HCQ+AZ.

risk of mechanical ventilation, 29.0% higher, RR 1.29, p = 0.09, treatment 48 of 305 (15.7%), control 95 of 1,302 (7.3%), adjusted, Aetion, HCQ.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.

Stewart et al., 3/17/2021, retrospective, USA, North America, peer-reviewed, 37 authors.

Dang et al., bioRxiv, doi:10.1101/2021.03.16.435741 (Preprint) (In Vitro)

Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein

Microscopy/spectroscopy study showing that HCQ binds to both N-terminal domain and C-terminal domain of SARS-CoV-2 nucleocapsid protein to inhibit
their interactions with nucleic acids and disrupt NA-induced liquid-liquid phase separation essential for the viral life cycle including the package of gRNA and N protein into new virions. These results suggest that HCQ may achieve its
anti-SARS-CoV-2 activity by interfering in several key steps of the viral life cycle.

Dang et al., 3/17/2021, preprint, 2 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Roy et al., medRxiv, doi:10.1101/2021.03.08.21252883 (Preprint)

Outcome of Different Therapeutic Interventions in Mild COVID-19 Patients in a Single OPD Clinic of West Bengal: A Retrospective study

Retrospective database analysis of 56 mild COVID-19 patients, all treated with vitamin C, vitamin D, and zinc, comparing ivermectin + doxycycline (n=14), AZ (n=13), HCQ (n=14), and SOC (n=15), finding that all groups recover quickly, and there was no significant difference between the groups.

relative time to clinical response of wellbeing, 2.4% lower, relative time 0.98, p = 0.96, treatment 14, control 15.

Excluded in after exclusion results of meta analysis: no serious outcomes reported and fast recovery in treatment and control groups, there is little room for a treatment to improve results.

Roy et al., 3/12/2021, retrospective, database analysis, India, South Asia, preprint, 5 authors, dosage not specified.

Vivanco-Hidalgo et al., Eurosurveillance, doi:/10.2807/1560-7917.ES.2021.26.9.2001202 (Peer Reviewed)

Incidence of COVID-19 in patients exposed to chloroquine and hydroxychloroquine: results from a population-based prospective cohort in Catalonia, Spain, 2020

Retrospective database analysis of chronic HCQ users and matched control patients, failing to match or adjust for the very different baseline risk for systemic autoimmune disease patients. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

risk of hospitalization, 46.0% higher, RR 1.46, p = 0.10, treatment 40 of 6,746 (0.6%), control 50 of 13,492 (0.4%), adjusted.

risk of case, 8.0% higher, RR 1.08, p = 0.50, treatment 97 of 6,746 (1.4%), control 183 of 13,492 (1.4%), adjusted.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Vivanco-Hidalgo et al., 3/9/2021, retrospective, Spain, Europe, peer-reviewed, 8 authors.

Martin-Vicente et al., medRxiv, doi:10.1101/2021.03.08.21253121 (Preprint)

Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients

Retrospective 92 ICU patients with almost all treated with HCQ and only one non-HCQ treated patient that died, showing unadjusted non-statistically significant lower mortality with treatment.

risk of death, 59.3% lower, RR 0.41, p = 0.41, treatment 37 of 91 (40.7%), control 1 of 1 (100.0%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, treatment or control group size extremely small.

Martin-Vicente et al., 3/8/2021, retrospective, Spain, Europe, preprint, 38 authors.

Salvador et al., Cureus, doi:10.7759/cureus.13687 (Peer Reviewed)

Clinical Features and Prognostic Factors of 245 Portuguese Patients Hospitalized With COVID-19

Prospective study of 245 hospitalized patients, 121 treated with HCQ, showing lower (non-statistically significant) mortality and higher ventilation at 30 days. Confounding by indication is likely.

risk of death, 32.9% lower, RR 0.67, p = 0.10, treatment 28 of 121 (23.1%), control 58 of 124 (46.8%), OR converted to RR, multivariate.

risk of mechanical ventilation, 447.8% higher, RR 5.48, p = 0.003, treatment 32 of 121 (26.4%), control 12 of 124 (9.7%), OR converted to RR, multivariate.

risk of death/intubation, 16.7% lower, RR 0.83, p = 0.21, treatment 51 of 121 (42.1%), control 63 of 124 (50.8%), OR converted to RR, univariate.

Salvador et al., 3/4/2021, prospective, Portugal, Europe, peer-reviewed, 10 authors.

Pham et al., Rheumatology Advances in Practice, 10.1093/rap/rkab014 (Peer Reviewed)

Failure of chronic hydroxychloroquine in preventing severe complications of COVID-19 in patients with rheumatic diseases

Tiny retrospective database analysis of hospitalized COVID-19 patients with rheumatologic disease containing 14 chronic HCQ and 28 control patients. Patients are very poorly matched. Bias against HCQ is clear in the abstract which mentions differences favoring HCQ but ignores those favoring control (large differences in ethnicity, rheumatic conditions, hypertension, coronary artery disease, solid organ transplant recipients, immunosuppresive drugs). 61% of control patients also received HCQ. Adherence for chronic HCQ patients was not examined. Despite the very large differences between the groups, no adjustments are made. The study claims that HCQ did not prevent severe cases, but the study is among hospitalized patients, i.e., they already have cases severe enough for hospitalization - this study can not identify a protective effect of HCQ that reduces the probability of disease severe enough for hospitalization.

risk of death, 19.7% lower, RR 0.80, p = 0.77, treatment 2 of 14 (14.3%), control 5 of 28 (17.9%), OR converted to RR, univariate.

risk of ICU admission, 35.5% higher, RR 1.35, p = 0.61, treatment 4 of 14 (28.6%), control 6 of 28 (21.4%), OR converted to RR, univariate.

Pham et al., 3/2/2021, retrospective, USA, North America, peer-reviewed, 5 authors.

Thakar et al., Indian J. Med. Res., doi:10.4103/ijmr.IJMR_3665_20 (Peer Reviewed)

Chloroquine nasal drops in asymptomatic & mild COVID-19: An exploratory randomized clinical trial

Small RCT for CQ nasal drops suggesting efficacy in preventing infection, while no significant difference was seen for patients that already had mild COVID-19.

Thakar et al., 2/28/2021, peer-reviewed, 11 authors.

Bhandari et al., International Journal of Medicine and Public Health, doi:10.5530/ijmedph.2021.1.4 (Peer Reviewed)

A Preventive Study on Hydroxychloroquine Prophylaxis against COVID-19 in Health Care Workers at a Tertiary Care Center in North India

Retrospective 4,239 healthcare workers using HCQ prophylaxis showing no mortality, 8 mild symptomatic cases, and 85 asymptomatic cases, with the cases occuring mostly in the first week.

Bhandari et al., 2/28/2021, India, South Asia, peer-reviewed, 10 authors.

Amaravadi et al., medRxiv, doi:10.1101/2021.02.22.21252228 (Preprint)

Hydroxychloroquine for SARS-CoV-2 positive patients quarantined at home: The first interim analysis of a remotely conducted randomized clinical trial

Tiny early-terminated 34 patient RCT for outpatient treatment showing faster recovery with treatment (not statistically significant). All patients recovered (3 control patients recovered after crossover to the treatment arm). There was no mortality and only one hospitalization on day 0 before treatment. There were no severe adverse events.

risk of not reaching lowest symptom score at day 7 mid-recovery, 60.0% lower, RR 0.40, p = 0.13, treatment 3 of 15 (20.0%), control 6 of 12 (50.0%).

relative time to first occurrence of lowest symptom score, 42.9% lower, relative time 0.57, p = 0.21, treatment 15, control 12.

relative time to release from quarantine, 27.3% lower, relative time 0.73, p = 0.28, treatment 16, control 13.

Amaravadi et al., 2/26/2021, Double Blind Randomized Controlled Trial, USA, North America, preprint, 20 authors, dosage 400mg bid days 1-14.

Tanriverdi et al., Turkish Journal of Medical Sciences, doi:doi:10.3906/sag-2005-82 (Peer Reviewed)

Hydroxychloroquine plus azithromycin and early hospital admission are beneficial in COVID-19 patients: Turkish experience with real-life data

Retrospective 83 hospitalized patients in Turkey confirming that earlier treatment is better, and showing that the addition of AZ to HCQ reduced hospitalization time.

Tanriverdi et al., 2/26/2021, peer-reviewed, 8 authors.

Giraud-Gatineau et al., Research Square, doi:rs.3.rs-251817/v1 (Preprint)

The Need for Early Management in Patients With COVID-19

Review of early treatment of COVID-19 at IHU Méditerranée Infection in France, including HCQ+AZ treatment, comparing outcomes to those for all of France. Age-standardized mortality was lower with early treatment for all periods of the epidemic. Authors recommend early treatment for all age groups.

Giraud-Gatineau et al., 2/26/2021, preprint, 9 authors.

Gonzalez et al., medRxiv, doi:10.1101/2021.02.18.21252037 (Preprint)

Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial

RCT late stage severe condition (93% SOFA ≥ 2, 96% APACHE ≥ 8) high comorbidity hospitalized patients in Mexico with 33 HCQ and 37 control patients not finding significant differences. NCT04391127.

risk of death, 62.6% lower, RR 0.37, p = 0.27, treatment 2 of 33 (6.1%), control 6 of 37 (16.2%).

risk of respiratory deterioration or death, 25.3% lower, RR 0.75, p = 0.57, treatment 6 of 33 (18.2%), control 9 of 37 (24.3%).

risk of no hospital discharge, 12.1% higher, RR 1.12, p = 1.00, treatment 3 of 33 (9.1%), control 3 of 37 (8.1%).

Gonzalez et al., 2/23/2021, Double Blind Randomized Controlled Trial, Mexico, North America, preprint, mean age 53.8, 13 authors.

Bae et al., Viruses 2021, doi:10.3390/v13020329 (Peer Reviewed)

Recent Hydroxychloroquine Use Is Not Significantly Associated with Positive PCR Results for SARS-CoV-2: A Nationwide Observational Study in South Korea

Retrospective database analysis of prior HCQ usage in South Korea, showing non-statistically significantly lower mortality and cases with treatment.

risk of case, 30.3% lower, RR 0.70, p = 0.18, treatment 16 of 743 (2.2%), control 91 of 2,698 (3.4%), OR converted to RR, PSM.

risk of case, 19.5% lower, RR 0.81, p = 0.50, treatment 16 of 743 (2.2%), control 91 of 2,698 (3.4%), OR converted to RR, PSM, adjusted for region.

risk of case, 30.3% lower, RR 0.70, p = 0.30, treatment 16 of 743 (2.2%), control 91 of 2,698 (3.4%), OR converted to RR, PSM, adjusted for immunosuppresant use.

risk of case, 40.2% lower, RR 0.60, p = 0.09, OR converted to RR, PSM, HCQ >= 6 months.

Bae et al., 2/20/2021, retrospective, propensity score matching, South Korea, Asia, peer-reviewed, 8 authors.

Lamback et al., The Brazilian Journal of Infectious Diseases, doi:10.1016/j.bjid.2021.101549 (Peer Reviewed)

Hydroxychloroquine with azithromycin in patients hospitalized for mild and moderate COVID-19

Retrospective 193 hospitalized patients in Brazil not finding a significant difference with HCQ.

The control group was composed of patients refusing HCQ or with contraindications. Time based confounding is very likely because HCQ became more controversial in Brazil over the time covered (Mar - Jun 2020), while overall treatment protocols during this period improved dramatically, i.e., more control patients (those refusing HCQ) likely come later in the period when treatment protocols were greatly improved.

The paper does not mention the word "confounding" or make any adjustments.

risk of death, 8.9% lower, RR 0.91, p = 0.83, treatment 11 of 101 (10.9%), control 11 of 92 (12.0%).

risk of ICU admission, 19.9% higher, RR 1.20, p = 0.61, treatment 25 of 101 (24.8%), control 19 of 92 (20.7%).

hospitalization time, 12.5% lower, relative time 0.88, treatment 101, control 92.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Lamback et al., 2/19/2021, retrospective, Brazil, South America, peer-reviewed, 10 authors.

Awad et al., American Journal of Health-System Pharmacy, doi:10.1093/ajhp/zxab056 (Peer Reviewed)

Impact of hydroxychloroquine on disease progression and ICU admissions in patients with SARS-CoV-2 infection

This paper has inconsistent values - the number of treatment and control patients differs in the text and Table 1, we have used treatment 188 and control 148. Retrospective 336 hospitalized patients in the USA showing higher mortality, ICU admission, and intubation with treatment. Confounding by indication is likely. Time varying confounding is also likely due to declining usage over the early period when overall treatment protocols were also improving dramatically. Authors and reviewers appear to be unfamiliar with either of these.

risk of death, 19.1% higher, RR 1.19, p = 0.60, treatment 56 of 188 (29.8%), control 37 of 148 (25.0%).

risk of mechanical ventilation, 460.7% higher, RR 5.61, p < 0.001, treatment 64 of 188 (34.0%), control 9 of 148 (6.1%), adjusted, OR converted to RR.

risk of ICU admission, 463.4% higher, RR 5.63, p < 0.001, treatment 67 of 188 (35.6%), control 9 of 148 (6.1%), adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, substantial unadjusted confounding by indication likely.

Awad et al., 2/18/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

Lora-Tamayo et al., J. Infection, doi:10.1016/j.jinf.2021.02.011 (Peer Reviewed)

Early Lopinavir/ritonavir does not reduce mortality in COVID-19 patients: results of a large multicenter study

Lopinavir/ritonavir retrospective study also showing univariate results for HCQ, with significantly lower mortality.

risk of death, 50.5% lower, RR 0.50, p < 0.001, treatment 7,192, control 1,361, OR converted to RR, univariate, control prevalence approximated with overall prevalence.

Lora-Tamayo et al., 2/11/2021, retrospective, Spain, Europe, peer-reviewed, 10 authors.

Desai et al., J. Clinical Medicine, doi:10.3390/jcm10040686 (Peer Reviewed)

The Use of Antiviral Agents against SARS-CoV-2: Ineffective or Time and Age Dependent Result? A Retrospective, Observational Study among COVID-19 Older Adults

Retrospective 143 COVID-19 hospitalized patients >65yo, showing adjusted OR for antiviral treatment starting within 6 days of 0.44 [0.2-0.9], p = 0.02, compared to treatment started later.

Desai et al., 2/10/2021, peer-reviewed, 9 authors.

Thompson et al., NCT04332991 (Preprint)

Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID)

Late stage (65% on oxygen at baseline) low-dose RCT, not showing significant differences with treatment.

risk of death, 6.2% higher, RR 1.06, p = 0.85, treatment 25 of 241 (10.4%), control 25 of 236 (10.6%), adjusted, OR converted to RR, day 28.

risk of death, 51.0% higher, RR 1.51, p = 0.28, treatment 18 of 241 (7.5%), control 14 of 236 (5.9%), adjusted, OR converted to RR, day 14.

risk of 7-point scale, 3.1% higher, RR 1.03, p = 0.87, treatment 241, control 236, day 28, RR approximated with OR.

risk of 7-point scale, 2.0% lower, RR 0.98, p = 0.91, treatment 241, control 236, day 14, RR approximated with OR.

Thompson et al., 2/9/2021, Double Blind Randomized Controlled Trial, USA, North America, preprint, 1 author.

Lounnas e al., Archives of Microbiology & Immunology, doi: (Peer Reviewed) (meta analysis)

Revisiting a Meta-analysis Shows that Hydroxychloroquine with Azithromycin may be Efficient in Covid-19 patients

Analysis of the Fiolet meta analysis and correction of bias evaluation, showing HCQ RR 0.45 [0.31-0.59], and HCQ+AZ RR 0.34 [0.06-0.61].

Lounnas et al., 2/9/2021, peer-reviewed, 4 authors.

Purwati et al., Biochemistry Research International, doi:10.1155/2021/6685921 (Peer Reviewed)

A Randomized, Double-Blind, Multicenter Clinical Study Comparing the Efficacy and Safety of a Drug Combination of Lopinavir/Ritonavir-Azithromycin, Lopinavir/Ritonavir-Doxycycline, and Azithromycin-Hydroxychloroquine for Patients Diagnosed with Mild to Moderate COVID-19 Infections

RCT 754 patients comparing HCQ+AZ along with other treatment groups using lopinavir/ritonavir and doxycycline to a control group taking AZ, finding significantly faster viral clearance with all treatment groups. (The labels in Figure 2 appear to be reversed).

risk of no virological cure, 66.3% lower, RR 0.34, p < 0.001, treatment 38 of 121 (31.4%), control 111 of 119 (93.3%), day 7.

Purwati et al., 2/9/2021, Double Blind Randomized Controlled Trial, Indonesia, South Asia, peer-reviewed, 12 authors.

Fitzgerald et al., medRxiv, doi:10.1101/2021.02.03.21251069 (Preprint)

Risk Factors for Infection and Health Impacts of the COVID-19 Pandemic in People with Autoimmune Diseases

Retrospective 4666 people with autoimmune or inflammatory conditions, showing HCQ adjusted risk of COVID-19 OR 0.91 [0.68-1.23]. Results are not adjusted for the significantly different risk of COVID-19 depending on the type and severity of autoimmune or inflammatory condition.

risk of case, 8.5% lower, RR 0.91, p = 0.54, treatment 65 of 1,072 (6.1%), control 200 of 3,594 (5.6%), adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: not fully adjusting for the baseline risk differences within systemic autoimmune patients.

Fitzgerald et al., 2/5/2021, retrospective, USA, North America, preprint, 34 authors.

Hernandez-Cardenas et al., medRxiv, doi:10.1101/2021.02.01.21250371 (Preprint)

Hydroxychloroquine for the treatment of severe respiratory infection by COVID-19: a randomized controlled trial

Very late stage RCT with 214 patients, mean SpO₂ 65%, 162 on mechanical ventilation, showing no significant difference in mortality.

Patients not intubated at baseline show greater improvement, HR 0.43 [0.09-2.03].

Table 4 shows different results to the abstract - table 4 adjusted HR 0.80 [0.51-1.23], abstract HR 0.88 [0.51-1.53]. There was no significant difference in severe adverse events.

risk of death, 12.0% lower, RR 0.88, p = 0.66, treatment 106, control 108.

risk of death, 57.0% lower, RR 0.43, p = 0.29, subgroup not intubated at baseline.

Hernandez-Cardenas et al., 2/5/2021, Randomized Controlled Trial, Mexico, North America, preprint, 6 authors.

Ouedraogo et al., Revue des Maladies Respiratoires, doi:10.1016/j.rmr.2021.02.001 (Peer Reviewed)

Factors associated with the occurrence of acute respiratory distress and death in patients with COVID-19 in Burkina Faso

Retrospective 456 patients in Burkina Faso showing lower risk of ARDS (p=0.001) and mortality (p=0.38) with HCQ.

risk of death, 33.0% lower, RR 0.67, p = 0.38, treatment 397, control 59, multivariate.

risk of ARDS, 68.0% lower, RR 0.32, p = 0.001, treatment 397, control 59, multivariate, RR approximated with OR.

Ouedraogo et al., 2/5/2021, retrospective, Burkina Faso, Africa, peer-reviewed, 14 authors.

Alexander et al., medRxiv, doi:10.1101/2021.01.28.21250706 (Review) (Preprint)

Early Multidrug Outpatient Treatment of SARS-CoV-2 Infection (COVID-19) and Reduced Mortality Among Nursing Home Residents

Review of studies on treatment of COVID-19 for nursing home residents, concluding that there is a large >60% mortality risk reduction associated with multidrug treatment using two or more intracellular anti-infectives (HCQ and either AZM or DOXY) combined with other agents including corticosteroids, anti-thrombotics, and nutraceuticals. Authors note there is also recent focus on ivermectin and favorable evidence for bromhexine.

Alexander et al., 2/1/2021, preprint, 11 authors.

Ubaldo et al., Critical Care Research and Practice, 10.1155/2021/7510306 (Peer Reviewed)

COVID-19: A Single-Center ICU Experience of the First Wave in the Philippines

Retrospective ICU patients in the Philippines showing unadjusted HCQ RR 0.82, p = 0.64.

risk of death, 18.4% lower, RR 0.82, p = 0.64, treatment 17 of 25 (68.0%), control 5 of 6 (83.3%), COVID-19 positive patients.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, very late stage, ICU patients, unadjusted results with no group details.

Ubaldo et al., 2/1/2021, retrospective, Philippines, Asia, peer-reviewed, 3 authors.

Naderi et al., Immunopathologia Persa, doi:10.34172/ipp.2021.29 (Preprint)

Prophylactic effects of hydroxychloroquine on the incidence of COVID-19 in patients with rheumatic arthritis: an observational cohort study

Prospective observational study of 215 RA patients treated with HCQ showing 9 cases, 1 hospitalization (without ICU/intubation), and no mortality.

Naderi et al., 1/31/2021, preprint, 7 authors.

Roig et al., Revista Espanola de Quimioterapia, doi:10.37201/req/130.2020 (Peer Reviewed)

Clinical and pharmacological data in COVID-19 hospitalized nonagenarian patients

Retrospective 79 hospitalized nonagenarian patients showing unadjusted HCQ mortality RR 0.84, p = 0.76.

risk of death, 15.6% lower, RR 0.84, p = 0.76, treatment 33 of 67 (49.3%), control 7 of 12 (58.3%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Roig et al., 1/31/2021, retrospective, Spain, Europe, peer-reviewed, 6 authors.

Di Castelnuovo et al., Journal of Healthcare Engineering, doi:10.1155/2021/5556207 (preprint 1/29/2021) (Peer Reviewed)

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering

Retrospective 4,396 hospitalized patients in Italy showing significantly lower mortality with HCQ treatment, and identifying greater efficacy for a subgroup of patients in clustering analysis.

risk of death, 40.0% lower, RR 0.60, p < 0.001, treatment 3,270, control 1,000, OR converted to RR, multivariate Cox proportional hazards model 4, control prevalence approximated with overall prevalence.

Di Castelnuovo et al., 1/29/2021, retrospective, Italy, Europe, peer-reviewed, 112 authors.

Trefond et al., Revue du Rhumatisme, doi:10.1016/j.rhum.2021.09.004 (preprint 1/27/2021) (Peer Reviewed)

Effet d’un traitement par hydroxychloroquine prescrit comme traitement de fond de rhumatismes inflammatoires chroniques ou maladies auto-immunes systémiques sur les tests diagnostiques et l’évolution de l’infection à SARS CoV-2: étude de 871 patients

Retrospective 71 chronic HCQ patients compared with 191 matched controls, analyzing only those with a highly suspected or confirmed diagnosis of COVID-19. No significant difference was found in outcomes, however matching failed with extreme confounding - 77.5% of HCQ patients with systemic autoimmune diseases vs. 21.5% of control patients.

Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

risk of death, 16.6% higher, RR 1.17, p = 0.80, treatment 4 of 68 (5.9%), control 12 of 183 (6.6%), adjusted, OR converted to RR.

risk of death/ICU, 78.2% higher, RR 1.78, p = 0.21, treatment 8 of 71 (11.3%), control 18 of 191 (9.4%), adjusted, OR converted to RR.

risk of hospitalization, 44.9% higher, RR 1.45, p = 0.12, treatment 24 of 71 (33.8%), control 53 of 191 (27.7%), adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients, significant unadjusted confounding possible, excessive unadjusted differences between groups.

Trefond et al., 1/27/2021, retrospective, France, Europe, peer-reviewed, 21 authors.

Eftekhar et al., medRxiv, doi:10.1101/2021.01.16.21249941 (Preprint)

Hydroxychloroquine and azithromycin: As a double edge sword for COVID-19?

Retrospective 172 hospitalized patients, 83% treated and HCQ+AZ and 17% with HCQ, not finding a significant difference in QTc prolongation, but recommending careful monitoring for the use of HCQ+AZ; especially in males, patients with high-risk Tisdale score, and in patients who have baseline QTc interval ≥ 450 milliseconds.

Eftekhar et al., 1/26/2021, preprint, 6 authors.

Dabbous et al., Archives of Virology, doi:10.1007/s00705-021-04956-9 (Peer Reviewed)

Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study

This study was retracted.

Dabbous et al., 1/25/2021, peer-reviewed, 10 authors.

Hussein et al., Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129979 (Peer Reviewed)

Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19

Molecular dynamics analysis recommending Zn (CQ) Cl2(H2O) and Zn (HCQ) Cl2(H2O) as potential inhibitors for COVID-19 M^pro. Zn (HCQ) Cl2(H2O) exhibited a strong binding to the main protease receptor, forming eight hydrogen bonds.

Hussein et al., 1/25/2021, peer-reviewed, 2 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Zelenko, Z., Preprint (Preprint)

Nebulized Hydroxychloroquine for COVID-19 Treatment: 80x Improvement in Breathing

Report on the use of nebulized HCQ showing much more rapid improvement compared to tablets, with 95% of patients experiencing improved breathing within 1 hour. Author notes that the effectiveness of HCQ is time and dose dependent, with a primary issue being the time it takes for a therapeutic dosage to reach the lungs, and that treatment with tablets may take an average of 80 hours to achieve significant clinical improvement.

Author notes that it may take 3-7 days to achieve optimal alveolar concentrations with tablets, whereas nebulized HCQ administered as microdroplets directly to the lungs achieves optimal alveolar concentration in approximately one hour and is associated with faster clinical improvement, reduction in pulmonary complications, and a reduction in medical costs.

Zelenko et al., 1/24/2021, preprint, 1 author.

Cifuentes et al., Medicina Clínica (English Edition), doi:10.1016/j.medcle.2020.10.012 (Peer Reviewed)

Incidence of COVID-19 in patients under chronic treatment with hydroxychloroquine

Retrospective 3,817 chronic HCQ patients showing 4.4% COVID-19 positive rate, 1.3% severe. There is no comparison with a control group. Authors note that there was a 3.6% incidence among 2,032,863 patients in one of the regions (Castilla La Mancha), however they provide no information on this group - it is expected that the mostly systemic autoimmune disease patients in the treatment group are older on average. Additonally, other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

Cifuentes et al., 1/23/2021, peer-reviewed, 18 authors.

Li et al., Science China Life Sciences, doi:10.1007/s11427-020-1871-4 (Peer Reviewed)

Evaluation of the efficacy and safety of hydroxychloroquine in comparison with chloroquine in moderate and severe patients with COVID-19

Small RCT comparing HCQ and CQ in China with 88 very late stage (17.6 days from onset to hospitalization and ~10 days to randomization) patients. The primary clinical outcomes (TTCR and TTCI) were not significantly different. Authors note that HCQ may have more promising efficacy in immune system modulation, indicated by ferritin reduction in the moderate cases and improvement of CT scores and lymphocyte counts in the severe cases. HCQ and CQ were well tolerated.

Authors also compare RCT patients to a matched sample of non-RCT patients in the same hospital, showing shorter time to discharge with CQ/HCQ, but not statistically significant due to the small size.

risk of no hospital discharge, 50.0% lower, RR 0.50, p = 0.09, treatment 14, control 14, RCT patients vs. matched sample of non-treated patients.

Li et al., 1/18/2021, retrospective, China, Asia, peer-reviewed, 21 authors.

Li et al., Research Square, doi:10.21203/rs.3.rs-119202/v1 (Preprint)

Treatment of COVID-19 patients with hydroxychloroquine or chloroquine: A retrospective analysis

Small retrospective database analysis of 37 late stage patients hospitalized in an intensive care center in China, not finding a significant difference in viral shedding. Pateints were all in serious condition. There was only one death however the group is not specified. Confounding by indication is likely.

time to viral-, 40.0% higher, relative time 1.40, p = 0.06, treatment 18, control 19.

Li et al., 1/12/2021, retrospective, database analysis, China, Asia, preprint, 5 authors.

Rangel et al., Journal of the American Academy of Dermatology, doi:10.1016/j.jaad.2020.10.098 (Peer Reviewed)

Chronic Hydroxychloroquine Therapy and COVID-19 Outcomes: A Retrospective Case-Control Analysis

Retrospective 50 COVID-19 patients that take chronic HCQ, compared to a matched sample of patients not taking chronic HCQ, showing lower mortality and ICU admission, and shorter hospitalization for HCQ patients, but not statistically significant due to the small number of events.

The actual benefit for HCQ could be much larger. The study does not address the risk of being sick enough to visit the hospital. HCQ users are likely systemic autoimmune disease patients and authors do not adjust for the very different baseline risk for these patients. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

risk of death, 25.1% lower, RR 0.75, p = 0.77, treatment 4 of 50 (8.0%), control 11 of 103 (10.7%), from all patients.

risk of hospitalization, 22.2% lower, RR 0.78, p = 0.29, treatment 17 of 50 (34.0%), control 45 of 103 (43.7%).

hospitalization time, 41.2% lower, relative time 0.59, p = 0.12, treatment 21, control 54.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Rangel et al., 1/10/2021, retrospective, USA, North America, peer-reviewed, 5 authors.

Yegerov et al., medRxiv, doi:10.1101/2021.01.06.20249091 (Preprint)

Epidemiological and Clinical Characteristics, and Virologic Features of COVID-19 Patients in Kazakhstan: a Nation-Wide, Retrospective, Cohort Study

Retrospective 1,072 hospitalized patients in Kazakhstan showing no mortality for HCQ treated patients, however only 23 patients received treatment - this result is not statistically significant.

risk of death, 95.3% lower, RR 0.05, p = 1.00, treatment 0 of 23 (0.0%), control 20 of 1,049 (1.9%), relative risk is not 0 because of continuity correction due to zero events.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Yegerov et al., 1/8/2021, retrospective, Kazakhstan, Asia, preprint, 8 authors.

Baildya et al., Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129891 (Peer Reviewed)

Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies

Molecular docking study of 16 drugs showing CQ had the highest binding affinity with ACE2, and molecular dynamics study of the docked CQ-ACE2 structure. Authors conclude that CQ binds reasonably strongly with ACE2 and the stable ACE2-CQ may prevent further binding of ACE2 with the SARS-CoV-2 spike protein.

Baildya et al., 1/7/2021, peer-reviewed, 3 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Noureddine et al., Journal of King Saud University - Science, doi:10.1016/j.jksus.2020.101334 (Peer Reviewed)

Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: molecular docking and DFT calculations

In silico analysis of hydroxychloroquine and hydroxychloroquine sulfate predicting that hydroxychloroquine sulfate is more stable and effective for COVID-19.

Noureddine et al., 1/6/2021, peer-reviewed, 5 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Gautret et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106236 (Peer Reviewed)

Safety profile of hydroxychloroquine and azithromycin combined treatment in COVID-19 patients

Report on the safety of HCQ+AZ with 3,737 COVID-19 patients. 138 had contraindications and treatment was discontinued in 12 cases due to QTc prolongation. There were no cases of torsade de pointe or sudden death.

Gautret et al., 1/4/2021, peer-reviewed, 4 authors.

Sarfaraz et al., medRxiv, doi:10.1101/2020.12.28.20248920 (Preprint)

Determinants of in-hospital mortality in COVID-19; a prospective cohort study from Pakistan

Retrospective 186 hospitalized patients in Pakistan showing unadjusted HCQ mortality RR 1.45, p = 0.07. Confounding by indication is likely.

risk of death, 45.0% higher, RR 1.45, p = 0.07, treatment 40 of 94 (42.6%), control 27 of 92 (29.3%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, significant unadjusted confounding possible, unadjusted results with no group details.

Sarfaraz et al., 1/2/2021, retrospective, Pakistan, South Asia, preprint, 7 authors.

Lotfy et al., Turk. Thorac. J., doi:10.5152/TurkThoracJ.2021.20180 (Peer Reviewed)

Use of Hydroxychloroquine in Patients with COVID-19: A Retrospective Observational Study

Retrospective 202 patients in Saudi Arabia not showing significant differences with treatment. No information is provided on how patients were selected for treatment, there may be significant confounding by indication. Time varying confounding is also likely as HCQ became controversial during the period studied, therefore HCQ use was likely more frequent toward the beginning of the period, a time when overall treatment protocols were significantly worse.

risk of death, 24.8% higher, RR 1.25, p = 0.76, treatment 6 of 99 (6.1%), control 5 of 103 (4.9%).

risk of mechanical ventilation, 41.2% higher, RR 1.41, p = 0.34, treatment 19 of 99 (19.2%), control 14 of 103 (13.6%).

risk of ICU admission, 16.5% higher, RR 1.17, p = 0.53, treatment 28 of 99 (28.3%), control 25 of 103 (24.3%).

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, substantial unadjusted confounding by indication likely.

Lotfy et al., 1/1/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, mean age 55.0, 3 authors.

Sands et al., International Journal of Infectious Diseases, doi:/10.1016/j.ijid.2020.12.060 (Peer Reviewed)

No clinical benefit in mortality associated with hydroxychloroquine treatment in patients with COVID-19

Retrospective database analysis of 1,669 patients in the US showing OR 1.81, p = 0.01. Confounding by indication is likely.

COVID-19 was determined via PCR+ results, therefore authors include patients asymptomatic for COVID-19, but in the hospital for other reasons. While authors adjust for severity, the method used is very poor. 93.5% of patients are classified as "mild", which is patients with no documented care in a critical care unit within 8 hours of admission. Therefore almost all patients are in the same category, and those in a different category may be due to symptoms unrelated to COVID-19. Lower bias toward male patients in the control group also agrees with the hypothesis that the control group is made up of more people that were in hospital for another reason.

Since the analysis covers the initial period of the pandemic in the USA, it is likely that HCQ was used more often earlier in the analysis period when treatment protocols were considerably worse. It's unclear why the analysis only considers patients up to April 27, when the manuscript was submitted in October.

For other issues see [1].

[1] ijidonline.com/article/S1201-9712(21)00165-X/pdf

risk of death, 69.9% higher, RR 1.70, p = 0.01, treatment 101 of 973 (10.4%), control 56 of 696 (8.0%), OR converted to RR.

Excluded in after exclusion results of meta analysis: includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons, substantial unadjusted confounding by indication likely.

Sands et al., 1/1/2021, retrospective, database analysis, USA, North America, peer-reviewed, 10 authors.

Matada et al., Bioorganic & Medicinal Chemistry, doi:10.1016/j.bmc.2020.115973 (Review) (Peer Reviewed)

A comprehensive review on the biological interest of quinoline and its derivatives

Review of quinolone and derivatives, natural and drug sources, and biological activity.

Matada et al., 12/31/2020, peer-reviewed, 3 authors.

Psevdos et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofaa439.721 (Peer Reviewed)

Corona Virus Disease-19 (COVID-19) in a Veterans Affairs Hospital at Suffolk County, Long Island, New York

Retrospective 67 hospitalized patients in the USA showing non-statistically significant unadjusted increased mortality with HCQ. Confounding by indication is likely.

Time varying confounding is likely. HCQ became controversial and was suspended during the end of the period studied, therefore HCQ use was likely more frequent toward the beginning of the study period, a time when overall treatment protocols were significantly worse.

risk of death, 63.5% higher, RR 1.63, p = 0.52, treatment 17 of 52 (32.7%), control 3 of 15 (20.0%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, no treatment details, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, substantial unadjusted confounding by indication likely.

Psevdos et al., 12/31/2020, retrospective, USA, North America, peer-reviewed, 3 authors.

Texeira et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofaa439.560 (Peer Reviewed)

Characteristics and outcomes of COVID-19 patients admitted to a regional health system in the southeast

Retrospective 161 hospitalized patients in the USA showing non-statistically significant unadjusted increased mortality with HCQ. Confounding by indication is likely.

Time varying confounding is likely. HCQ became controversial and was suspended towards the end of the period studied, therefore HCQ use was likely more frequent toward the beginning of the study period, a time when overall treatment protocols were significantly worse.

risk of death, 79.3% higher, RR 1.79, p = 0.10, treatment 17 of 65 (26.2%), control 14 of 96 (14.6%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, no treatment details, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, substantial unadjusted confounding by indication likely.

Texeira et al., 12/31/2020, retrospective, USA, North America, peer-reviewed, 6 authors.

Vernaz et al., Swiss Medical Weekly, doi:10.4414/smw.2020.20446 (Peer Reviewed)

Early experimental COVID-19 therapies: associations with length of hospital stay, mortality and related costs

Retrospective 840 hospitalized patients in Switzerland showing non-statistically significant lower mortality with HCQ but significantly longer hospitalization times. Confounding by indication is likely. PSM fails to adjust for severity with a 16% higher mNEWS score for HCQ vs. SOC in the matched cohort.

Time varying confounding is likely. HCQ became controversial and was suspended towards the end of the period studied, therefore HCQ use was likely more frequent toward the beginning of the study period, a time when overall treatment protocols were significantly worse.

Authors note: "overall, there was an indication bias, with the reason of prescription being associated with the outcome of interest. Indeed, patients with more severe COVID-19 were more likely to receive experimental therapies."

risk of death, 15.3% lower, RR 0.85, p = 0.71, treatment 12 of 93 (12.9%), control 16 of 105 (15.2%), HCQ vs. SOC, PSM.

hospitalization time, 49.0% higher, relative time 1.49, p = 0.002, treatment 93, control 105, HCQ vs. SOC, PSM.

Excluded in after exclusion results of meta analysis: substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically, substantial unadjusted confounding by indication likely.

Vernaz et al., 12/31/2020, retrospective, propensity score matching, Switzerland, Europe, peer-reviewed, 15 authors.

McCullough et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.264 (Review) (Peer Reviewed)

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

Review urging early treatment of COVID-19 with sequential multidrug treatment that has been shown to be safe and effective. Proposed treatment includes zinc, vitamin D & C, quercetin, and depending on age, comorbidities, and symptoms may include >=2 of HCQ, ivermectin, favipiravir; AZM/DOXY; corticosteroids; colchicine; bamlanivimab; aspirin; LMWH; and supplemental oxygen.

McCullough et al., 12/30/2020, peer-reviewed, 58 authors.

Procter et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.260 (Peer Reviewed)

Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection

Retrospective 922 outpatients, with 320 treated early due to age>50 or comorbidities, showing 2.2% hospitalization and 0.3% death, which authors note is considerably lower than reported in other studies in their region.

At least two of zinc, HCQ, and ivermectin were used, along with one antibiotic, and budesonide and/or dexamethasone.

Procter et al., 12/30/2020, peer-reviewed, 6 authors.

Güner et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2020.12.017 (Peer Reviewed)

Comparing ICU Admission Rates of Mild/Moderate COVID-19 Patients Treated with Hydroxychloroquine, Favipiravir, and Hydroxychloroquine plus Favipiravir

Retrospective 824 hospitalized patients in Turkey showing lower ICU admission for HCQ vs. favipiravir.

risk of ICU admission, 77.3% lower, RR 0.23, p = 0.16, treatment 604, control 100, IPTW multivariate analysis, HCQ vs. favipiravir.

Güner et al., 12/29/2020, retrospective, Turkey, Europe, peer-reviewed, 23 authors.

Cordtz et al., Rheumatology, doi:10.1093/rheumatology/keaa897 (Peer Reviewed)

Incidence and severeness of COVID-19 hospitalisation in patients with inflammatory rheumatic disease: a nationwide cohort study from Denmark

Retrospective 58,052 rheumatic disease patients in Denmark showing that RA patients have a higher risk of COVID-19 hospitalization in general. HCQ treated patients show lower risk, although this is not statistically significant with only 3 hospitalizations for HCQ treated patients.

HR 0.76 [0.23-2.52] time-dependent exposure model
HR 0.45 [0.11-1.92] time-fixed exposure model

risk of hospitalization, 24.0% lower, RR 0.76, p = 0.67, treatment 3 of 2,722 (0.1%), control 38 of 26,718 (0.1%), adjusted, time-dependent exposure model.

risk of hospitalization, 55.0% lower, RR 0.45, p = 0.28, treatment 3 of 2,722 (0.1%), control 38 of 26,718 (0.1%), adjusted, time-fixed exposure model.

Cordtz et al., 12/28/2020, retrospective, population-based cohort, Denmark, Europe, peer-reviewed, 10 authors.

Chari et al., Blood, doi:10.1182/blood.2020008150 (Peer Reviewed)

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set

Retrospective multiple myeloma patients showing lower mortality with HCQ treatment, unadjusted RR 0.67, p = 0.17 (data is in the supplementary material).

risk of death, 33.1% lower, RR 0.67, p = 0.17, treatment 8 of 29 (27.6%), control 195 of 473 (41.2%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Chari et al., 12/24/2020, retrospective, multiple countries, multiple regions, peer-reviewed, median age 69.0, 25 authors.

Su et al., BioScience Trends, doi:10.5582/bst.2020.03340 (Peer Reviewed)

Efficacy of early hydroxychloroquine treatment in preventing COVID-19 pneumonia aggravation, the experience from Shanghai, China

85% lower disease progression with early use of HCQ. Retrospective 616 patients in China showing adjusted progression HR 0.15, p = 0.006.

risk of progression, 84.9% lower, RR 0.15, p = 0.006, treatment 261, control 355, adjusted, binary logistic regression.

improvement time, 24.0% lower, relative time 0.76, p = 0.02, treatment 261, control 355, adjusted, Cox proportional hazards regression.

Su et al., 12/23/2020, retrospective, China, Asia, peer-reviewed, 9 authors, dosage 400mg days 1-10, 400mg daily for 10-14 days.

Taccone et al., The Lancet Regional Health - Europe, doi:10.1016/j.lanepe.2020.100019 (Peer Reviewed)

The role of organizational characteristics on the outcome of COVID-19 patients admitted to the ICU in Belgium

Retrospective 1,747 ICU patients in Belgium showing lower mortality with HCQ, multivariate mixed effects analysis HCQ aOR 0.64 [0.45-0.92].

risk of death, 24.7% lower, RR 0.75, p = 0.02, treatment 449 of 1,308 (34.3%), control 183 of 439 (41.7%), OR converted to RR.

Taccone et al., 12/23/2020, retrospective, Belgium, Europe, peer-reviewed, 10 authors.

Cangiano et al., Aging, doi:10.18632/aging.202307 (Peer Reviewed)

Mortality in an Italian nursing home during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests

73% lower mortality with HCQ. Analysis of 98 PCR+ nursing home residents in Italy, mean age 90, showing HCQ mortality RR 0.27, p = 0.03. Subject to confounding by contraindication. The paper provides the p value for regression but not the effect size.

risk of death, 73.4% lower, RR 0.27, p = 0.03, treatment 5 of 33 (15.2%), control 37 of 65 (56.9%).

Cangiano et al., 12/22/2020, retrospective, Italy, Europe, peer-reviewed, 14 authors.

Huh et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.12.041 (Peer Reviewed)

Association of prescribed medications with the risk of COVID-19 infection and severity among adults in South Korea

Retrospective database analysis with 17 existing users of HCQ and 5 severe cases, showing no significant difference for cases and higher risk for severe cases. However, HCQ users are likely systemic autoimmune disease patients and authors do not adjust for the very different baseline risk for these patients. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

risk of progression, 251.0% higher, RR 3.51, p = 0.11, treatment 5 of 8 (62.5%), control 873 of 2,797 (31.2%), adjusted, multivariate.

risk of case, 6.0% lower, RR 0.94, p = 0.82, treatment 17 of 122 (13.9%), control 7,324 of 43,924 (16.7%), adjusted, multivariate.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Huh et al., 12/19/2020, retrospective, database analysis, South Korea, Asia, peer-reviewed, 8 authors.

Matangila et al., PLoS ONE, doi:10.1371/journal.pone.0244272 (Peer Reviewed)

Clinical characteristics of COVID-19 patients hospitalized at Clinique Ngaliema, a public hospital in Kinshasa, in the Democratic Republic of Congo: A retrospective cohort study

55% lower death with HCQ+AZ. Retrospective 160 hospitalized patients in the Democratic Republic of Congo, 92% receiving HCQ+AZ, showing adjusted OR 0.24 [0.03-2.2].

risk of death, 54.9% lower, RR 0.45, p = 0.21, treatment 25 of 147 (17.0%), control 8 of 13 (61.5%), adjusted, OR converted to RR.

Matangila et al., 12/18/2020, retrospective, DR Congo, Africa, peer-reviewed, median age 54.0, 12 authors.

Signes-Costa et al., Archivos de Bronconeumología, doi:10.1016/j.arbres.2020.11.012 (Peer Reviewed)

Prevalence and 30-day mortality in hospitalized patients with COVID-19 and prior lung diseases

47% lower mortality with HCQ/CQ. Retrospective 1,271 patients with lung disease in Canada, China, Cuba, Ecuador, Germany, Italy and Spain, 83% treated with HCQ/CQ.

Multivariable Cox regression HCQ/CQ mortality hazard ratio HR 0.53, p < 0.001.

risk of death, 47.0% lower, RR 0.53, p < 0.001, treatment 4,854, control 993, adjusted.

Signes-Costa et al., 12/16/2020, retrospective, multiple countries, multiple regions, peer-reviewed, 28 authors.

Gönenli et al., Research Square, doi:0.21203/rs.3.rs-107937/v1 (Preprint)

Prophylactic use of Hydroxychloroquine among Physicians working in Pandemic Hospitals

Small prophylaxis survey showing lower, but not statistically significant, progression to pneumonia (3 of 148 HCQ, 12 of 416 control), RR 0.70, p = 0.77. There was a higher incidence of cases with HCQ, OR 1.19, p = 0.58, which may be due to survey bias, treatment self-selection, and inconsistent regimens. Improvement on severity may be related to the much higher HCQ concentration in lung tissue, and also reflect that binary PCR does not distinguish replication-competence. Details of the pneumonia numbers for treatment/control are from the author.

risk of pneumonia, 29.7% lower, RR 0.70, p = 0.77, treatment 3 of 148 (2.0%), control 12 of 416 (2.9%).

risk of case, 18.9% higher, RR 1.19, p = 0.58, treatment 8 of 148 (5.4%), control 20 of 416 (4.8%), OR converted to RR.

Gönenli et al., 12/16/2020, retrospective, Turkey, Europe, preprint, survey, 4 authors.

De Luna et al., medRxiv, doi:10.1101/2020.12.11.20247437 (Preprint)

Clinical and Demographic Characteristics of COVID-19 Patients Admitted in a Tertiary Care Hospital in the Dominican Republic

Retrospective 150 patients in the Dominican Republic, 132 treated with HCQ, showing higher mortality with treatment in unadjusted results. Confounding by indication is likely.

risk of death, 104.5% higher, RR 2.05, p = 0.69, treatment 15 of 132 (11.4%), control 1 of 18 (5.6%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, substantial unadjusted confounding by indication likely.

De Luna et al., 12/14/2020, retrospective, Dominican Republic, Caribbean, preprint, 10 authors.

Sofian et al., Wiener Medizinische Wochenschrift, doi:10.1007/s10354-020-00793-8 (Peer Reviewed)

SARS-CoV‑2, a virus with many faces: a series of cases with prolonged persistence of COVID-19 symptoms

Report on a series of 10 patients experiencing prolonged COVID-19 symptoms that were given HCQ 250mg bid for 5 days, with resolution of symptoms in all cases, and patients reporting they felt much better 2 days after treatment initiation.

Sofian et al., 12/14/2020, peer-reviewed, 7 authors.

Orioli et al., Diabetes & Metabolic Syndrome: Clinical Research & Reviews, doi:10.1016/j.dsx.2020.12.020 (Peer Reviewed)

Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: A retrospective study from an academic center in Belgium

Small retrospective study of 73 diabetic patients in Belgium, 55 HCQ patients, showing HCQ RR 0.87, p = 1.0.

risk of death, 12.7% lower, RR 0.87, p = 1.00, treatment 8 of 55 (14.5%), control 3 of 18 (16.7%).

Orioli et al., 12/14/2020, retrospective, Belgium, Europe, peer-reviewed, 9 authors.

Naseem et al., medRxiv, doi:10.1101/2020.12.13.20247254 (Preprint)

Predicting mortality in SARS-COV-2 (COVID-19) positive patients in the inpatient setting using a Novel Deep Neural Network

Retrospective 1,214 hospitalized patients in Pakistan, 77 HCQ patients, showing 33% lower mortality with HCQ, multivariate Cox HR 0.67, p = 0.34.

risk of death, 33.3% lower, RR 0.67, p = 0.34, treatment 77, control 1,137, multivariate Cox.

Naseem et al., 12/14/2020, retrospective, Pakistan, South Asia, preprint, 5 authors.

Tan et al., Virus Research, doi:10.1016/j.virusres.2020.198262 (Peer Reviewed)

A retrospective comparison of drugs against COVID-19

Retrospective 333 patients in China, with only 8 HCQ patients, showing shorter duration of hospitalization with HCQ.

hospitalization time, 35.2% lower, relative time 0.65, p = 0.04, treatment 8, control 277.

Tan et al., 12/14/2020, retrospective, China, Asia, peer-reviewed, 7 authors.

Bielza et al., Journal of the American Medical Directors Association, doi:10.1016/j.jamda.2020.12.003 (Peer Reviewed)

Clinical characteristics, frailty and mortality of residents with COVID-19 in nursing homes of a region of Madrid

Retrospective 630 elderly patients in Spain showing lower mortality with HCQ treatment, unadjusted relative risk RR 0.78, p = 0.09. HCQ was used more often with patients that were hospitalized (24% versus 3% use in the nursing homes). Median age 87.

risk of death, 21.5% lower, RR 0.78, p = 0.09, treatment 33 of 91 (36.3%), control 249 of 539 (46.2%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Bielza et al., 12/11/2020, retrospective, Spain, Europe, peer-reviewed, median age 87.0, 24 authors.

Sogut et al., The American Journal of Emergency Medicine, doi:10.1016/j.ajem.2020.12.014 (Peer Reviewed)

Safety and efficacy of hydroxychloroquine in 152 outpatients with confirmed COVID-19: A pilot observational study

Safety study of 152 outpatients concluding that HCQ is safe for COVID-19, was well tolerated, and was not associated with a risk of ventricular arrhythmia due to drug-induced QTc interval prolongation.

Sogut et al., 12/11/2020, peer-reviewed, 10 authors.

Jung et al., Clinical Microbiology and Infection, doi:10.1016/j.cmi.2020.12.003 (Peer Reviewed)

Effect of hydroxychloroquine pre-exposure on infection with SARS-CoV-2 in rheumatic disease patients: A population-based cohort study

Retrospective cohort study of RA and SLE patients not showing a significant difference in PCR+ cases. PCR+ does not distinguish asymptomatic cases or severity. There was only one death which was in the control group. No other information on severity is provided.

33% of the control group used HCQ within the last year. Remaining confounding by differences in the nature and severity of rheumatic disease is likely.

risk of death, 59.3% lower, RR 0.41, p = 1.00, treatment 0 of 649 (0.0%), control 1 of 1,417 (0.1%), relative risk is not 0 because of continuity correction due to zero events.

risk of case, 13.1% higher, RR 1.13, p = 0.86, treatment 15 of 649 (2.3%), control 31 of 1,417 (2.2%), adjusted.

Jung et al., 12/11/2020, retrospective, South Korea, Asia, peer-reviewed, 6 authors.

Alqassieh et al., F1000Research, Preprint (Preprint)

Clinical characteristics and predictors of the duration of hospital stay in COVID-19 patients in Jordan

Prospective observational study of 131 COVID-19 patients in Jordan, showing 18% shorter hospital stay with HCQ, p = 0.11.

hospitalization time, 18.2% lower, relative time 0.82, p = 0.11, treatment 63, control 68.

Alqassieh et al., 12/10/2020, prospective, Jordan, Middle East, preprint, 10 authors.

Italian Council of State (News)

Consiglio di Stato, sì all'uso dell'idrossiclorachina per la cura del Covid

Consiglio di Stato ruling in Italy re-establishes the right of Italian MDs to prescribe HCQ, which was suspended after the retracted Lancet study.

Italian Council of State et al., 12/10/2020, preprint.

Johnston et al., EClinicalMedicine, doi:10.1016/j.eclinm.2021.100773 (preprint 12/9) (Peer Reviewed)

Hydroxychloroquine with or Without Azithromycin for Treatment of Early SARS-CoV-2 Infection Among High-Risk Outpatient Adults: A Randomized Clinical Trial

Small early terminated late treatment RCT comparing vitamin C + folic acid, HCQ + folic acid, and HCQ+AZ, showing non-statistically significantly lower hospitalization with HCQ/HCQ+AZ, and faster viral clearance with HCQ. Enrollment was a median of 5.9 days after onset (6.2 and 6.3 in the treatment arms).

The median time to viral clearance for vitamin C + folic acid was 8 days in the preprint but changed to 7 days in the published paper without explanation.

Low risk patients, median age 37, no deaths (not matching the title which claims "high risk"). Post hoc addition of a new Ct threshold to obscure the statistically significant faster clearance. No analysis for time from symptom onset. Authors identify (relatively) low and high risk cohorts, but do not provide either viral shedding or symptom resolution results for the cohorts. NCT04354428. For other issues see [1].

[1] twitter.com/Covid19Crusher/status/1358066110105542658

risk of hospitalization, 29.9% lower, RR 0.70, p = 0.73, treatment 5 of 148 (3.4%), control 4 of 83 (4.8%), HCQ + folic acid and HCQ + AZ vs. vitamin C + folic acid.

risk of no recovery, 2.0% lower, RR 0.98, p = 0.95, treatment 30 of 60 (50.0%), control 34 of 72 (47.2%), adjusted, HCQ + folic acid vs. vitamin C + folic acid.

risk of no recovery, 9.9% higher, RR 1.10, p = 0.70, treatment 34 of 65 (52.3%), control 34 of 72 (47.2%), adjusted, HCQ + AZ vs. vitamin C + folic acid.

time to viral-, 28.6% lower, relative time 0.71, treatment 49, control 52, median time, HCQ + folic acid vs. vitamin C + folic acid.

time to viral-, 14.3% lower, relative time 0.86, treatment 51, control 52, median time, HCQ + AZ vs. vitamin C + folic acid.

risk of no virological cure, 38.3% lower, RR 0.62, p = 0.05, treatment 6 of 49 (12.2%), control 12 of 52 (23.1%), adjusted, HCQ + folic acid vs. vitamin C + folic acid.

risk of no virological cure, 20.0% lower, RR 0.80, p = 0.49, treatment 11 of 51 (21.6%), control 12 of 52 (23.1%), adjusted, HCQ + AZ vs. vitamin C + folic acid.

Johnston et al., 12/9/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 30 authors, dosage 400mg bid day 1, 200mg bid days 2-10.

Agusti et al., Enfermedades Infecciosas y Microbiología Clínica, doi:10.1016/j.eimc.2020.10.023 (Peer Reviewed)

Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: prospective, non-randomized trial

Small trial of low dose HCQ for healthcare workers with mild SARS-CoV-2 showing 68% lower progression to pneumonia, p = 0.21, and faster, but not statistically significant viral clearance.

There were no ICU admissions or deaths. Prospective non-randomized study. The figures and supplementary data are not currently available in the pre-proof edition.

risk of progression, 68.4% lower, RR 0.32, p = 0.21, treatment 2 of 87 (2.3%), control 4 of 55 (7.3%), pneumonia.

time to viral-, 31.8% lower, relative time 0.68, treatment 87, control 55.

Agusti et al., 12/9/2020, prospective, Spain, Europe, peer-reviewed, median age 37.0, 13 authors, dosage 400mg bid day 1, 200mg bid days 2-5.

Guglielmetti et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2020.11.012 (Peer Reviewed)

Severe COVID-19 pneumonia in Piacenza, Italy – a cohort study of the first pandemic wave

Retrospective 218 hospitalized patients in Italy showing non-statistically significant 35% lower mortality with HCQ, hazard ratio aHR 0.65 [0.33–1.30].

risk of death, 35.0% lower, RR 0.65, p = 0.22, treatment 181, control 37, adjusted, multivariable Cox.

Guglielmetti et al., 12/9/2020, retrospective, Italy, Europe, peer-reviewed, 16 authors.

Barnabas et al., Annals of Internal Medicine, doi:10.7326/M20-6519 (Peer Reviewed)

Hydroxychloroquine for Post-exposure Prophylaxis to Prevent Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Trial

Early terminated PEP RCT comparing HCQ and vitamin C with 781 low-risk patients (83% household contacts), reporting no significant differences.

Different results were reported at IDWeek from the AIM results.

The study enrolled people with their last exposure within 4 days, i.e., if someone was exposed for 30 days in a row, they could be enrolled anywhere from day 1 to day 34. Therefore many were likely infected earlier than the enrollment date. Note that PCR has a very high false negative rates, e.g., 100% on day 1 and 67% on day 4 here [1].

50% of infections were detected by day 4. With the PCR false negatives and treatment delays it is likely that a majority of infections happened before enrollment or before HCQ can reach therapeutic levels.

Significantly more cases were caught at baseline in the control group (54 vs. 29 for HCQ) and excluded from analysis.

The early presentation stated that therapy started one day after enrollment and study supplies were sent to the participant "either by courier or mail". The published paper changes this to "courier delivery within 48 hours".

Overall delays are unclear but may be:

time since first exposure - unlimited
time from last exposure to enrollment - 10% reported as >= 5 days
time to telehealth meeting - 1 day (3 days if Friday enrollment?)
time to receive medication - <48 hours (including weekends?)

Symptomatic in this study was based on CDC-defined symptoms which contain symptoms that may be due to HCQ side effects.

Some results have not been reported, including symptomatic @28 days. The study uses a low dosage over an extended period, therapeutic levels may only be reached nearer to day 14, if at all, so day 28 results should be more informative when available (although labeled a PEP trial, with the low dosage and continuous exposure for most participants it is more of a PrEP/PEP trial where benefit might be seen later as HCQ levels increase).

Endpoints were:

Primary outcomes:
PCR+ @28 days mITT - aHR 1.16 [0.77-1.73]
PCR+ @14 days mITT - aHR 1.10 [0.73-1.66] IDWeek report was different: aHR 0.99 [0.64-1.52]
PCR+ @14 days ITT - aHR 0.81 [0.57-1.14]

Secondary outcomes:
PCR+ symptomatic @28 days - NOT REPORTED YET
duration of shedding - NOT REPORTED YET

Not in study protocol:
PCR+ cumulative symptomatic @14 days - aHR 1.23 [0.76-1.99].

Dose in first 24 hours - 0.8g (compare with Boulware et al. 2g)
Dose in first 5 days - 1.6g (compare with Boulware et al. 3.8g)

Other research suggests vitamin C may be beneficial for COVID-19, e.g. [2]. No information on severity of cases is provided. Binary PCR does not distinguish replication-competence. There were 2 COVID-19 hospitalizations, one in each group. Side effects were similar for HCQ and placebo. 83% medication adherence at day 14.

COVID-19 PEP. NCT04328961.

[1] ncbi.nlm.nih.gov/pmc/articles/PMC7240870/

[2] researchsquare.com/article/rs-52778/v2

risk of hospitalization, 3.7% higher, RR 1.04, p = 1.00, treatment 1 of 407 (0.2%), control 1 of 422 (0.2%).

risk of case, 27.0% higher, RR 1.27, p = 0.33, treatment 43 of 353 (12.2%), control 33 of 336 (9.8%), adjusted, day 14 symptomatic mITT PCR+ AIM.

risk of case, 23.0% higher, RR 1.23, p = 0.41, treatment 40 of 317 (12.6%), control 32 of 309 (10.4%), adjusted, day 14 symptomatic mITT PCR+ IDWeek.

risk of case, 10.0% higher, RR 1.10, p = 0.66, treatment 53 of 353 (15.0%), control 45 of 336 (13.4%), adjusted, day 14 PCR+ mITT AIM.

risk of case, 1.0% lower, RR 0.99, p = 0.97, treatment 46 of 317 (14.5%), control 43 of 309 (13.9%), adjusted, day 14 PCR+ mITT IDWeek.

risk of case, 19.0% lower, RR 0.81, p = 0.23, treatment 82 of 387 (21.2%), control 99 of 393 (25.2%), adjusted, day 14 PCR+ ITT AIM.

Barnabas et al., 12/7/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 30 authors.

Ozturk et al., Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfaa271 (Peer Reviewed)

Mortality analysis of COVID-19 infection in chronic kidney disease, haemodialysis and renal transplant patients compared with patients without kidney disease: a nationwide analysis from Turkey

Retrospective 1210 hospitalized patients in Turkey focused on chronic kidney disease, haemodialysis and renal transplant patients, but also showing lower mortality with HCQ. Subject to confounding by indication.

risk of death, 43.9% lower, RR 0.56, p = 0.14, treatment 165 of 1,127 (14.6%), control 6 of 23 (26.1%), CQ/HCQ.

Ozturk et al., 12/4/2020, retrospective, Turkey, Europe, peer-reviewed, 70 authors.

Modrák et al., medRxiv, doi:10.1101/2020.12.03.20239863 (Preprint)

Detailed disease progression of 213 patients hospitalized with Covid-19 in the Czech Republic: An exploratory analysis

Retrospective 213 hospitalized patients in Czech Republic showing lower mortality with HCQ. Subject to confounding by indication.

risk of death, 59.0% lower, RR 0.41, p = 0.04, treatment 108, control 105, Cox (single).

Modrák et al., 12/4/2020, retrospective, Czech Republic, Europe, preprint, 26 authors.

Peng et al., Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfaa288 (Peer Reviewed)

Early versus late acute kidney injury among patients with COVID-19—a multicenter study from Wuhan, China

Retrospective 4020 hospitalized patients in China showing non-statistically significant lower risk of acute kidney injury with HCQ.

risk of progression, 10.8% lower, RR 0.89, p = 0.63, treatment 29 of 453 (6.4%), control 256 of 3,567 (7.2%), CQ/HCQ risk of AKI.

Peng et al., 12/4/2020, retrospective, China, Asia, peer-reviewed, 21 authors.

Wiseman et al., medRxiv, doi:10.1101/2020.11.29.20235218 (Preprint) (meta analysis)

Effective post-exposure prophylaxis of Covid-19 is associated with use of hydroxychloroquine: Prospective re-analysis of a public dataset incorporating novel data

6th independent analysis showing efficacy from the Boulware PEP trial. This prospective analysis corrects an error in the NEJM paper where shipping delays are omitted (still not corrected).

42% reduction in COVID-19 (9.6% vs. 16.5%), RR 0.58 [0.35 - 0.97], p=0.044, for the original trial 3 day specification.

risk of case, 42.0% lower, RR 0.58, p = 0.04, <= 3 days after exposure.

Wiseman et al., 12/2/2020, preprint, 4 authors.

Capsoni et al., Research Square, doi:10.21203/rs.3.rs-113418/v1 (Preprint)

CPAP Treatment In COVID-19 Patients: A Retrospective Observational Study In The Emergency Department

Small 52 patient retrospective study of patients with acute respiratory failure showing lower rates of intubation with HCQ.

risk of mechanical ventilation, 40.0% lower, RR 0.60, p = 0.30, treatment 12 of 40 (30.0%), control 6 of 12 (50.0%).

Capsoni et al., 12/1/2020, retrospective, Italy, Europe, preprint, 13 authors.

Abdulrahman et al., medRxiv, doi:10.1101/2020.11.25.20234914 (Preprint)

The efficacy and safety of hydroxychloroquine in COVID19 patients : a multicenter national retrospective cohort

Retrospective medical record analysis of acute care patients in Bahrain not showing a significant effect of HCQ.

Confounding by indication is likely. Matching appears not to have matched for baseline severity - 17.5% of HCQ patients required oxygen while only 12.6% of control patients did.

risk of death, 16.7% lower, RR 0.83, p = 1.00, treatment 5 of 223 (2.2%), control 6 of 223 (2.7%), PSM.

risk of death/intubation, 75.0% higher, RR 1.75, p = 0.24, treatment 12 of 223 (5.4%), control 7 of 223 (3.1%), adjusted, PSM.

Abdulrahman et al., 11/30/2020, retrospective, propensity score matching, Bahrain, Middle East, preprint, 9 authors.

Abd-Elsalam et al., Biological Trace Element Research, doi:10.1007/s12011-020-02512-1 (Peer Reviewed)

Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial

191 patient RCT in Egypt comparing the addition of zinc to HCQ, not showing a significant difference.

Clinical recovery at 28 days was 79.2% in the zinc group and 77.9% control, p = 0.969.

Mechanical ventilation was used with 4 patients in the zinc group and 6 control. There were 5 deaths in each group.

No information on baseline zinc values was recorded. We note that Egypt has a low rate of zinc deficiency so supplementation is less likely to be helpful in Egypt [1, 2]

[1] ncbi.nlm.nih.gov/pmc/articles/PMC3510072/

[2] ncbi.nlm.nih.gov/pmc/articles/PMC3510072/bin/pone.0050568.s003.xls

Abd-Elsalam et al., 11/29/2020, peer-reviewed, 10 authors.

Lambermont et al., Critical Care Explorations, doi:10.1097/CCE.0000000000000305 (Peer Reviewed)

Predictors of Mortality and Effect of Drug Therapies in Mechanically Ventilated Patients With Coronavirus Disease 2019: A Multicenter Cohort Study

Retrospective 247 mechanically ventilated patients showing lower mortality with HCQ, but not statistically significant on multiple Cox regression.

The paper gives the p value for multiple Cox (0.46) and simple Cox (0.02), but does not specify the adjusted risk values.

risk of death, 32.3% lower, RR 0.68, p = 0.46, treatment 97 of 225 (43.1%), control 14 of 22 (63.6%), adjusted.

Lambermont et al., 11/28/2020, retrospective, Belgium, Europe, peer-reviewed, 15 authors.

Ruiz et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106247 (Peer Reviewed)

Hydroxychloroquine lung pharmacokinetics in critically ill patients infected with COVID-19

HCQ lung pharmacokinetic study confirming that lung concentrations can be much higher than plasma.

The median lung epithelial lining fluid concentration was 38 times higher than plasma concentrations. 22 COVID-19 patients, median age 59.5.

Dosage determinations in studies assuming equilibrium between epithelium and plasma concentrations may lead to overly high dosages.

Authors find the median ELF concentration of HCQ above the maximum EC₅₀ value for 400 mg x 1 /day and 200 mg x 3 /day, 7-12 days after treatment initiation.

Ruiz et al., 11/28/2020, peer-reviewed, 14 authors.

Rodriguez-Gonzalez et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106249 (Peer Reviewed)

COVID-19 in hospitalized patients in Spain: a cohort study in Madrid

Retrospective 1255 patients in Spain showing lower mortality with HCQ. Subject to confounding by indication.

risk of death, 22.8% lower, RR 0.77, p = 0.26, treatment 251 of 1,148 (21.9%), control 17 of 60 (28.3%).

Rodriguez-Gonzalez et al., 11/28/2020, retrospective, Spain, Europe, peer-reviewed, 20 authors.

van Halem et al., BMC Infect Dis., doi:10.1186/s12879-020-05605-3 (Peer Reviewed)

Risk factors for mortality in hospitalized patients with COVID-19 at the start of the pandemic in Belgium: a retrospective cohort study

Retrospective 319 hospitalized patients in Belgium showing lower mortality with HCQ, although not reported to be statistically significant.

risk of death, 31.6% lower, RR 0.68, p = 0.05, treatment 34 of 164 (20.7%), control 47 of 155 (30.3%).

van Halem et al., 11/27/2020, retrospective, Belgium, Europe, peer-reviewed, 10 authors.

Burdick et al., Journal of Clinical Medicine, doi:10.3390/jcm9123834 (Peer Reviewed)

Is Machine Learning a Better Way to IdentifyCOVID-19 Patients Who Might Benefit fromHydroxychloroquineTreatment?—The IDENTIFY Trial

290 patient observational trial in the USA, not showing a significant difference with HCQ treatment overall, but showing significantly lower mortality in a subgroup of patients where HCQ is expected to be beneficial based on a machine learning algorithm.

risk of death, 59.0% higher, RR 1.59, p = 0.12, treatment 142, control 148, adjusted, all patients.

risk of death, 71.0% lower, RR 0.29, p = 0.01, treatment 26, control 17, adjusted, subgroup of patients where treatment is predicted to be beneficial.

Burdick et al., 11/26/2020, prospective, USA, North America, peer-reviewed, 14 authors.

Abbas et al., Int. J. Clin. Pract., doi:10.1111/ijcp.13856 (Peer Reviewed)

Assessment of COVID-19 Treatment containing both Hydroxychloroquine and Azithromycin: A Natural Clinical Trial

Prospective study of 161 hospitalized patients in Iraq showing HCQ+AZ appears to help recovery. Most mortality was in patients that were already in critical condition on admission and died before treatment could be effective.

Abbas et al., 11/24/2020, prospective, Iraq, Middle East, peer-reviewed, 8 authors.

Qin et al., Thrombosis Research, doi:10.1016/j.thromres.2020.11.020 (Peer Reviewed)

Low molecular weight heparin and 28-day mortality among patients with coronavirus disease 2019: A cohort study in the early epidemic era

Low molecular weight heparin study also showing results for HCQ treatment, unadjusted HCQ mortality relative risk RR 0.66, p = 0.61.

risk of death, 34.3% lower, RR 0.66, p = 0.61, treatment 3 of 43 (7.0%), control 75 of 706 (10.6%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Qin et al., 11/23/2020, retrospective, China, Asia, peer-reviewed, 17 authors.

Revollo et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkaa477 (Peer Reviewed)

Hydroxychloroquine pre-exposure prophylaxis for COVID-19 in healthcare workers

Retrospective PrEP analysis with 69 healthcare workers on PrEP HCQ, and 418 control.

Authors report PCR and IgG results, with no baseline results for either. Authors note they "identified 69 HCWs receiving HCQ" while providing no information as to why or when they started HCQ.

No conclusions can be drawn from this study because many workers may have been positive before starting HCQ. Only 14% of workers chose to use HCQ and they may have been motivated to do so because they had an infection.

Authors perform several different adjustments, finding very different results. No information on death, hospitalization, symptoms, or severity is provided. Details on timing of serology and baseline serology status is not provided. Potential bias due to self-selection for risk.

25% of infections were detected before 7 days, indicating that they actually happened earlier (PCR false positive is very high initially). It is likely that many infections were before HCQ could reach therapeutic levels.

risk of case, 23.0% lower, RR 0.77, p = 0.52, treatment 16 of 69 (23.2%), control 65 of 418 (15.6%), adjusted, PSM, risk of PCR+.

risk of case, 43.0% higher, RR 1.43, p = 0.42, treatment 17 of 60 (28.3%), control 62 of 404 (15.3%), adjusted, PSM, risk of IgG+.

Revollo et al., 11/21/2020, retrospective, propensity score matching, Spain, Europe, peer-reviewed, 16 authors.

Omrani et al., EClinicalMedicine, doi:10.1016/j.eclinm.2020.100645 (Peer Reviewed)

Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19

Low risk patient RCT for HCQ+AZ and HCQ vs. control, not showing any significant differences.

Authors note that the results are not applicable to higher risk patients; that positive PCR may simply reflect detection of inactive (non-infectious) viral remnants; that an alternative dosage regimen may be more effective; and that medication adherence was unknown.

HCQ dosing was 600mg/day for 1 week, therapeutic levels may not be reached for several days. There were no deaths or serious adverse events.

risk of hospitalization, 12.5% lower, RR 0.88, p = 1.00, treatment 7 of 304 (2.3%), control 4 of 152 (2.6%), HCQ+AZ or HCQ vs. control.

risk of symptomatic at day 21, 25.8% lower, RR 0.74, p = 0.58, treatment 9 of 293 (3.1%), control 6 of 145 (4.1%), HCQ+AZ or HCQ vs. control.

risk of Ct<=40 at day 14, 10.3% higher, RR 1.10, p = 0.13, treatment 223 of 295 (75.6%), control 98 of 143 (68.5%), HCQ+AZ or HCQ vs. control.

Omrani et al., 11/20/2020, Randomized Controlled Trial, Qatar, Middle East, peer-reviewed, 19 authors, dosage 600mg days 1-6.

Falcone et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofaa563 (Peer Reviewed)

Role of low-molecular weight heparin in hospitalized patients with SARS-CoV-2 pneumonia: a prospective observational study

Prospective observational study of 315 hospitalized patients in Italy showing 65% lower mortality with HCQ. The median treatment delay was 6 days for survivors and 6.5 days for non-survivors. Mortality relative risk:

RR 0.35, p = 0.2, propensity score matched
RR 0.75, p = 0.36, multivariate Cox regression
RR 0.43, p < 0.001, univariate Cox regression

risk of death, 65.0% lower, RR 0.35, p = 0.20, treatment 40 of 238 (16.8%), control 30 of 77 (39.0%), adjusted, PSM.

risk of death, 25.0% lower, RR 0.75, p = 0.36, treatment 40 of 238 (16.8%), control 30 of 77 (39.0%), adjusted, multivariate Cox regression.

risk of death, 57.0% lower, RR 0.43, p < 0.001, treatment 40 of 238 (16.8%), control 30 of 77 (39.0%), adjusted, univariate Cox regression.

Falcone et al., 11/19/2020, prospective, propensity score matching, Italy, Europe, peer-reviewed, 19 authors.

Budhiraja et al., medRxiv, doi:10.1101/2020.11.16.20232223 (Preprint)

Clinical Profile of First 1000 COVID-19 Cases Admitted at Tertiary Care Hospitals and the Correlates of their Mortality: An Indian Experience

Retrospective 976 hospitalized patients with 834 treated with HCQ+AZ showing HCQ mortality relative risk RR 0.35, p < 0.0001. Note that in this case HCQ was recommended for mild/moderate cases, so more severe cases may not have received HCQ (which may also be why they became severe cases). We note that this is opposite to a common bias in HCQ studies - in many cases HCQ was more likely to be given to more severe cases.

risk of death, 65.4% lower, RR 0.35, p < 0.001, treatment 69 of 834 (8.3%), control 34 of 142 (23.9%).

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Budhiraja et al., 11/18/2020, retrospective, India, South Asia, preprint, 12 authors.

Boari et al, Biosci. Rep., doi:10.1042/BSR20203455 (Peer Reviewed)

Prognostic factors and predictors of outcome in patients with COVID-19 and related pneumonia: a retrospective cohort study

Retrospective 258 hospitalized patients in Italy showing lower mortality with HCQ treatment, unadjusted relative risk RR 0.455, p<0.001. Data is in the supplementary appendix.

risk of death, 54.5% lower, RR 0.45, p < 0.001, treatment 41 of 202 (20.3%), control 25 of 56 (44.6%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Boari et al., 11/17/2020, retrospective, Italy, Europe, peer-reviewed, 20 authors.

Sheshah et al., Diabetes Research and Clinical Practice, doi:10.1016/j.diabres.2020.108538 (Peer Reviewed)

Prevalence of Diabetes, Management and Outcomes among Covid-19 Adult Patients Admitted in a Specialized Tertiary Hospital in Riyadh, Saudi Arabia

Retrospective 300 hospitalized patients in Saudi Arabia showing HCQ adjusted odds ratio aOR 0.12, p < 0.001.

risk of death, 80.0% lower, RR 0.20, p < 0.001, treatment 267, control 33, OR converted to RR.

Sheshah et al., 11/13/2020, retrospective, Saudi Arabia, Middle East, peer-reviewed, 8 authors.

Simova et al., New Microbes and New Infections, doi:10.1016/j.nmni.2020.100813 (Peer Reviewed)

Hydroxychloroquine for prophylaxis and treatment of COVID-19 in health care workers

100% reduction in hospitalization and cases with early treatment using HCQ+AZ+zinc. Brief report on healthcare workers in Bulgaria.

0 hospitalizations with treatment vs. 2 for control
0 PCR+ at day 14 with treatment vs. 3 for control

33 treatment patients and 5 control patients.

No serious adverse events. This paper reports on both PEP and early treatment, we have separated the two studies.

risk of hospitalization, 93.8% lower, RR 0.06, p = 0.01, treatment 0 of 33 (0.0%), control 2 of 5 (40.0%), relative risk is not 0 because of continuity correction due to zero events.

risk of viral+ at day 14, 95.8% lower, RR 0.04, p = 0.001, treatment 0 of 33 (0.0%), control 3 of 5 (60.0%), relative risk is not 0 because of continuity correction due to zero events.

Simova et al., 11/12/2020, retrospective, Bulgaria, Europe, peer-reviewed, 5 authors, dosage 200mg tid days 1-14.

Simova et al., New Microbes and New Infections, doi:10.1016/j.nmni.2020.100813 (Peer Reviewed)

Hydroxychloroquine for prophylaxis and treatment of COVID-19 in health care workers

100% reduction in cases with HCQ+zinc post-exposure prophylaxis. Brief report for healthcare workers in Bulgaria.

0 cases with treatment vs. 3 for control.

156 treatment patients and 48 control patients.

No serious adverse events. This paper reports on both PEP and early treatment, we have separated the two studies.

risk of case, 92.7% lower, RR 0.07, p = 0.01, treatment 0 of 156 (0.0%), control 3 of 48 (6.2%), relative risk is not 0 because of continuity correction due to zero events.

Simova et al., 11/12/2020, retrospective, Bulgaria, Europe, peer-reviewed, 5 authors.

Tchounga et al., Journal of Pharmaceutical and Biomedical Analysis, doi:10.1016/j.jpba.2020.113761 (Peer Reviewed) (meta analysis)

Composition analysis of falsified chloroquine phosphate samples seized during the COVID-19 pandemic

Analysis of fake CQ tablets finding:

- no CQ in six samples, substituted with metronidazole (at sub-therapeutic levels) or paracetamol.
- trace levels of paracetamol and chloramphenicol in four and two samples respectively.
- CQ levels too low in two samples.

Tchounga et al., 11/12/2020, peer-reviewed, 7 authors.

Águila-Gordo et al., Revista Española de Geriatría y Gerontología, doi:10.1016/j.regg.2020.09.006 (Peer Reviewed)

Mortality and associated prognostic factors in elderly and very elderly hospitalized patients with respiratory disease COVID-19

67% lower mortality with HCQ. Retrospective 416 elderly patients in Spain showing adjusted HCQ mortality hazard ratio HR 0.33, p = 0.1.

risk of death, 67.0% lower, RR 0.33, p = 0.10, treatment 151 of 346 (43.6%), control 47 of 70 (67.1%), adjusted.

Águila-Gordo et al., 11/11/2020, retrospective, Spain, Europe, peer-reviewed, mean age 84.4, 6 authors.

Khamis et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.11.008 (Peer Reviewed)

Randomized Controlled Open Label Trial on the Use of Favipiravir Combined with Inhaled Interferon beta-1b in Hospitalized Patients with Moderate to Severe COVID-19 Pneumonia

Small 89 patient RCT comparing favipiravir and inhaled interferon with HCQ for moderate to severe COVID-19 pneumonia, not finding significant differences.

Khamis et al., 11/9/2020, peer-reviewed, 11 authors.

Rodriguez et al., Medicina Intensiva, doi:10.1016/j.medine.2020.05.005 (Peer Reviewed)

Severe infection due to the SARS-CoV-2 coronavirus: Experience of a tertiary hospital with COVID-19 patients during the 2020 pandemic

Small prospective study of 43 hospitalized patients with 39 taking HCQ, showing unadjusted mortality relative risk RR 0.41, p=0.23.

risk of death, 59.0% lower, RR 0.41, p = 0.23, treatment 8 of 39 (20.5%), control 2 of 4 (50.0%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Rodriguez et al., 11/9/2020, prospective, Spain, Europe, peer-reviewed, 13 authors.

Self et al., JAMA, doi:10.1001/jama.2020.22240 (Peer Reviewed)

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial

Early terminated very late stage (65% on supplemental oxygen) RCT with 242 HCQ and 237 control patients not showing a significant difference, 28 day mortality adjusted odds ratio aOR 0.93 [0.48-1.85].

For the subgroup not on supplemental oxygen at baseline (relatively early treatment), the odds ratio for the 7 point outcome scale is:

aOR 0.61 [0.34-1.08]

Dosage may be too low:

Dose in first 24 hours - 1g (compare to Boulware et al. 2g)
Dose in 5 days - 2.4g (compare to Boulware et al. 3.8g)

Dosage note: Boulware 2g within 24 hours includes the second day dose. Note two important differences with the RECOVERY/SOLIDARITY dosage which is believed to be dangerously high - in RECOVERY/SOLIDARITY the total dose is much higher, which is problematic because the half-life of HCQ is very long, and it is given to patients that are already in very serious condition.

Note the paper reports primary outcome values with OR>1 favoring HCQ, we have converted to OR<1 favoring HCQ. Subgroup analysis is in the supplemental appendix.

risk of death, 6.2% higher, RR 1.06, p = 0.85, treatment 25 of 241 (10.4%), control 25 of 236 (10.6%), adjusted, OR converted to RR.

Self et al., 11/9/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 33 authors.

Brown et al., Annals of the American Thoracic Society, doi:10.1513/AnnalsATS.202008-940OC (Peer Reviewed)

Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial

Small early terminated very late stage (86% on oxygen, 44% enrolled in the ICU) RCT comparing HCQ vs. AZ, not finding a significant difference between the two treatments. There is no comparison with a control group. HCQ patients not in the ICU at enrollment (slightly earlier treatment) did better, OR 0.95 vs. 1.13.

HCQ dosage is relatively low:

Dose in first 24 hours - 1g (compare to Boulware et al. 2g)
Dose in 5 days - 2.4g (compare to Boulware et al. 3.8g)

Brown et al., 11/9/2020, peer-reviewed, 17 authors.

Núñez-Gil et al., Intern. Emerg. Med., doi:10.1007/s11739-020-02543-5 (Peer Reviewed)

Mortality risk assessment in Spain and Italy, insights of the HOPE COVID-19 registry

Retrospective database study of 1,021 patients in Ecuador, Germany, Italy, and Spain, showing HCQ propensity score adjusted mortality odds ratio aOR 0.88, p=0.005.

risk of death, 7.9% lower, RR 0.92, p = 0.005, treatment 200 of 686 (29.2%), control 100 of 268 (37.3%), adjusted, OR converted to RR.

Núñez-Gil et al., 11/9/2020, retrospective, database analysis, multiple countries, multiple regions, peer-reviewed, median age 68.0, 49 authors.

Mathai et al., J. Marine Medical Society, doi:10.4103/jmms.jmms_115_20 (Peer Reviewed)

Hydroxychloroquine as pre-exposure prophylaxis against COVID-19 in health-care workers: A single-center experience

90% reduction in cases with HCQ pre-exposure prophylaxis. Retrospective 604 healthcare workers.

risk of case, 89.5% lower, RR 0.10, p < 0.001, treatment 10 of 491 (2.0%), control 22 of 113 (19.5%).

risk of case, 88.5% lower, RR 0.12, p < 0.001, treatment 5 of 491 (1.0%), control 10 of 113 (8.8%), symptomatic.

Mathai et al., 11/6/2020, retrospective, India, South Asia, peer-reviewed, 3 authors.

Datta et al., Journal of Vaccines & Vaccination, S6:1000002 (Peer Reviewed)

No Role of HCQ in COVID-19 Prophylaxis: A Survey amongst Indian Doctors

Survey of Indian doctors not finding a significant effect of HCQ prophylaxis.

risk of case, 22.1% lower, RR 0.78, p = 0.47, treatment 16 of 146 (11.0%), control 19 of 135 (14.1%).

Datta et al., 11/6/2020, retrospective, India, South Asia, peer-reviewed, 7 authors.

Dhibar et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106224 (Peer Reviewed)

Post Exposure Prophylaxis with Hydroxychloroquine (HCQ) for the Prevention of COVID-19, a Myth or a Reality? The PEP-CQ Study

41% reduction in cases with HCQ PEP. Prospective open label trial with 132 HCQ patients and 185 control patients showing RR 0.59, p=0.03. 50% reduction in PCR+ cases, 44% reduction in symptomatic cases. No serious adverse events. Relatively low dosage, the PEP group received HCQ 800mg on day one followed by 400mg once weekly for 3 weeks. NCT04408456.

risk of case, 41.0% lower, RR 0.59, p = 0.03, treatment 14 of 132 (10.6%), control 36 of 185 (19.5%), adjusted.

risk of case, 50.0% lower, RR 0.50, p = 0.04, treatment 10 of 132 (7.6%), control 28 of 185 (15.1%), adjusted, PCR+.

risk of symptomatic case, 43.9% lower, RR 0.56, p = 0.21, treatment 6 of 132 (4.5%), control 15 of 185 (8.1%), adjusted.

Dhibar et al., 11/6/2020, prospective, India, South Asia, peer-reviewed, 13 authors.

Maldonado et al., Nefrología, doi:10.1016/j.nefro.2020.09.002 (Peer Reviewed)

COVID-19 incidence and outcomes in a home dialysis unit in Madrid (Spain) at the height of the pandemic

Very small retrospective of 12 dialysis patients showing 1/11 deaths with HCQ and 1/1 without HCQ.

risk of death, 90.9% lower, RR 0.09, p = 0.17, treatment 1 of 11 (9.1%), control 1 of 1 (100.0%).

Excluded in after exclusion results of meta analysis: treatment or control group size extremely small.

Maldonado et al., 11/5/2020, retrospective, Spain, Europe, peer-reviewed, 10 authors.

Rodriguez-Nava et al., Mayo Clinic Proceedings: Innovations, Quality & Outcomes (Peer Reviewed)

Clinical characteristics and risk factors for mortality of hospitalized patients with COVID-19 in a community hospital: A retrospective cohort study

Retrospective 313 patients, mostly critical stage and mostly requiring respiratory support, showing unadjusted RR 1.06, p = 0.77. Confounding by indication likely.

risk of death, 6.3% higher, RR 1.06, p = 0.77, treatment 22 of 65 (33.8%), control 79 of 248 (31.9%), unadjusted.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, excessive unadjusted differences between groups, unadjusted results with no group details.

Rodriguez-Nava et al., 11/5/2020, retrospective, USA, North America, peer-reviewed, median age 68.0, 8 authors.

Salazar et al., The American Journal of Pathology, doi:10.1016/j.ajpath.2020.10.008 (Peer Reviewed)

Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti–Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG

Convalescent plasma study also showing mortality based on HCQ treatment, unadjusted hazard ratio uHR 1.37, p = 0.28. Confounding by indication is likely.

risk of death, 37.0% higher, RR 1.37, p = 0.28, treatment 12 of 92 (13.0%), control 80 of 811 (9.9%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, unadjusted results with no group details.

Salazar et al., 11/4/2020, retrospective, USA, North America, peer-reviewed, 19 authors.

Cadegiani et al., New Microbes and New Infections, doi:10.1016/j.nmni.2021.100915 (preprint 11/4/2020) (Peer Reviewed)

Early COVID-19 Therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in Outpatient Settings Significantly Improved COVID-19 outcomes compared to Known outcomes in untreated patients

Comparison of HCQ, nitazoxanide, and ivermectin showing similar effectiveness for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to the untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. 585 patients with mean treatment delay 2.9 days. There was no hospitalization, mechanical ventilation, or mortality with treatment. Control group 1 was a retrospectively obtained group of untreated patients of the same population.

risk of death, 81.2% lower, RR 0.19, p = 0.21, treatment 0 of 159 (0.0%), control 2 of 137 (1.5%), relative risk is not 0 because of continuity correction due to zero events, control group 1.

risk of mechanical ventilation, 95.1% lower, RR 0.05, p < 0.001, treatment 0 of 159 (0.0%), control 9 of 137 (6.6%), relative risk is not 0 because of continuity correction due to zero events, control group 1.

risk of hospitalization, 98.3% lower, RR 0.02, p < 0.001, treatment 0 of 159 (0.0%), control 27 of 137 (19.7%), relative risk is not 0 because of continuity correction due to zero events, control group 1.

Cadegiani et al., 11/4/2020, prospective, Brazil, South America, peer-reviewed, 4 authors, dosage 400mg days 1-5.

Behera et al., PLoS ONE, doi:10.1371/journal.pone.0247163 (preprint 11/3) (Peer Reviewed)

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study

Retrospective matched case-control prophylaxis study for HCQ, ivermectin, and vitamin C with 372 healthcare workers, showing lower COVID-19 incidence for all treatments, with statistical significance reached for ivermectin.

HCQ OR 0.56, p = 0.29
Ivermectin OR 0.27, p < 0.001
Vitamin C OR 0.82, p = 0.58

risk of case, 27.9% lower, RR 0.72, p = 0.29, treatment 7 of 19 (36.8%), control 179 of 353 (50.7%), adjusted, OR converted to RR, model 2 conditional logistic regression.

risk of case, 26.3% lower, RR 0.74, p = 0.25, treatment 7 of 19 (36.8%), control 179 of 353 (50.7%), OR converted to RR, matched pair analysis.

Behera et al., 11/3/2020, retrospective, India, South Asia, peer-reviewed, 13 authors.

López et al., Annals of Pediatrics, doi:10.1016/j.anpedi.2020.10.017 (Peer Reviewed)

Telemedicine follow-ups for COVID-19: experience in a tertiary hospital

Retrospective 72 pediatric patients showing HCQ associated with a shorter duration of fever (p=0.023), less progression (p=0.016), and fewer return visits to the ER (p=0.017).

risk of progression, 64.3% lower, RR 0.36, p = 0.02, treatment 5 of 36 (13.9%), control 14 of 36 (38.9%).

López et al., 11/2/2020, retrospective, Spain, Europe, peer-reviewed, 7 authors.

Szente Fonseca et al., Travel Medicine and Infectious Disease, doi:10.1016/j.tmaid.2020.101906 (Peer Reviewed)

Risk of Hospitalization for Covid-19 Outpatients Treated with Various Drug Regimens in Brazil: Comparative Analysis

64% lower hospitalization with HCQ. Retrospective 717 patients in Brazil with early treatment, adjusted OR 0.32, p=0.00081, for HCQ versus no medication, and OR 0.45, p=0.0065, for HCQ vs. anything else.

risk of hospitalization, 64.0% lower, RR 0.36, p < 0.001, treatment 25 of 175 (14.3%), control 89 of 542 (16.4%), adjusted, OR converted to RR, HCQ vs. nothing.

risk of hospitalization, 50.5% lower, RR 0.49, p = 0.006, treatment 25 of 175 (14.3%), control 89 of 542 (16.4%), adjusted, OR converted to RR, HCQ vs. anything else.

Szente Fonseca et al., 10/31/2020, retrospective, Brazil, South America, peer-reviewed, mean age 50.6, 10 authors, dosage 400mg bid day 1, 400mg qd days 2-5.

Tehrani et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.10.071 (Peer Reviewed)

Risk factors for mortality in adult COVID-19 patients: frailty predicts fatal outcome in older patients

Retrospective 255 hospitalized patients, 65 treated with HCQ, showing unadjusted RR 0.87, p=0.63. Confounding by indication is likely.

risk of death, 13.4% lower, RR 0.87, p = 0.63, treatment 16 of 65 (24.6%), control 54 of 190 (28.4%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, unadjusted results with no group details.

Tehrani et al., 10/30/2020, retrospective, Sweden, Europe, peer-reviewed, 5 authors.

Arleo et al., medRxiv, doi:10.1101/2020.10.26.20219154 (Preprint)

Clinical Course and Outcomes of coronavirus disease 2019 (COVID-19) in Rheumatic Disease Patients on Immunosuppression: A case Cohort Study at a Single Center with a Significantly Diverse Population

Retrospective hospitalized rheumatic disease patients showing 50% lower mortality for patients on HCQ.

risk of death, 50.0% lower, RR 0.50, p = 0.67, treatment 1 of 20 (5.0%), control 5 of 50 (10.0%), all patients.

risk of death, 52.0% lower, RR 0.48, p = 0.64, treatment 1 of 10 (10.0%), control 5 of 24 (20.8%), inpatients.

Arleo et al., 10/27/2020, retrospective, USA, North America, preprint, 5 authors.

Choi et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.10.062 (Peer Reviewed)

Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study

Health insurance database analysis failing to adjust for disease severity and not finding a significant difference in time to PCR- for LPV/r and HCQ.

There are large differences in severity across groups. Authors did PSM but chose not to prioritize severity, resulting in incomparable groups, e.g., baseline pneumonia of 44% in the HCQ group and 15% in the control group (after PSM).

Authors note this but offer no explanation for not correcting for severity: "However, the disease severity and proportion of accompanying pneumonia were still significantly higher in the LPV/r and HCQ-group".

median time to PCR-, 22.0% higher, relative time 1.22, p < 0.001, treatment 701, control 701.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Choi et al., 10/27/2020, retrospective, database analysis, South Korea, Asia, peer-reviewed, 8 authors.

Frontera et al., Research Square, doi:10.21203/rs.3.rs-94509/v1 (Preprint)

Treatment with Zinc is Associated with Reduced In-Hospital Mortality Among COVID-19 Patients: A Multi-Center Cohort Study

Retrospective 3,473 hospitalized patients showing lower mortality with HCQ+zinc.

risk of death, 37.0% lower, RR 0.63, p = 0.01, treatment 121 of 1,006 (12.0%), control 424 of 2,467 (17.2%), adjusted, PSM.

risk of death, 24.0% lower, RR 0.76, p = 0.02, treatment 121 of 1,006 (12.0%), control 424 of 2,467 (17.2%), adjusted, regression.

Frontera et al., 10/26/2020, retrospective, propensity score matching, USA, North America, preprint, median age 64.0, 14 authors, this trial uses multiple treatments in the treatment arm (combined with zinc) - results of individual treatments may vary.

Goenka et al., SSRN, doi:10.2139/ssrn.3689618 (Preprint)

Seroprevalence of COVID-19 Amongst Health Care Workers in a Tertiary Care Hospital of a Metropolitan City from India

Study of SARS-CoV-2-IgG antibodies in 1122 health care workers in India finding 87% lower positives for adequate HCQ prophylaxis, 1.3% HCQ versus 12.3% for no HCQ prophylaxis.

Adequate prophylaxis is defined as 400mg 1/wk for >6 weeks.

risk of IgG positive, 87.2% lower, RR 0.13, p = 0.03, treatment 1 of 77 (1.3%), control 115 of 885 (13.0%), adjusted, OR converted to RR.

Goenka et al., 10/24/2020, retrospective, India, South Asia, preprint, 11 authors.

Coll et al., American Journal of Transplantation, doi:10.1111/ajt.16369 (Peer Reviewed)

Covid‐19 in transplant recipients: the spanish experience

Retrospective 652 transplant recipient patients in Spain showing 46% lower mortality for patients treated with HCQ, unadjusted relative risk RR 0.54, p<0.0001.

risk of death, 45.6% lower, RR 0.54, p < 0.001, treatment 55 of 307 (17.9%), control 108 of 328 (32.9%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Coll et al., 10/23/2020, retrospective, Spain, Europe, peer-reviewed, median age 61.0, 29 authors.

Lano et al., Clinical Kidney Journal, 13:5, October 2020, 878–888, doi:10.1093/ckj/sfaa199 (Peer Reviewed)

Risk factors for severity of COVID-19 in chronic dialysis patients from a multicentre French cohort

33% lower mortality with HCQ+AZ, p=0.28. Retrospective 122 French dialysis patients.

69% lower combined mortality/ICU, p=0.11, for the subgroup not requiring O2 on diagnosis (slightly earlier treatment).

risk of death, 33.1% lower, RR 0.67, p = 0.28, treatment 56, control 66, adjusted, OR converted to RR.

risk of death/ICU, 38.9% lower, RR 0.61, p = 0.23, treatment 17 of 56 (30.4%), control 28 of 66 (42.4%), adjusted, OR converted to RR.

risk of death/ICU, 68.7% lower, RR 0.31, p = 0.11, treatment 4 of 36 (11.1%), control 11 of 31 (35.5%), not requiring O2 on diagnosis (relatively early treatment).

Lano et al., 10/21/2020, retrospective, France, Europe, peer-reviewed, median age 73.5, 30 authors.

Dubee et al., Clinical Microbiology and Infection, doi:10.1016/j.cmi.2021.03.005 (preprint 10/21) (Peer Reviewed)

Hydroxychloroquine in mild-to-moderate COVID-19: a placebo-controlled double blind trial

Small early terminated late stage (60% on oxygen) RCT in France showing 46% lower mortality.

mortality at 28 days relative risk RR 0.54 [0.21-1.42]
combined mortality/intubation at 28 days relative risk RR 0.74 [0.33-1.70]

If not stopped early and the same trend continued, statistical significance would be reached on 28 day mortality after ~550 patients (1,300 patients were planned).

Mortality results are not provided for subgroups. For the subgroups receiving AZ:

No safety concerns were identified. This study has been presented as negative, however the results do not support that conclusion.

NCT04325893

risk of death at day 28, 46.0% lower, RR 0.54, p = 0.21, treatment 6 of 124 (4.8%), control 11 of 123 (8.9%).

risk of combined intubation/death at day 28, 26.0% lower, RR 0.74, p = 0.48, treatment 9 of 124 (7.3%), control 12 of 123 (9.8%).

Dubee et al., 10/21/2020, Randomized Controlled Trial, France, Europe, peer-reviewed, median age 77.0, 18 authors.

Ñamendys-Silva et al., Heart & Lung, doi:10.1016/j.hrtlng.2020.10.013 (Peer Reviewed)

Outcomes of patients with COVID-19 in the Intensive Care Unit in Mexico: A multicenter observational study

Retrospective 164 ICU patients in Mexico showing 32% lower mortality with HCQ+AZ and 37% lower with CQ.

HCQ+AZ vs. neither HCQ or CQ relative risk RR 0.68, p = 0.03
CQ vs. neither HCQ or CQ relative risk RR 0.63, p = 0.02
HCQ+AZ or CQ vs. neither relative risk RR 0.65, p = 0.006

risk of death, 32.3% lower, RR 0.68, p = 0.18, treatment 24 of 54 (44.4%), control 42 of 64 (65.6%), HCQ+AZ vs. neither HCQ or CQ.

risk of death, 37.1% lower, RR 0.63, p = 0.09, treatment 19 of 46 (41.3%), control 42 of 64 (65.6%), CQ vs. neither HCQ or CQ.

risk of death, 34.5% lower, RR 0.66, p = 0.006, treatment 43 of 100 (43.0%), control 42 of 64 (65.6%), HCQ+AZ or CQ.

Ñamendys-Silva et al., 10/21/2020, retrospective, database analysis, Mexico, North America, peer-reviewed, mean age 57.3, 18 authors.

IHU Marseille (Preprint) (meta analysis)

Meta-analysis on chloroquine derivatives and COVID-19 mortality

Updated meta analysis of 41 studies showing CQ/HCQ OR 0.57, p<0.0001 from clinical studies.

For big data studies authors find inconsistent results and OR 0.83, p=0.0014, and for all studies combined OR 0.72, p<0.0001.

IHU Marseille et al., 10/20/2020, preprint, 1 author.

Solh et al., medRxiv, doi:10.1101/2020.10.16.20214130 (Preprint)

Clinical course and outcome of COVID-19 acute respiratory distress syndrome: data from a national repository

Retrospective database analysis of 7,816 Veterans Affairs hospitalized patients analyzing progression to ARDS and 30-day mortality from ARDS. Confounding by indication is likely. Chronological bias is likely, with HCQ more likely to be used earlier on, before significant improvements in overall treatment.

No results are provided for HCQ for progression to ARDS.

risk of death, 18.0% higher, RR 1.18, p = 0.17, treatment 131 of 265 (49.4%), control 134 of 378 (35.4%), adjusted.

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline, substantial unadjusted confounding by indication likely.

Solh et al., 10/20/2020, retrospective, database analysis, USA, North America, preprint, 5 authors.

Mohana et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.10.031 (preprint 8/17) (Peer Reviewed)

Hydroxychloroquine Safety Outcome within Approved Therapeutic Protocol for COVID-19 Outpatients in Saudi Arabia

Safety study of 2,733 patients in Saudi Arabia showing HCQ in mild to moderate cases in an outpatient setting, within the protocol recommendation and inclusion/exclusion criteria, is safe, highly tolerable, and has minimal side effects. No ICU admission or deaths were reported.

Mohana et al., 10/17/2020, peer-reviewed, 15 authors.

Guisado-Vasco (Peer Reviewed)

Clinical characteristics and outcomes among hospitalized adults with severe COVID-19 admitted to a tertiary medical center and receiving antiviral, antimalarials, glucocorticoids, or immunomodulation with tocilizumab or cyclosporine: A retrospective observational study (COQUIMA cohort)

Retrospective 607 patients reporting results for early outpatient HCQ use with mortality odds ratio OR 0.092 [0.022-0.381], p = 0.001 (65 patients), and for hospital use, mortality odds ratio OR 0.737 [0.38-1.41], p = 0.36 (558 patients). Median age 69.

risk of death, 20.3% lower, RR 0.80, p = 0.36, treatment 127 of 558 (22.8%), control 14 of 49 (28.6%), adjusted, OR converted to RR.

outpatient use, 88.0% lower, RR 0.12, p = 0.001, treatment 2 of 65 (3.1%), control 139 of 542 (25.6%), adjusted, OR converted to RR.

Guisado-Vasco et al., 10/15/2020, retrospective, Spain, Europe, peer-reviewed, median age 69.0, 25 authors.

SOLIDARITY Trial Consortium, NEJM, doi:10.1056/NEJMoa2023184 (preprint 10/15) (Peer Reviewed)

Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results

WHO SOLIDARITY open-label trial with 954 very late stage (64% on oxygen/ventilation) HCQ patients, mortality relative risk RR 1.19 [0.89-1.59], p=0.23.

HCQ dosage very high as in RECOVERY, 1.6g in the first 24 hours, 9.6g total over 10 days, only 25% less than the high dosage that Borba et al. show greatly increases risk (OR 2.8) [1].

Authors state they do not know the weight or obesity status of patients to analyze toxicity (since they do not adjust dosage based on patient weight, toxicity may be higher in patients of lower weight).

KM curves show a spike in HCQ mortality days 5-7, corresponding to ~90% of the total excess seen at day 28 (a similar spike is seen in the RECOVERY trial).

Almost all excess mortality is from ventilated patients.

Authors refer to a lack of excess mortality in the first few days to suggest a lack of toxicity, but they are ignoring the very long half-life of HCQ and the dosing regimen - much higher levels of HCQ will be reached later. Increased mortality in Borba et al. occurred after 2 days.

An unspecified percentage used the more toxic CQ. No placebo used.

For more on the dosing problems see
[2], also noting that concentrations vary substantially in different tissues and lung concentration may be >30x plasma concentration.

[1] c19hcq.com/borba.html

[2] kristianfranciscomillanielsen.medium.com/analysis-of-the-hydroxychloroquine-dosing-regimen-in-reco..

risk of death, 19.0% higher, RR 1.19, p = 0.23, treatment 104 of 947 (11.0%), control 84 of 906 (9.3%).

Excluded in after exclusion results of meta analysis: excessive dosage in late stage patients, results do not apply to typical dosages, very late stage, >50% on oxygen/ventilation at baseline.

SOLIDARITY et al., 10/15/2020, Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, baseline oxygen requirements 64.0%, 15 authors.

Annie et al., Pharmacotherapy, doi:10.1002/phar.2467 (Peer Reviewed)

Hydroxychloroquine in hospitalized COVID‐19 patients: Real world experience assessing mortality

Retrospective database analysis with PSM not including COVID-19 severity, finding mortality OR 0.95 [0.62-1.46] for HCQ, and 1.24 [0.70-2.22] for HCQ+AZ. Confounding by indication likely.

risk of death, 4.3% lower, RR 0.96, p = 0.83, treatment 48 of 367 (13.1%), control 50 of 367 (13.6%), OR converted to RR.

risk of death, 20.5% higher, RR 1.21, p = 0.46, treatment 29 of 199 (14.6%), control 24 of 199 (12.1%), OR converted to RR.

Excluded in after exclusion results of meta analysis: confounding by indication is likely and adjustments do not consider COVID-19 severity.

Annie et al., 10/12/2020, retrospective, database analysis, USA, North America, peer-reviewed, 5 authors.

Sili et al., medRxiv, doi:10.1101/2020.10.09.20209775 (Preprint)

Factors associated with progression to critical illness in 28 days among COVID-19 patients: results from a tertiary care hospital in Istanbul, Turkey

Analysis of hospitalized patients in Turkey showing HCQ was given to 99.2% of patients and the incidence of critical illness was lower than most studies. Authors note "whether HCQ administration lowered the rates of critical illness development is beyond the scope of this study." There is no comparison with a control group.

Sili et al., 10/11/2020, Turkey, Europe, preprint, 21 authors.

Aparisi et al., medRxiv, doi:10.1101/2020.10.06.20207092 (Preprint)

Low-density lipoprotein cholesterol levels are associated with poor clinical outcomes in COVID-19

Retrospective 654 hospitalized patients focused on low-density lipoprotein cholesterol levels, also showing results for HCQ with 605 HCQ patients, unadjusted 30 day mortality relative risk RR 0.37, p = 0.008.

risk of death, 63.0% lower, RR 0.37, p = 0.008, treatment 122 of 605 (20.2%), control 27 of 49 (55.1%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Aparisi et al., 10/8/2020, prospective, Spain, Europe, preprint, 18 authors.

Soto-Becerra et al., medRxiv, doi:10.1101/2020.10.06.20208066 (Preprint)

Real-World Effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: Results of a target trial emulation using observational data from a nationwide Healthcare System in Peru

Retrospective database study of 5683 patients, 692 received HCQ/CQ+AZ, 200 received HCQ/CQ, 203 received ivermectin, 1600 received AZ, 358 received ivermectin+AZ, and 2630 received standard of care.

This study includes anyone with ICD-10 COVID-19 codes which includes asymptomatic PCR+ patients, therefore many patients in the control group are likely asymptomatic with regards to SARS-CoV-2, but in the hospital for another reason. For those that had symptomatic COVID-19, there is also likely significant confounding by indication.

In this study all medications show higher mortality at day 30, which is consistent with asymptomatic (for COVID-19) or mild condition patients being more common in the control group.

For ivermectin they show 30 day mortality aHR = 1.39 [0.88 - 2.22]. KM curves show that the treatment groups were in more serious condition, and also that after about day 35 survival became better with ivermectin. The last day available for ivermectin shows RR 0.83, p = 0.01. More than the total excess mortality happened on the first day. This is consistent with treated patients being in more serious condition, and with many of the control group patients being in hospital for something unrelated to COVID-19.

Authors use a machine learning based propensity scoring system that appears over-parameterized and likely to result in significant overfitting and inaccurate results. Essentially they test for all interactions between two and three covariates. The nature and large number of covariates means many random correlations may be found. COVID-19 severity is not used.

This study also does not compare treatments with a control group not receiving the treatment - authors put patients receiving treatments after 48 hours in the control group.

Authors state that outcomes within 24 hours were excluded, however KM curves show significant mortality at day 1 (only for the treatment groups).

Several protocol violations and missing data have also been reported in this study: [1, 2].

See also: [3].

Ivermectin dosage details: [4]

[1] trialsitenews.com/systemic-unreported-protocol-violations-in-key-ivermectin-study/

[2] trialsitenews.com/missing-data-in-soto-becerra-et-al-the-one-study-showing-worse-outcomes-with-ive..

[3] twitter.com/Covid19Crusher/status/1315461049034907650

[4] cdn.www.gob.pe/uploads/document/file/830595/RM_375-2020-MINSA.PDF

risk of death, 18.1% lower, RR 0.82, p < 0.001, treatment 346 of 692 (50.0%), control 1,606 of 2,630 (61.1%), day 54 (last day available) weighted KM.

risk of death, 84.0% higher, RR 1.84, p = 0.02, treatment 165 of 692 (23.8%), control 401 of 2,630 (15.2%), adjusted, day 30.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.

Soto-Becerra et al., 10/8/2020, retrospective, database analysis, Peru, South America, preprint, median age 59.4, 4 authors.

Ader et al., Clinical Microbiology and Infection, doi:10.1016/j.cmi.2021.05.020 (Peer Reviewed)

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

Early terminated very late stage (95% on oxygen at baseline) DISCOVERY trial. 4% more patients were on ventilation at baseline in the HCQ group.

risk of death at day 29, 6.4% lower, RR 0.94, p = 1.00, treatment 11 of 145 (7.6%), control 12 of 148 (8.1%).

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline.

Ader et al., 10/6/2020, Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, baseline oxygen requirements 95.4%, 58 authors.

Mori et al., Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2020.09.003 (Peer Reviewed)

Triple therapy with hydroxychloroquine, azithromycin, and ciclesonide for COVID-19 pneumonia

Small case study of 5 patients in Japan showing improvement with HCQ+AZ+ciclesonide.

Mori et al., 10/5/2020, peer-reviewed, 3 authors.

Prodromos et al., New Microbes and New Infections, doi:10.1016/j.nmni.2020.100776 (Peer Reviewed) (meta analysis)

Hydroxychloroquine is effective, and consistently so used early, for Covid-19: A systematic review

Meta analysis of 43 studies: "HCQ was found consistently effective against COVID-19 when used early, in the outpatient setting. It was found overall effective also including inpatient studies. No unbiased study found worse outcomes with HCQ use. No mortality or serious safety adverse event was found.

Prodromos et al., 10/5/2020, peer-reviewed, 2 authors.

Nachega et al., The American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.20-1240 (Peer Reviewed)

Clinical Characteristics and Outcomes of Patients Hospitalized for COVID-19 in Africa: Early Insights from the Democratic Republic of the Congo

Retrospective 766 hospitalized patients in DRC showing mortality reduced from 29% to 11%, and improvement at 30 days increased from 65% to 84%.

Mortality cox regression adjusted hazard ratio aHR 0.26, p < 0.001
Risk of no improvement adjusted odds ratio aOR 0.28, p < 0.001

Using marginal structural model analysis these risks became:

Mortality MSM adjusted odds ratio aOR 0.65, p = 0.166
Risk of no improvement MSM adjusted odds ratio aOR = 0.65, p = 0.132

Median age 46, 630 treated with CQ+AZ.

risk of death, 27.6% lower, RR 0.72, p = 0.17, treatment 69 of 630 (11.0%), control 28 of 96 (29.2%), adjusted, OR converted to RR.

risk of no improvement, 25.8% lower, RR 0.74, p = 0.13, adjusted, OR converted to RR.

Nachega et al., 10/2/2020, retrospective, database analysis, DR Congo, Africa, peer-reviewed, median age 46.0, 25 authors.

Almazrou et al., Saudi Pharmaceutical Journal, doi:10.1016/j.jsps.2020.09.019 (Peer Reviewed)

Comparing the impact of Hydroxychloroquine based regimens and standard treatment on COVID-19 patient outcomes: A retrospective cohort study

Retrospective 161 hospitalized patients in Saudi Arabia showing lower ventilation and ICU admission with HCQ, but not statistically significant with the small sample sizes.

risk of mechanical ventilation, 65.0% lower, RR 0.35, p = 0.16, treatment 3 of 95 (3.2%), control 6 of 66 (9.1%).

risk of ICU admission, 21.0% lower, RR 0.79, p = 0.78, treatment 8 of 95 (8.4%), control 7 of 66 (10.6%).

Almazrou et al., 10/1/2020, retrospective, Saudi Arabia, Middle East, peer-reviewed, 5 authors.

Garcia-Albeniz et al., medRxiv, doi:10.1101/2020.09.29.20203869 (Preprint) (meta analysis)

Brief communication: A meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19

Combination of the four underpowered prophylaxis RCTs to date showing statistically significant results, RR 0.78 [0.61-0.99].

The actual effect of HCQ is likely to be higher for several reasons: the trials did not adjust for losses to follow-up or other deviations from protocol. There was very long treatment delays in the postexposure prophylaxis trials - in one trial, about a third of participants were enrolled 4 days after exposure with an additional shipping delay of ~46 hours on average, in the other, participants were enrolled up to 7 days after exposure, with an unknown additional delay before treatment, and results suggesting that exposure detection was delayed.

For other reasons see: [1, 2, 3, 4].

[1] c19hcq.com/boulware.html

[2] c19hcq.com/mitjapep.html

[3] c19hcq.com/rajasingham.html

[4] c19hcq.com/abella.html

risk of case, 22.0% lower, RR 0.78, p = 0.04.

Garcia-Albeniz et al., 10/1/2020, preprint, 5 authors.

Yadav et al., ResearchGate, doi:10.13140/RG.2.2.34411.77603 (Preprint)

Sero-survey for health-care workers provides corroborative evidence for the effectiveness of Hydroxychloroquine prophylaxis against COVID-19 infection

ICMR seroprevalence survey of 500 healthcare workers in India, 279 taking HCQ prophylaxis, showing a significantly lower risk with treatment, and lower severity.

risk of hospitalization, 82.4% lower, RR 0.18, p = 0.01, treatment 2 of 279 (0.7%), control 9 of 221 (4.1%), PCR+.

risk of IgG+, 41.8% lower, RR 0.58, p = 0.05, treatment 17 of 178 (9.6%), control 27 of 221 (12.2%), OR converted to RR, multivariate logistic regression.

risk of IgG+, 79.0% lower, RR 0.21, p = 0.09, treatment 1 of 39 (2.6%), control 27 of 221 (12.2%), HCQ >10 weeks.

risk of IgG+, 52.4% lower, RR 0.48, p = 0.14, treatment 5 of 86 (5.8%), control 27 of 221 (12.2%), HCQ 6-10 weeks.

risk of IgG+, 69.9% higher, RR 1.70, p = 0.12, treatment 11 of 53 (20.8%), control 27 of 221 (12.2%), HCQ <6 weeks.

Yadav et al., 9/30/2020, retrospective, India, South Asia, preprint, 11 authors.

Polat et al., Medical Journal of Bakirkoy, 16:3, 280-6, doi:10.5222/BMJ.2020.50469 (Peer Reviewed)

Hydroxychloroquine Use on Healthcare Workers Exposed to COVID-19 -A Pandemic Hospital Experience

Small prophylaxis study of 208 healthcare workers in Turkey, 138 with high risk exposure received HCQ, while 70 with low and medium risk exposure did not. COVID-19 cases were lower in the treatment group, relative risk RR 0.43, p = 0.026. Since the control group had lower risk, the actual benefit may be larger.

risk of case, 57.0% lower, RR 0.43, p = 0.03, treatment 12 of 138 (8.7%), control 14 of 70 (20.0%).

Polat et al., 9/30/2020, prospective, Turkey, Europe, peer-reviewed, 3 authors.

Ayerbe et al., Internal and Emergency Medicine, doi:0.1007/s11739-020-02505-x (Peer Reviewed)

The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients

2075 hospital patients in Spain showing HCQ reduces mortality 52%, odds ratio OR 0.39, p<0.001, after adjustment for age, gender, temperature > 37 °C, and saturation of oxygen < 90% treatment with azithromycin, steroids, heparin, tocilizumab, a combination of lopinavir with ritonavir, and oseltamivir, and date of admission (model 4).

risk of death, 52.2% lower, RR 0.48, p < 0.001, treatment 237 of 1,857 (12.8%), control 49 of 162 (30.2%), adjusted, OR converted to RR.

Ayerbe et al., 9/30/2020, retrospective, database analysis, Spain, Europe, peer-reviewed, 3 authors.

Ladapo et al., medRxiv, doi:10.1101/2020.09.30.20204693 (Preprint) (meta analysis)

Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis

Meta analysis of prophylactic and early treatment RCTs, 24% reduction in cases, hospitalization or death with HCQ, RR 0.76, p=0.025. No serious adverse cardiac events were reported. 5,577 patients.

The Boulware study provides a breakdown for treatment delay. For the case of < ~4 days (2 days enrollment, ~46 hours shipping), the result of the meta analysis becomes RR 0.68, p=0.0097.

The actual effect may be larger due to treatment delays, followup loss, protocol deviation, active placebos, no severity analysis for cases, and suboptimal regimens.

For the individual studies see [1, 2, 3, 4, 5].

[1] c19hcq.com/boulware.html

[2] c19hcq.com/mitjapep.html

[3] c19hcq.com/rajasingham.html

[4] c19hcq.com/skipper.html

[5] c19hcq.com/mitja.html

risk of cases/death/hospitalization, 24.0% lower, RR 0.76, p = 0.03.

Ladapo et al., 9/30/2020, preprint, 4 authors.

Abella et al., JAMA Internal Medicine, doi:doi:10.1001/jamainternmed.2020.6319 (Peer Reviewed)

Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers

Very small early-terminated underpowered PrEP RCT with 64/61 HCQ/control patients and only 8 infections, HCQ infection rate 6.3% versus control 6.6%, RR 0.95 [0.25 - 3.64].

There was no hospitalization or death, no significant difference in QTc, no severe adverse events, no cardiac events (e.g., syncope and arrhythmias) observed. Medication adherence was 81%. Therapeutic levels of HCQ may not have been reached by the time of the infection in the first week.

2 infections were reported to be after discontinuation of the medication, but the authors do not specify which arm these were in. Hypothetically, if these were both in the HCQ arm, the resulting RR for treatment would be much lower.

risk of case, 5.0% lower, RR 0.95, p = 1.00, treatment 4 of 64 (6.2%), control 4 of 61 (6.6%).

Abella et al., 9/30/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 18 authors.

Lammers et al., Int. J. Infectious Diseases, doi:10.1016/j.ijid.2020.09.1460 (Peer Reviewed)

Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients

Observational study 1,064 hospitalized patients in the Netherlands, 53% reduced risk of transfer to the ICU for mechanical ventilation with HCQ treatment starting on the first day of admission.

Weighted propensity score adjusted hazard ratio for transfer to the ICU with HCQ treatment, HR = 0.47, p = 0.008. For CQ, HR = 0.8, p = 0.207. Mortality results in this study are only for mortality before transfer to the ICU. The combined ICU/death HR was 0.68, p = 0.024 for HCQ, and 0.85, p = 0.224 for CQ.

Observational, multicenter, cohort study of hospitalized COVID-19 patients. 189 HCQ patients, 377 CQ, 498 control.

risk of death/ICU, 32.0% lower, RR 0.68, p = 0.02, treatment 30 of 189 (15.9%), control 101 of 498 (20.3%), adjusted.

Lammers et al., 9/29/2020, prospective, Netherlands, Europe, peer-reviewed, 18 authors.

Dabbous et al., Scientific Reports, doi:10.1038/s41598-021-85227-0 (preprint 9/29/20) (Peer Reviewed)

Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial

This paper has been retracted [1].

[1] nature.com/articles/s41598-021-98683-5

Dabbous et al., 9/29/2020, peer-reviewed, 11 authors.

Luco, J., Trends Med, doi:10.15761/TiM.1000268 (Peer Reviewed) (meta analysis)

Hydroxychloroquine as post-exposure prophylaxis for Covid-19: Why simple data analysis can lead to the wrong conclusions from well-designed studies

Reanalysis of Boulware et al. PEP trial data showing statistically significant improvements with HCQ.

Luco et al., 9/28/2020, peer-reviewed, 1 author.

Gasperetti et al., EP Europace, doi:10.1093/europace/euaa216 (Peer Reviewed)

Arrhythmic safety of hydroxychloroquine in COVID-19 patients from different clinical settings

Safety study of 649 patients finding that HCQ administration is safe for short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths.

Arrhythmic safety data from a large cohort of patients treated with HCQ alone or in combination with other QT-prolonging drugs.

Gasperetti et al., 9/24/2020, peer-reviewed, 23 authors.

Shoaibi et al., medRxiv, doi:10.1101/2020.09.23.20199463 (Preprint)

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients

Retrospective database analysis focused on Famotidine but also showing results for HCQ users, with unadjusted mortality RR 0.85, p<0.001 (13.6% vs. 16.1%).

risk of death, 15.4% lower, RR 0.85, p < 0.001, treatment 686 of 5,047 (13.6%), control 3,923 of 24,404 (16.1%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Shoaibi et al., 9/24/2020, retrospective, database analysis, USA, North America, preprint, 5 authors.

Ulrich et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofaa446 (Peer Reviewed)

Treating Covid-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind, Randomized Controlled Trial in Hospitalized Patients

Small RCT on very late stage use of HCQ, with 48% on oxygen at baseline. 67 HCQ patients, 61 control.

Baseline states were not comparable - 82% more HCQ patients had the highest severity at baseline, there was 32% more male HCQ patients, and 44% more control patients used AZ. The HCQ group also had significantly more patients with cerebrovascular disease, cardiovascular disease (non-hypertension), renal disease (non-dialysis), and a history of organ transplants.

30 day mortality RR 1.06, p = 1.0.

risk of death, 6.0% higher, RR 1.06, p = 1.00, treatment 7 of 67 (10.4%), control 6 of 61 (9.8%).

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline.

Ulrich et al., 9/23/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, baseline oxygen requirements 63.3%, mean age 66.2, 18 authors.

Serrano et al., Ann. Oncol., 2020, Sep, 31, S1026, doi:10.1016/j.annonc.2020.08.1830 (Peer Reviewed)

COVID-19 and lung cancer: What do we know?

Small retrospective study of 22 lung cancer patients, 14 treated with HCQ+AZ, showing HCQ+AZ mortality relative risk RR 0.57, p = 0.145.

risk of death, 43.0% lower, RR 0.57, p = 0.14, treatment 6 of 14 (42.9%), control 6 of 8 (75.0%).

Serrano et al., 9/22/2020, retrospective, Spain, Europe, peer-reviewed, 8 authors.

Gentry et al., Lancet Rheumatology, doi:10.1016/S2665-9913(20)30305-2 (Peer Reviewed)

Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study

Retrospective patients with rheumatologic conditions showing zero of 10,703 COVID-19 deaths for HCQ patients versus 7 of 21,406 propensity matched control patients (not statistically significant). The average age of HCQ patients is slightly lower 64.8 versus 65.4 control.

COVID-19 cases OR 0.79, p=0.27. There are several significant differences in the propensity matched patients that could affect results, e.g., 20.9% SLE versus 24.7%.

risk of death, 91.3% lower, RR 0.09, p = 0.10, treatment 0 of 10,703 (0.0%), control 7 of 21,406 (0.0%), relative risk is not 0 because of continuity correction due to zero events, COVID-19 mortality within all patients.

risk of death, 90.7% lower, RR 0.09, p = 0.19, treatment 0 of 31 (0.0%), control 7 of 78 (9.0%), relative risk is not 0 because of continuity correction due to zero events, mortality for infected patients.

risk of case, 20.9% lower, RR 0.79, p = 0.27, treatment 31 of 10,703 (0.3%), control 78 of 21,406 (0.4%), OR converted to RR.

Gentry et al., 9/21/2020, retrospective, database analysis, USA, North America, peer-reviewed, 6 authors.

Rajasingham et al., medRxiv, doi:10.1101/2020.09.18.20197327 (Peer Reviewed)

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial

PrEP RCT showing HR 0.73, p = 0.12. Trial halted after 47% enrollment, p < 0.05 will be reached at ~75% enrollment if similar results continue.

HR 0.66/0.68 for full medication adherence, 0.72/0.74, p = 0.18/0.22 overall (1x/2x dosing). Efficacy for first responders was higher, OR 0.32, p = 0.01. First responders had a much higher incidence, allowing greater power, and reducing the effect of confounders such as misdiagnosis of other conditions or survey issues.

Performance is similar to placebo for the first 3 weeks. The effect may be greater with a dosage regimen that achieves therapeutic levels faster [1]. ~40% of participants suspected they might have had COVID-19 before the trial, the effect in people without prior COVID-19 may be higher.

Authors note:

- the trial was underpowered
- investigation into more frequent dosing may be warranted
- insufficient dosing with no participants achieving more than the in vitro EC₅₀

Internet survey RCT subject to survey bias. There were no deaths or ICU admissions. Low risk healthcare workers, median age ~40. 494 1x/week dosing, 495 2x/week dosing, 494 control participants (1x and 2x participants received the same overall dosage). COVID PREP. NCT04328467.

[1] tandfonline.com/doi/full/10.1080/00498254.2020.1824301

risk of hospitalization, 50.1% lower, RR 0.50, p = 1.00, treatment 1 of 989 (0.1%), control 1 of 494 (0.2%).

risk of case, 27.0% lower, RR 0.73, p = 0.12, treatment 58 of 989 (5.9%), control 39 of 494 (7.9%).

Rajasingham et al., 9/21/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 22 authors.

Grau-Pujol et al., Trials, doi:10.1186/s13063-021-05758-9 (Peer Reviewed)

Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a double-blind, placebo-controlled randomized clinical trial

Small PrEP RCT showing that PrEP with HCQ is safe at the dosage used. There were no deaths, hospitalizations, or serious adverse events.

The paper states: "Among all trial participants at the end of the first month (n=253), only one participant from the placebo arm (1/116, 0.8%), tested positive for SARS-CoV-2 PCR and for a SARS-CoV-2 serology test".

The abstract states: "only one participant in each group was diagnosed with COVID-19".

risk of case, 10.6% lower, RR 0.89, p = 1.00, treatment 1 of 142 (0.7%), control 1 of 127 (0.8%).

Grau-Pujol et al., 9/21/2020, Randomized Controlled Trial, Spain, Europe, peer-reviewed, 22 authors.

Lofgren et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofaa500 (preprint 9/21) (Peer Reviewed)

Safety of Hydroxychloroquine among Outpatient Clinical Trial Participants for COVID-19

Analysis of 2,795 outpatients not showing significant safety concerns with HCQ. No deaths were related to HCQ. There was one serious event requiring hospitalization, identical to the frequency with placebo.

Lofgren et al., 9/21/2020, peer-reviewed, 26 authors.

Axfors et al., Nature, doi:10.1038/s41467-021-22446-z (Peer Reviewed) (meta analysis)

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Meta analysis assigning 89% weight to the RECOVERY and SOLIDARITY trials, producing the same result. These trials used excessively high non-patient-customized dosage in very sick late stage patients, results are not generalizable to typical dosage or earlier treatment.

For CQ, this study assigns 97% weight to Borba et al., however this study does not have a control group, comparing two different dosages of CQ.

Of the 29 early treatment trials (including 6 RCTs), authors include the results of only one where they include a non-hospitalized death.

Axfors et al., 9/18/2020, peer-reviewed, 97 authors.

Karatza et al., Xenobiotica (Peer Reviewed)

Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients’ characteristics: a review of the literature and simulations

Analysis of HCQ dosing, suggesting that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects.

For instance, the dosing scheme proposed for a 70kg adult with moderate COVID-19 symptoms would be 600mg upon diagnosis, 400mg after 12h, 300mg after 24h, 200mg after 36h, followed by 200mg BID for 4 days, followed by 200mg OD for 5 days.

Suboptimal dosing regimens that do not fully account for the long half-life of HCQ or the patient characteristics are likely contribute to either limited efficacy where therapeutic levels take too long to reach, or significant adverse effects due to excessive dosage.

Karatza et al., 9/16/2020, peer-reviewed, 4 authors.

Ashinyo et al., Pan African Medical Journal, 37:1, doi:10.11604/pamj.supp.2020.37.1.25718 (Peer Reviewed)

Clinical characteristics, treatment regimen and duration of hospitalization among COVID-19 patients in Ghana: a retrospective cohort study

Retrospective 307 hospital patients in Ghana showing 33% reduction in hospitalization time with HCQ, 29% reduction with HCQ+AZ, and 37% reduction with CQ+AZ.

hospitalization time, 33.0% lower, relative time 0.67, p = 0.03, treatment 61, control 61.

Ashinyo et al., 9/15/2020, retrospective, Ghana, Africa, peer-reviewed, 16 authors.

Lauriola et al., Clinical and Translational Science, doi:10.1111/cts.12860 (Peer Reviewed)

Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in COVID‐19 patients

Retrospective 377 patients, 73% reduction in mortality with HCQ+AZ, adjusted hazard ratio HR 0.27 [0.17-0.41]. Mean age 71.8. No serious adverse events. Subject to incomplete adjustment for confounders.

risk of death, 73.5% lower, RR 0.27, p < 0.001, treatment 102 of 297 (34.3%), control 35 of 63 (55.6%), adjusted.

Lauriola et al., 9/14/2020, retrospective, Italy, Europe, peer-reviewed, mean age 71.8, 10 authors.

Sulaiman et al., medRxiv, doi:10.1101/2020.09.09.20184143 (Preprint)

The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study

Observational prospective 5,541 patients, adjusted HCQ mortality odds ratio OR 0.36, p = 0.012. Adjusted hospitalization OR 0.57, p < 0.001. Zinc supplementation was used in all cases. Early treatment in ambulatory fever clinics in Saudi Arabia.

risk of death, 63.7% lower, RR 0.36, p = 0.01, treatment 7 of 1,817 (0.4%), control 54 of 3,724 (1.5%), adjusted, OR converted to RR.

risk of hospitalization, 38.6% lower, RR 0.61, p = 0.001, treatment 171 of 1,817 (9.4%), control 617 of 3,724 (16.6%), adjusted, OR converted to RR.

Sulaiman et al., 9/13/2020, prospective, Saudi Arabia, Middle East, preprint, 22 authors, dosage 400mg bid day 1, 200mg bid days 2-5.

Heberto et al., IJC Heart & Vasculature, doi:10.1016/j.ijcha.2020.100638 (Peer Reviewed)

Implications of myocardial injury in Mexican hospitalized patients with coronavirus disease 2019 (COVID-19)

Observational prospective 254 hospitalized patients, HCQ+AZ mortality odds ratio OR 0.36, p = 0.04. Ventilation OR 0.20, p = 0.008.

risk of death, 53.9% lower, RR 0.46, p = 0.04, treatment 139, control 115, OR converted to RR.

risk of mechanical ventilation, 65.1% lower, RR 0.35, p = 0.008, treatment 139, control 115, OR converted to RR.

Heberto et al., 9/12/2020, prospective, Mexico, North America, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary.

Alamdari et al., Tohoku J. Exp. Med., 2020, 252, 73-84, doi:10.1620/tjem.252.73 (Peer Reviewed)

Mortality Risk Factors among Hospitalized COVID-19 Patients in a Major Referral Center in Iran

Retrospective 459 patients in Iran with 93% treated with HCQ, showing HCQ mortality RR 0.45, p = 0.028. HCQ was the only antiviral that showed a significant difference. There was relatively few control patients and the result is subject to confounding by indication. Average admission delay 5.72 days.

risk of death, 55.0% lower, RR 0.45, p = 0.03, treatment 54 of 427 (12.6%), control 9 of 32 (28.1%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Alamdari et al., 9/9/2020, retrospective, Iran, Middle East, peer-reviewed, 14 authors.

Kirenga et al., BMJ Open Respiratory Research, doi:10.1136/bmjresp-2020-000646 (Peer Reviewed)

Characteristics and outcomes of admitted patients infected with SARS-CoV-2 in Uganda

Prospective 56 patients in Uganda, 29 HCQ and 27 control, showing 25.6% faster recovery with HCQ, 6.4 vs. 8.6 days (p = 0.20). There was no ICU admission, mechanical ventilation, or death.

Treatment delay is not specified but at least a portion of patients appear to have been treated early.

median time to recovery, 25.6% lower, relative time 0.74, p = 0.20, treatment 29, control 27.

Kirenga et al., 9/9/2020, prospective, Uganda, Africa, peer-reviewed, 29 authors, dosage not specified.

Rentsch et al., The Lancet Rheumatology, doi:10.1016/S2665-9913(20)30378-7 (preprint 9/9, https://www.medrxiv.org/content/10.1101/2020.09.04.20187781v1) (Peer Reviewed)

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform

Observational database study of RA/SLE patients in the UK, 194,637 RA/SLE patients with 30,569 having >= 2 HCQ prescriptions in the prior 6 months, HCQ HR 1.03 [0.80-1.33] (HR 0.78 before adjustments).

70 patients with HCQ prescriptions died. One major problem is that there is no knowlege of medication adherence for these 70 - for example, it is possible that they were part of the expected percentage of patients that did not take the medication as prescribed, invalidating the result. Other limitations include confounding by use of bDMARDs and confounding by severity of rheumatological disease.

risk of death, 3.0% higher, RR 1.03, p = 0.83, treatment 70 of 30,569 (0.2%), control 477 of 164,068 (0.3%), adjusted.

Excluded in after exclusion results of meta analysis: not fully adjusting for the baseline risk differences within systemic autoimmune patients, medication adherence unknown and may significantly change results.

Rentsch et al., 9/9/2020, retrospective, population-based cohort, database analysis, United Kingdom, Europe, peer-reviewed, 34 authors.

Laplana et al., PLOS ONE, doi:10.1371/journal.pone.0243598 (Peer Reviewed)

Lack of protective effect of chloroquine derivatives on COVID-19 disease in a Spanish sample of chronically treated patients

Survey of 319 autoimmune disease patients taking CQ/HCQ with 5.3% COVID-19 incidence, compared to a control group from the general population (matched on age, sex, and region, but not adjusted for autoimmune disease), with 3.4% incidence.

It not clear why authors did not compare with autoimmune patients not on CQ/HCQ. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1], which is the observed real-world risk, taking into account factors such as these patients potentially being more careful to avoid exposure. If we adjust for the different baseline risk, the result becomes RR 0.36, p<0.001, suggesting a substantial benefit for HCQ/CQ treatment (as shown in other studies).

There may also be significant survey bias - those experiencing COVID-19 may be more likely to respond to the survey.

Authors note that they "could not eliminate completely the possibility of some bias due to the intrinsic condition of the individuals within the treatment group that are undergoing chloroquine or derivative drug treatment due to other diseases that alter their health status and may have different comorbidities", however they could account for one significant bias by comparing with matched autoimmune disease patients.

[1] c19hcq.com/ferri.html

risk of case, 56.0% higher, RR 1.56, p = 0.24, treatment 17 of 319 (5.3%), control 11 of 319 (3.4%).

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Laplana et al., 9/9/2020, retrospective, Spain, Europe, peer-reviewed, survey, 3 authors.

IHU, Expert Review of Clinical Immunology (Review) (Peer Reviewed)

Natural history and therapeutic options for COVID-19

Review of the current state of knowledge regarding the natural history of and therapeutic options for COVID-19.

Treatment with an oral combination of hydroxychloroquine, azithromycin and zinc may represent the best current therapeutic option in relation to its antiviral and
immunomodulatory effects.

IHU et al., 9/7/2020, peer-reviewed, 1 author.

Synolaki et al., medRxiv, doi:10.1101/2020.09.05.20184655 (Preprint)

The Activin/Follistatin-axis is severely deregulated in COVID-19 and independently associated with in-hospital mortality

Retrospective 117 patients, 58 HCQ showing lower mortality for HCQ patients.

Version 1 of this paper stated: "HCQ, AZ, [and ...] were found to be independently associated with survival when treatment commenced at FACTCLINYCoD scores <3".

risk of death, 23.6% lower, RR 0.76, p = 0.27, treatment 21 of 98 (21.4%), control 60 of 214 (28.0%).

Synolaki et al., 9/5/2020, retrospective, Greece, Europe, preprint, 20 authors.

Furtado et al., The Lancet, doi:10.1016/S0140-6736(20)31862-6 (Peer Reviewed)

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

Small RCT comparing the addition of AZ for very late stage patients on ventilation or oxygen. No significant difference was found, OR 1.36, p=0.11. One notable result is that even within this extremely late stage population, results suggest increased efficacy with the addition of AZ for patients with earlier use of AZ/HCQ, OR 0.71, p=0.28.

Patients received 8g of HCQ over 10 days, approaching the high levels used in the RECOVERY trial (9.2g over 10 days), showing significantly more adverse events than typical trials.

Since all patients were on HCQ, this study does not provide information on the efficacy of HCQ.

Furtado et al., 9/4/2020, peer-reviewed, 33 authors.

Wang et al., Phytomedicine, doi:10.1016/j.phymed.2020.153333 (Peer Reviewed) (In Vitro)

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus

In Vitro study providing novel insights into the molecular mechanism of CQ/HCQ treatment, showing that CQ and HCQ both inhibit the entrance of 2019-nCoV into cells by blocking the binding of the virus with ACE2.

Wang et al., 9/2/2020, peer-reviewed, 34 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Heras et al., European Geriatric Medicine, doi:10.1007/s41999-020-00432-w (preprint 9/2) (Peer Reviewed)

COVID-19 mortality risk factors in older people in a long-term care center

Retrospective 100 elderly nursing home patients, HCQ+AZ mortality 11.4% vs. control 61.9%, RR 0.18, p<0.001. Median age 85.

COVID-19 confirmed. 70% treated with HCQ+AZ. Details of differences between groups are not provided, and no adjustments are made. It is not clear how the groups were selected. Authors indicate treatment was early but do not specify the treatment delay.

risk of death, 95.6% lower, RR 0.04, p = 0.004, treatment 8 of 70 (11.4%), control 16 of 30 (53.3%), adjusted.

Heras et al., 9/2/2020, retrospective, Andorra, Europe, peer-reviewed, median age 85.0, 13 authors, dosage not specified.

de la Iglesia et al., medRxiv, doi:10.1101/2020.08.31.20185314 (Preprint)

Hydroxicloroquine for pre-exposure prophyylaxis for SARS-CoV-2

Analysis of autoimmune disease patients on HCQ, compared to a control group from the general population (matched on age and sex, but not adjusted for autoimmune disease), showing non-significant differences between groups.

Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1], which is the observed real-world risk, taking into account factors such as these patients potentially being more careful to avoid exposure.

If we adjust for the different baseline risk, the mortality result becomes RR 0.35, p=0.23, suggesting a substantial benefit for HCQ treatment (as shown in other studies).

[1] c19hcq.com/ferri.html

risk of hospitalization, 50.0% higher, RR 1.50, p = 1.00, treatment 3 of 687 (0.4%), control 2 of 688 (0.3%).

risk of case, 42.6% higher, RR 1.43, p = 0.15, treatment 42 of 648 (6.5%), control 30 of 660 (4.5%), suspected COVID-19.

risk of case, 7.8% lower, RR 0.92, p = 0.84, treatment 12 of 678 (1.8%), control 13 of 677 (1.9%), confirmed COVID-19.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

de la Iglesia et al., 9/2/2020, retrospective, database analysis, Spain, Europe, preprint, 17 authors.

Hecel et al., Pharmaceuticals, 13:9, 228, doi:10.3390/ph13090228 (Review) (Peer Reviewed)

Zinc(II)—The Overlooked Éminence Grise of Chloroquine’s Fight against COVID-19?

Review of zinc as an inhibitor of SARS-CoV-2′s RNA-dependent RNA polymerase, and zinc ionophores including CQ/HCQ, showing the latest evidence for zinc and CQ/HCQ having antiviral, and in particular anticoronaviral action.

Hecel et al., 9/1/2020, peer-reviewed, 11 authors.

Elbazidi et al., New Microbes and New Infections, doi:10.1016/j.nmni.2020.100749 (Peer Reviewed)

Pandemic and social changes, political fate

Analysis of US states and countries. Country analysis shows a significant correlation between the dates of decisions to adopt/decline HCQ, and corresponding trend changes in CFR. US state analysis shows a significant correlation between CFR and the level of acceptance of HCQ.

Elbazidi et al., 9/1/2020, peer-reviewed, 2 authors.

Albani et al., J, Clinical Medicine, doi:10.3390/jcm9092800 (Peer Reviewed)

Impact of Azithromycin and/or Hydroxychloroquine on Hospital Mortality in COVID-19

Retrospective 1376 hospitalized patients in Italy, 211 treated with HCQ and 166 with HCQ+AZ.

risk of death, 18.4% lower, RR 0.82, p = 0.15, treatment 60 of 211 (28.4%), control 172 of 605 (28.4%), adjusted, OR converted to RR, HCQ vs. neither.

risk of death, 9.0% higher, RR 1.09, p = 0.54, treatment 60 of 211 (28.4%), control 172 of 605 (28.4%), adjusted, OR converted to RR, HCQ+AZ vs. neither.

risk of ICU admission, 9.2% higher, RR 1.09, p = 0.70, treatment 73 of 211 (34.6%), control 46 of 605 (7.6%), adjusted, OR converted to RR, HCQ vs. neither.

risk of ICU admission, 71.3% higher, RR 1.71, p < 0.001, treatment 73 of 211 (34.6%), control 46 of 605 (7.6%), adjusted, OR converted to RR, HCQ+AZ vs. neither.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial time varying confounding likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Albani et al., 8/30/2020, retrospective, Italy, Europe, peer-reviewed, 11 authors.

Castillo et al., Journal of Steroid Biochemistry and Molecular Biology, 203, October 2020, doi:10.1016/j.jsbmb.2020.105751 (Peer Reviewed)

Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study

RCT on calcifediol (25-hydroxyvitamin D) treatment for hospitalized COVID-19 patients showing significantly reduced intensive care unit admissions. All patients received standard care including HCQ+AZ. Significantly lower ICU admission with the addition of calcifediol - adjusted odds ratio 0.03 [0.003-0.25]. No deaths for calcifediol (0/50), 2 deaths for SOC (2/26).

Castillo et al., 8/29/2020, peer-reviewed, 7 authors.

Fried et al., Clinical Infectious Disease, doi:10.1093/cid/ciaa1268 (Peer Reviewed)

Patient Characteristics and Outcomes of 11,721 Patients with COVID19 Hospitalized Across the United States

Database analysis of 11,721 hospitalized patients, 4,232 on HCQ. Strong evidence for confounding by indication and compassionate use of HCQ. 24.9% of HCQ patients were on mechanical ventilation versus 12.2% control. Ventilation mortality was 70.5% versus 11.6%.

This study does not adjust for the differences in comorbid conditions and disease severity, and therefore does not make a conclusion. Unadjusted HCQ mortality was 24.8% versus control 19.6%. Adjusting for ventilation only gives us 17.7% HCQ versus 19.6% control (adjusting the HCQ group to have the same proportion of ventilation patients), RR 0.90. Hopefully authors can do a full adjustment analysis. Comorbidities may favor control, while patients remaining in the hospital (5.3%) may favor HCQ (other studies show faster resolution for HCQ patients).

Data inconsistencies have been found in this study, for example 99.4% of patients treated with HCQ were treated in urban hospitals, compared to 65% of untreated patients (Supplemental Table 3), while patients are distributed in a more balanced manner between teaching or not-teaching hospitals, as well as in the most urbanized (Northeast) and less urbanized (Midwest) regions of the United States [1].

[1] academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1618/5934822

risk of death, 27.0% higher, RR 1.27, p < 0.001, treatment 1,048 of 4,232 (24.8%), control 1,466 of 7,489 (19.6%).

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups, substantial unadjusted confounding by indication likely.

Fried et al., 8/28/2020, retrospective, database analysis, USA, North America, peer-reviewed, 11 authors.

Ferri at al., Clinical Rheumatology, doi:0.1007/s10067-020-05334-7 (Peer Reviewed)

COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series

Analysis of 1641 systemic autoimmune disease patients showing csDMARD (HCQ etc.) RR 0.37, p=0.015.

csDMARDs include HCQ, CQ, and several other drugs, so the effect of HCQ/CQ alone could be higher.

This study also confirms that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, OR 4.42, p<0.001 (this is the observed real-world risk which takes into account factors such as these patients potentially being more careful to avoid exposure).

(results are for "definite + highly suspected" cases and the main result is presented in the paper as the OR for not taking csDMARDs, we have converted this to RR for taking csDMARDs).

risk of COVID-19 case, 63.0% lower, RR 0.37, p = 0.01, treatment 9 of 994 (0.9%), control 16 of 647 (2.5%).

Ferri et al., 8/27/2020, retrospective, Italy, Europe, peer-reviewed, survey, 29 authors.

Fiolet et al., Clinical Microbiology and Infection (Peer Reviewed) (meta analysis)

Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis

Meta analysis of late stage studies (and one early treatment study with only 2 deaths), showing HCQ RR 0.83 [0.65-1.06], before exclusions RR 0.80 [0.65-1.0].

Authors claim "HCQ alone is not effective", but the result directly contradicts this, RR 0.83 [0.65-1.06], i.e., inconclusive but much more likely to be effective than not.

There are many errors in this meta analysis which introduce critical bias, for example:

- Very biased sample of studies, including <4% of early treatment studies (only 1), and <30% of late treatment studies, focused on negative studies.

- Arshad et al. (propensity matched HR 0.49, p=0.009) was excluded because the authors claim a "critical" risk of confounding bias due to steroid use, however steroids were controlled for in the multivariate and propensity analyses [1].

- For Skipper et al., authors use an RR of 1.01, however the study had one hospitalized control death and one non-hospitalized HCQ death. Since the HCQ death was non-hospitalized, it may not be caused by COVID-19, or the patient did not receive standard care, therefore this should not be treated as equal to the control death. Further, medication adherence was only 77%, the HCQ patient may not have taken the medication (Skipper et al. neglects to answer this question). In any case, including a trial with only 1-2 deaths is likely to increase bias.

- Cavalcanti et al. received the lowest bias rating, despite having treatment delayed up to 14 days after symptoms, randomizing 14% of patients in the ICU, having significant protocol deviations, unusually low medication adherence, randomization that resulted in 64.3% male patients (HCQ) vs. 54.2% (control), and excluding patients already receiving longer and potentially therapeutic doses of the study treatments.

- Sbidian el al. received the lowest bias rating, however many more control patients are still in hospital at 28 days suggesting there will be a significant improvement when extending past 28 days.

- The RECOVERY trial received the lowest bias rating, despite using a very high dose likely responsible for the increased mortality. Results of this trial are not relevant to use at normal dosages.

- Inclusion criteria required RT-PCR confirmed cases, but this was disregarded when including Horby et al. (very negative, excessive dose) and Skipper et al.

- Authors do not consider different treatment delays, risk level of patients, differences in dosage, or usage of Zinc.

Also see many other reports of problems and fatal flaws: [2, 3, 4, 5, 6]

This analysis is also missing several recent studies, for a more up-to-date analysis see [7].

[1] ijidonline.com/article/S1201-9712(20)30604-4/fulltext

[2] clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30649-2/fulltext

[3] mediterranee-infection.com/wp-content/uploads/2020/04/Response-to-Fiolet-et-al-Manuscript.pdf

[4] francesoir.fr/societe-sante/covid-19-les-anti-hydroxychloroquine-et-une-certaine-science-francaise..

[5] twitter.com/Covid19Crusher/status/1299746474478243841

[6] twitter.com/Covid19Crusher/status/1321426322049142791

[7] c19hcq.com/ihu.html

Fiolet et al., 8/26/2020, peer-reviewed, 6 authors.

Ip et al., BMC Infectious Diseases, doi:10.1186/s12879-021-05773-w (preprint 8/25) (Peer Reviewed)

Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: A multi-center observational study

Retrospective 1,274 outpatients, 47% reduction in hospitalization with HCQ with propensity matching, HCQ OR 0.53 [0.29-0.95]. Sensitivity analyses revealed similar associations.

Adverse events were not increased (2% QTc prolongation events, 0% arrhythmias).

risk of death, 54.5% lower, RR 0.45, p = 0.43, treatment 2 of 97 (2.1%), control 44 of 970 (4.5%).

risk of ICU admission, 28.6% lower, RR 0.71, p = 0.79, treatment 3 of 97 (3.1%), control 42 of 970 (4.3%).

risk of hospitalization, 37.3% lower, RR 0.63, p = 0.04, treatment 21 of 97 (21.6%), control 305 of 970 (31.4%), adjusted, OR converted to RR.

Ip et al., 8/25/2020, retrospective, database analysis, USA, North America, peer-reviewed, 25 authors, dosage not specified.

Di Castelnuovo et al., European J. Internal Medicine, doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed)

Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study

Retrospective 3,451 hospitalized patients, 30% reduction in mortality with HCQ after propensity adjustment, HR 0.70 [0.59 - 0.84].

risk of death, 30.0% lower, RR 0.70, p < 0.001, treatment 386 of 2,634 (14.7%), control 90 of 817 (11.0%), adjusted.

Di Castelnuovo et al., 8/25/2020, retrospective, Italy, Europe, peer-reviewed, 110 authors.

Catteau et al., Int. J. Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106144 (Peer Reviewed)

Low-dose Hydroxychloroquine Therapy and Mortality in Hospitalized Patients with COVID-19: A Nationwide Observational Study of 8075 Participants

Retrospective 8,075 hospitalized patients, 4,542 low-dose HCQ, 3,533 control. 35% lower mortality for HCQ (17.7% vs. 27.1%), adjusted HR 0.68 [0.62–0.76]. Low-dose HCQ monotherapy was independently associated with lower mortality in hospitalized patients.

Patients exposed to others therapies (TCZ, AZ, LPV/RTV) were excluded.

Statistical analysis was performed by an independent group. Calendar time of prescription and immortal time bias was taken into account. Corticosteroids prescriptions was low in both groups.

risk of death, 32.0% lower, RR 0.68, p < 0.001, treatment 804 of 4,542 (17.7%), control 957 of 3,533 (27.1%).

Catteau et al., 8/24/2020, retrospective, database analysis, Belgium, Europe, peer-reviewed, 11 authors.

Pasquini et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkaa321 (Peer Reviewed)

Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU

Retrospective 51 ICU patients under mechanical ventilation, 33 treated with HCQ, showing unadjusted lower mortality with treatment.

risk of death, 16.4% lower, RR 0.84, p = 0.34, treatment 23 of 33 (69.7%), control 15 of 18 (83.3%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Pasquini et al., 8/23/2020, retrospective, Italy, Europe, peer-reviewed, 9 authors.

Ly et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106219 (preprint 8/21) (Peer Reviewed)

Pattern of SARS-CoV-2 infection among dependant elderly residents living in retirement homes in Marseille, France, March-June 2020

Retrospective analysis of retirement homes, HCQ+AZ >= 3 days mortality OR 0.37, p=0.02. 1690 elderly residents (mean age 83), 226 infected residents, 116 treated with HCQ+AZ >= 3 days.

Detection via mass screening also showed significant improvements (16.9% vs. 40.6%, OR 0.20, p=0.001), suggesting that earlier detection and treatment is more successful.

risk of death, 55.6% lower, RR 0.44, p = 0.02, treatment 18 of 116 (15.5%), control 29 of 110 (26.4%), adjusted, OR converted to RR.

Ly et al., 8/21/2020, retrospective, France, Europe, peer-reviewed, mean age 83.0, 21 authors, dosage 200mg tid days 1-10.

Lane et al., The Lancet Rheumatology, doi:10.1016/S2665-9913(20)30276-9 (Peer Reviewed)

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study

Retrospective study of RA patients using HCQ vs. sulfasalazine (another DMARD). HCQ treatment showed no increased risk in the short term (up to 30 days) among patients with RA. Long term use was associated with excess cardiovascular mortality.

Addition of AZ increased the risk of cardiovascular mortality with combined use up to 30 days. This is several times longer than typical COVID-19 use. This result also comes from just 2 of the 14 databases, with the negative result from just one database (VA) and much lower statistically insignifant difference in mortality from the other database (Clinformatics).

Confounding by indication. Patients conditions vary, the severity of a patient's RA or other conditions was not taken into account. Results varied widely across different databases, and different subsets of databases were used in different analyses. Baseline risk of serious adverse events unknown. Health care database analysis subject to misclassification errors.

Lane et al., 8/21/2020, peer-reviewed, 62 authors.

Gonzalez et al., medRxiv, doi:10.1101/2020.08.18.20172874 (Preprint)

The Prognostic Value of Eosinophil Recovery in COVID-19: A Multicentre, Retrospective Cohort Study on Patients Hospitalised in Spanish Hospitals

Retrospective study focused on eosinophil recovery with 9,644 hospitalized patients in Spain, showing lower mortality for HCQ (14.7% vs 29.2%, p<0.001), and AZ (15.3% vs. 18.4%, p<0.001). With a multivariate model including potential confounding factors, HCQ and AZ are associated with lower mortality, HCQ OR 0.662, p=0.057.

risk of death, 26.6% lower, RR 0.73, p = 0.06, treatment 1,246 of 8,476 (14.7%), control 341 of 1,168 (29.2%), adjusted, OR converted to RR.

Gonzalez et al., 8/21/2020, retrospective, database analysis, Spain, Europe, preprint, 25 authors.

Dubernet et al., J. Global Antimicrobial Resistance, doi:10.1016/j.jgar.2020.08.001 (Peer Reviewed)

A comprehensive strategy for the early treatment of COVID-19 with azithromycin/hydroxychloroquine and/or corticosteroids: results of a retrospective observational study in the French overseas department of Reunion Island

Retrospective analysis of 36 hospitalized patients showing HCQ/AZ associated with lower ICU admission, p=0.008. Median age 66, no mortality. Confounding by indication, however it was patients with hypoxemic pneumonia that were treated with HCQ/AZ, patients were not treated with HCQ/AZ if they didn't need oxygen therapy.

risk of ICU admission, 87.6% lower, RR 0.12, p = 0.008, treatment 1 of 17 (5.9%), control 9 of 19 (47.4%).

Dubernet et al., 8/20/2020, retrospective, France, Europe, peer-reviewed, median age 66.0, 20 authors.

Prodromos, C., New Microbes and New Infections, doi:10.1016/j.nmni.2020.100747 (Peer Reviewed)

Hydroxychloroquine is protective to the heart, not harmful: A systematic review

Review concluding that HCQ/AZ does not cause Torsade de Pointes or related deaths, HCQ decreases cardiac events, and HCQ should not be restricted in use for COVID-19 patients because of fear of cardiac mortality.

Prodromos et al., 8/20/2020, peer-reviewed, 3 authors.

Pinato et al., Cancer Discovery, doi:10.1158/2159-8290.CD-20-0773 (Peer Reviewed)

Clinical portrait of the SARS-CoV-2 epidemic in European cancer patients

Restrospective 890 cancer patients with COVID-19, adjusted mortality HR for HCQ/CQ 0.41, p<0.0001.

Confirmed SARS-CoV-2 infection was required, which may help focus on more severe cases. Analysis with Cox proportional hazard model. Potential unmeasured confounders.

risk of death, 59.0% lower, RR 0.41, p < 0.001, treatment 30 of 182 (16.5%), control 181 of 446 (40.6%).

Pinato et al., 8/18/2020, retrospective, multiple countries, multiple regions, peer-reviewed, 64 authors.

Peters et al., Clinical Microbiology and Infection, doi:10.1016/j.cmi.2020.10.004 (preprint 8/15) (Peer Reviewed)

Outcomes of Persons With COVID-19 in Hospitals With and Without Standard Treatment With (Hydroxy)chloroquine

Retrospective study of HCQ use in 9 hospitals in the Netherlands, showing no significant difference in mortality with HCQ/CQ or dexamethasone. Late stage (admitted to hospital with positive test or CT scan abnormalities). 4 of 7 hospitals started treatment only after further deterioration. Short cutoff (21 days) - other studies have shown treated patient cases resolved faster and more control patients remaining in hospital at this time.

In the preprint, 58 of 341 control patients died. In the journal version, 53 of 353 control patients died.

Significant differences between hospitals - HCQ hospitals had significantly older patients with significantly more comorbidities. Non-HCQ hospitals were "tertiary academic centres" whereas HCQ hospitals were "secondary care hospitals". Residual confounding likely. This study compares overcrowded regular hospitals with undercrowded academic hospitals.

A subset of patients were excluded due to transfer to other hospitals. This introduces bias because patients in critical condition are not transferred. For examples, patients benefiting from HCQ treatment may have been transferred to the tertiary centres and excluded from analysis, increasing the percentage of critical cases in the secondary hospitals.

Among the seven (H)CQ-hospitals, the timing of start of (H)CQ treatment differed; three hospitals started at the moment of COVID-19 diagnosis, four started after diagnosis but only when patients clinically deteriorated e.g., when there was an increase in respiratory rate or increase in use of supplemental oxygen.

Most patients received CQ instead of the safer HCQ, receiving late treatment with CQ. Patients were given an initial dose of 600mg CQ then every 12 hours, for 5 days a dose of 300 mg, for a total of 3600mg CQ. This dose is likely to be toxic, see for example [1].

Authors mention a subset of hospitals started treatment relatively earlier, which seems like the most important area to analyze, but no results are provided.

[1] apps.who.int/iris/bitstream/handle/10665/65773/WHO_MAL_79.906.pdf

risk of death, 9.0% higher, RR 1.09, p = 0.57, treatment 419 of 1,596 (26.3%), control 53 of 353 (15.0%), adjusted.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Peters et al., 8/15/2020, retrospective, Netherlands, Europe, peer-reviewed, 21 authors.

Abd-Elsalam et al., American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.20-0873 (Peer Reviewed)

Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study

Small RCT in Egypt with 97/97 HCQ/control patients, showing 58% more recovery @28days for HCQ (53.6% HCQ, 34% control), p=0.009 (0.06 in the paper refers to the 5 combined recovery/death/ICU values).

No significant difference in ventilation and mortality (<=6 examples in each case). Authors note the "sample size was not adequately powered for [the] survival endpoint".

Other studies have also shown treated patient cases resolved faster. Continuing analysis past 28 days would be useful. Group characteristics are given, with for example 36% vs. 26% smokers, but they do not identify which group is which. Group 1 and 2 have 97 patients but the total given is 175.

risk of death, 20.0% higher, RR 1.20, p = 1.00, treatment 6 of 97 (6.2%), control 5 of 97 (5.2%).

risk of no recovery at day 28, 30.0% lower, RR 0.70, p = 0.009, treatment 45 of 97 (46.4%), control 64 of 97 (66.0%).

Abd-Elsalam et al., 8/14/2020, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 10 authors.

Roomi et al., J. Medical Internet Research, doi:10.2196/21758 (Peer Reviewed)

Efficacy of hydroxychloroquine and tocilizumab in patients with COVID-19: A single-center retrospective chart review

Retrospective 176 hospitalized patients (144 HCQ, 32 control) showing no significant differences with HCQ or TCZ. Confounding by indication.

risk of death, 37.7% higher, RR 1.38, p = 0.54, treatment 13 of 144 (9.0%), control 6 of 32 (18.8%), adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Roomi et al., 8/13/2020, retrospective, USA, North America, peer-reviewed, 11 authors.

Tarek et al., European Journal of Drug Metabolism and Pharmacokinetics, doi:10.1007/s13318-020-00640-6 (Peer Reviewed)

Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention

In Silico analysis of HCQ treatment showing concluding that HCQ may affect viral clearance if administered early enough when the virus is still confined to the pharyngeal cavity; HCQ's effects against SARS-CoV-2 might be exerted more through enhanced cell-mediated immunity than direct antiviral effects; and the effects of HCQ on SARS-CoV-2 viral load may be missed in clinical trials if measurements are not done at the peak of viral replication; and the effects are only evident at dosages able to guarantee a certain plasma drug concentration, i.e., > 400 mg/day.

Tarek et al., 8/11/2020, peer-reviewed, 2 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Bakhshaliyev et al., J. Electrocardiology, doi:10.1016/j.jelectrocard.2020.08.008 (Peer Reviewed)

The effect of 5-day course of hydroxychloroquine and azithromycin combination on QT interval in non-ICU COVID19(+) patient

Safety study of 109 patients showing 5 days of HCQ+AZ did not lead to clinically significant QT prolongation or other conduction delays compared to baseline ECG in non-ICU patients.

Bakhshaliyev et al., 8/11/2020, peer-reviewed, 5 authors.

Saleemi et al., medRxiv, doi:10.1101/2020.08.05.20151027 (Preprint)

Time to negative PCR from symptom onset in COVID-19 patients on Hydroxychloroquine and Azithromycin - A real world experience

Retrospective 65 HCQ+AZ, 20 control patients, showing median time to negative PCR of 23 days for HCQ+AZ vs. 19 days for control. Confounding by indication. 100% of non-HCQ group had mild disease vs. 63% of the HCQ+AZ group. More comorbidities and symptoms in the HCQ+AZ group.

median time to PCR-, 21.0% higher, relative time 1.21, p < 0.05, treatment 65, control 20.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Saleemi et al., 8/11/2020, retrospective, Saudi Arabia, Middle East, preprint, 5 authors.

Lopez et al., Int. J. Antimicrob. Agents, doi:/j.ijantimicag.2020.106136 (Peer Reviewed)

Effects of Hydroxychloroquine on Covid-19 in Intensive Care Unit Patients: Preliminary Results

Small retrospective study of 29 ICU patients comparing those with HCQ plasma concentration within target to those with a concentration below the target value, with no significant differences found. Mortality in the on-target group was 0% versus 17% for the off-target group, mortality relative risk 0.14, p = 0.16.

Lopez et al., 8/8/2020, peer-reviewed, 8 authors.

Salvarani et al., Arthritis & Rheumatology, doi:10.1002/art.41475 (Peer Reviewed)

Susceptibility to COVID‐19 in Patients Treated With Antimalarials: A Population‐Based Study in Emilia‐Romagna, Northern Italy

Comparison of CQ/HCQ users with the general population in a region of Italy, showing no significant difference in the probability of COVID-19.

CQ/HCQ users were mostly systemic autoimmune disease patients and authors do not adjust for the very different baseline risk for these patients. Other research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall, Ferri et al. show OR 4.42, p<0.001 [1].

[1] c19hcq.com/ferri.html

risk of case, 6.0% lower, RR 0.94, p = 0.75, RR approximated with OR.

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Salvarani et al., 8/6/2020, retrospective, population-based cohort, Italy, Europe, peer-reviewed, 18 authors.

McCullough et al., The American Journal of Medicine, doi:10.1016/j.amjmed.2020.07.003 (Review) (Peer Reviewed)

Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection

Review of pathophysiological principles related to early outpatient treatment and therapeutic approaches including reduction of reinoculation, combination antiviral therapy, immunomodulation, antiplatelet/antithrombotic therapy, and administration of oxygen, monitoring, and telemedicine.

Proposes an algorithm based on age and comorbidities that allows for a large proportion to be monitored and treated at home during self-isolation with the aim of reducing the risks of hospitalization and death.

McCullough et al., 8/6/2020, peer-reviewed, 23 authors.

Watanabe et al., Open Letter (Letter) (meta analysis)

Concerns regarding the misinterpretation of statistical hypothesis testing in clinical trials for COVID-19

Open letter signed by 38 professors and doctors regarding misinterpretation of statistics in HCQ RCTs.

Authors note [1] that data from RCTs for early treatment in outpatients to date actually show favorable effects, especially in high-risk patients such as the elderly, where efficacy was up to three times higher than in young people. Because most samples were made up of young people without comorbidities, the studies were statistically inconclusive with the entire samples. Authors note that instead of the papers reporting this, they incorrectly claim that the treatment had no effect compared to the placebo. “This misinterpretation in statistical tests is well known and explained in most undergraduate books in the field,” says Watanabe. "An article published in Nature last year states that about 51% of the work on clinical trials with this type of result has incorrect conclusions."

[1] veja.abril.com.br/saude/especialistas-contestam-estudos-que-nao-viram-beneficios-na-cloroquina/amp/

Watanabe et al., 8/6/2020, preprint, 42 authors.

Singer et al., Annals of the Rheumatic Diseases, doi:10.1136/annrheumdis-2020-218500 (Letter)

Hydroxychloroquine ineffective for COVID-19 prophylaxis in lupus and rheumatoid arthritis

Comparison of the percentage of SLE/RA patients on immunosuppressants that were taking HCQ, for COVID-19 diagnosis versus other infections or outpatient visits, finding a similar percentage in each case.

No mortality of severity information is provided to determine if HCQ treated patients fared better. No adjustment for concomitant medications or severity.

risk of case, 9.0% higher, RR 1.09, p = 0.62, treatment 55 of 10,700 (0.5%), control 104 of 22,058 (0.5%).

Excluded in after exclusion results of meta analysis: not fully adjusting for the baseline risk differences within systemic autoimmune patients.

Singer et al., 8/5/2020, retrospective, database analysis, USA, North America, preprint, 3 authors.

Kalligeros et al., Journal of Global Antimicrobial Resistance, doi:10.1016/j.jgar.2020.07.018 (Peer Reviewed)

Hydroxychloroquine use in hospitalised patients with COVID-19: An observational matched cohort study

Small retrospective database analysis of 36 patients receiving HCQ not showing significant differences. Confounding by indication is likely.

risk of death, 67.0% higher, RR 1.67, p = 0.57, treatment 36, control 72.

Kalligeros et al., 8/5/2020, retrospective, USA, North America, peer-reviewed, 13 authors.

Kamran et al., medRxiv, doi:10.1101/2020.07.30.20165365 (Preprint)

Clearing the fog: Is HCQ effective in reducing COVID-19 progression: A randomized controlled trial

Study of 349 low-risk hospitalized patients with 151 non-consenting or ineligible patients used as controls. SOC included zinc, vitamin C and vitamin D. A statistically significant improvement in PCR negativity is shown at day 7 with HCQ treatment, 52.1% (HCQ) versus 35.7% (control), p=0.001, but no statistically significant difference at day 14, or in progression. Patients were relatively young and there was no mortality. Only 3% of patients had any disease progression and all patients recovered, so there is little if any room for treatment benefit. Progression among higher-risk patients with comorbidities was lower with treatment (12.9% versus 28.6%, p=0.3, very few cases).

Despite the title, this is not an RCT since patients self-selected the arm, or were chosen based on allergies/contraindications. The treatment group had about twice the number of patients with comorbidities. Treatment delay is unknown - it was recorded but not reported in the paper.

Viral load was not measured. As with other studies, PCR may detect non-replicable viral nucleic acid, this is more likely at day 14. Details on the test accuracy are not provided, authors note that RT-PCR sensitivity ranges from 34-80%.

risk of progression, 5.0% lower, RR 0.95, p = 1.00, treatment 11 of 349 (3.2%), control 5 of 151 (3.3%).

risk of progression, 54.8% lower, RR 0.45, p = 0.30, treatment 4 of 31 (12.9%), control 2 of 7 (28.6%), with comorbidities.

risk of viral+ at day 7, 25.5% lower, RR 0.74, p = 0.001, treatment 349, control 151.

risk of viral+ at day 14, 10.0% higher, RR 1.10, p = 0.52, treatment 349, control 151.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Kamran et al., 8/4/2020, prospective, Pakistan, South Asia, preprint, 10 authors.

Berenguer et al., Clinical Microbiology and Infection, doi:10.1016/j.cmi.2020.07.024 (Peer Reviewed)

Characteristics and predictors of death among 4035 consecutively hospitalized patients with COVID-19 in Spain

Retrospective 4035 hospitalized patients in Spain showing reduced mortality with HCQ (data is in the supplementary appendix).

risk of death, 18.2% lower, RR 0.82, p < 0.001, treatment 681 of 2,618 (26.0%), control 438 of 1,377 (31.8%).

Berenguer et al., 8/3/2020, retrospective, Spain, Europe, peer-reviewed, 8 authors.

Yu et al., Science China Life Sciences, 2020 Aug 3, doi:10.1007/s11427-020-1782-1 (Letter)

Beneficial effects exerted by hydroxychloroquine in treating COVID-19 patients via protecting multiple organs

Retrospective 2,882 patients in China, median age 62, 278 receiving HCQ, median 10 days post hospitalization, showing that HCQ treatment can reduce systemic inflammation and inhibit the cytokine storm, thus protecting multiple organs from inflammatory injuries, such as detoxification in the liver and attenuation of cardiac injury. IL-6 levels significantly reduced after HCQ treatment, p<0.05, and elevated after HCQ withdrawal. The significantly lower dose used here is potentially related to the different observations from the RECOVERY trial results. Authors suggest that treatment should be started as soon as possible.

The 550 patients that were critically ill at baseline are reported in a separate paper. For the non-critically-ill patients at baseline, the proportion of patients that became critically ill was significantly lower for those treated with HCQ.

For the subset of patients that started HCQ treatment early only 1.4% died versus 3.9% for HCQ started late and 9.1% for control patients.

risk of progression to critical, 82.5% lower, RR 0.17, p = 0.05, treatment 1 of 231 (0.4%), control 32 of 1,291 (2.5%), baseline critical cohort reported separately in Yu et al..

risk of death, 85.0% lower, RR 0.15, p = 0.02, treatment 1 of 73 (1.4%), control 238 of 2,604 (9.1%), HCQ treatment started early vs. non-HCQ.

Yu et al., 8/3/2020, retrospective, China, Asia, preprint, median age 62.0, 6 authors.

Davido et al., Int. J. Antimicrobial Agents, 2020, doi:10.1016/j.ijantimicag.2020.106129 (Peer Reviewed)

Impact of medical care including anti-infective agents use on the prognosis of COVID-19 hospitalized patients over time

Retrospective of 132 hospitalized patients. HCQ+AZ(52)/AZ(28) significantly reduced death/ICU, HR=0.45, p=0.04. Adjusted for Charlson Comorbidity Index (including age), obesity, O2, lymphocyte count, and treatments. Mean delay from admission to treatment 0.7 days.

risk of intubation/hospitalization, 55.0% lower, RR 0.45, p = 0.04, treatment 12 of 80 (15.0%), control 13 of 40 (32.5%).

Davido et al., 8/2/2020, retrospective, France, Europe, peer-reviewed, 14 authors.

Sheaff, R., bioRxiv, doi:10.1101/2020.08.02.232892 (Preprint) (In Vitro)

A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity

In Vitro study presenting a new theory on SARS-CoV-2 infection and why HCQ/CQ provides benefits, which potentially explains the observed relationships with smoking, diabetes, obesity, age, and treatment delay, and confirms the importance of accurate dosing. Metabolic analysis revealed HCQ/CQ inhibit oxidative phosphorylation in mitochondria (likely by sequestering protons needed to drive ATP synthase), inhibiting infection and/or slowing replication.

Sheaff et al., 8/2/2020, preprint, 1 author.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Bernabeu-Wittel et al., J. Gerontol. A Biol. Sci. Med. Sci., doi:10.1093/gerona/glaa192 (Peer Reviewed)

Effectiveness of a On-Site Medicalization Program for Nursing Homes with COVID-19 Outbreaks

Retrospective 272 nursing home residents showing significantly improved survival after establishing a treatment program including HCQ with or without lopinavir/ritonavir and with the addition of adjuvant and antimicrobial treatments depending on circumstances. Dosage details are in the supplementary appendix. Mortality relative risk is from [1].

[1] c19hcq.com/alexander.html

risk of death, 59.0% lower, RR 0.41, p = 0.03, treatment 189, control 83.

Bernabeu-Wittel et al., 8/1/2020, retrospective, Spain, Europe, peer-reviewed, 13 authors, dosage 400mg bid day 1, 200mg bid days 2-7.

Mazzitelli et al., Travel Medicine and Infectious Disease, 37, doi:10.1016/j.tmaid.2020.101826 (Letter)

Apparent inefficacy of hydroxychloroquine combined with azithromycin on SARS-CoV-2 clearance in an incident cohort of geriatric patients with COVID-19

Report on HCQ+AZ use in 41 elderly high-risk patients. 29 of 30 patients with treatment >= 5 days survived. Only 10% were PCR negative after one week, however the Ct value is not specified.

Mazzitelli et al., 7/31/2020, preprint, 8 authors.

D'Arminio Monforte et al., Int. J. Infectious Diseases, doi:10.1016/j.ijid.2020.07.056 (Letter)

Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?

HCQ+AZ adjusted death HR 0.44, p=0.009. Propensity scores include baseline COVID-19 disease severity, age, gender, number of comorbidities, cardio-vascular disease, duration of symptoms, date of admission, baseline plasma CRP. IPW censoring. Retrospective study of 539 COVID-19 hospitalized patients in Milan, with treatment a median of 1 day after admission. HCQ 197 patients, HCQ+AZ 94, control 92. Control group received various other treatments. Authors excluded people receiving other drugs which could have biased the effect of HCQ when used in combination. Residual confounding is possible (e.g., people with CVD were more frequent in control), however people in the control group were more likely to require mechanical ventilation.

risk of death, 34.0% lower, RR 0.66, p = 0.12, treatment 53 of 197 (26.9%), control 47 of 92 (51.1%), adjusted.

HCQ+AZ, 56.0% lower, RR 0.44, p = 0.009, treatment 22 of 94 (23.4%), control 47 of 92 (51.1%), adjusted.

D'Arminio Monforte et al., 7/29/2020, retrospective, Italy, Europe, preprint, 5 authors.

BaŞaran et al., Turk. J. Med. Sci., doi:10.3906/sag-2006-173 (Peer Reviewed)

Outcome of Non-Critical COVID-19 Patients with Early Hospitalization and Early Antiviral Treatment Outside the ICU

Observational study of 174 hospitalized patients in Turkey, median age 45.4, 23 treated with HCQ, 113 with HCQ+AZ, and 32 with regimens including favipiravir. 75% reduction in the median time to clinical improvement for HCQ+AZ vs. FAV, RR 0.25, p<0.001. 83% reduction for HCQ. However, there was significant confounding by indication.

There were no significant adverse events.

BaŞaran et al., 7/28/2020, prospective, Turkey, Europe, peer-reviewed, 18 authors.

Mitjà et al., NEJM, doi:10.1056/NEJMoa2021801 (preprint 7/26) (Peer Reviewed)

A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease

Death rate reduced from 0.6% to 0.4%, RR 0.68, not statistically significant due to low incidence (8 control cases, 5 treatment cases).

For positive symptomatic cases, a greater effect is seen for nursing home residents, RR=0.49 [0.21 - 1.17], vs. overall 0.89, possibly because the exposure events are identified faster in this context, versus home exposure where testing of the source may be more delayed. The trial is too small for significance here. If the trend continued this result would be significant at p<0.05 after about 25% more patients were added.

There are 2 groups in this study: PCR+ at baseline (n=314) and PCR- at baseline (n=2000), which should be separated as they are different populations (primary outcome rates 18.6% and 22.2% compared to 3.0% and 4.3%). PCR+ already have COVID-19, so PEP analysis should be for the 2,000 PCR-, showing symptomatic COVID-19 of 4.3% (control) and 3.0% (treatment), RR 0.7, p=0.154.

The paper has different RR values here, stating that they are adjusted for contact-level variables. It is not clear how they are computed - the adjusted RR for the overall sample is 4% lower, for PCR+ it is 20% lower, but for PCR- it is 107% higher, even though PCR- represents 86% of the sample.

Hopefully, supplementary data will provide a breakdown on cases in this PCR- @baseline sample by number of days since exposure, and also provide relevant hospitalisation and death results.

Enrollment was up to 7 days after exposure, median 4 days. Treatment delay is unclear. The exposure event timing is not detailed. It appears to be based on the date of a positive test for a contact, which is likely to be much later than the actual exposure time. 13.1% were already positive at baseline, which is consistent with the actual exposure time being significantly earlier. PCR testing has a very high false-negative rate in early stages (e.g., 100% on day 1, 67% on day 4, and 20% on day 8 [1]), hence it is likely that a much higher percentage were infected at an unknown time before enrollment. Medication administration is not detailed. Sensitivity and specificity of the tests is not provided.

Given the delay identifying index cases, PCR test delay, and PCR false negative rate at early stages, the treatment delay in general was very long and could be over 2 weeks.

The RR for non-PCR positive at baseline is 0.74. Including the PCR-positive at baseline patients reduced this to 0.89. This is also consistent with earlier treatment being more effective.

The paper does not mention zinc. Zinc deficiency in Spain has been reported at 83% [2], this may significantly reduce effectiveness. HCQ is a zinc ionophore which increases cellular uptake, facilitating significant intracellular concentrations of zinc, and zinc is known to inhibit SARS-CoV RNA-dependent RNA polymerase activity, and is widely thought to be important for effectiveness with SARS-CoV-2 [3].

This study focuses on the existence of symptoms or PCR-positive results, however severity of symptoms is more important. Research has shown HCQ concentrations can be much higher in the lung compared to plasma [4], which may help minimize the occurrence of severe cases and death.

There is a treatment-delay response relationship consistent with an effective treatment, however the authors only provide 3 ranges and do not break down the earliest treatment delay times.

The definition of COVID-19 symptoms is very broad - just existence of a headache alone or muscle pain alone was considered COVID-19. There was an overall very low incidence of confirmed COVID-19 (138 cases across both arms). There were no serious adverse events that were adjudicated as being treatment related. Authors exclude those with symptoms in the previous two weeks, however, those with symptoms up to several months before may still test PCR-positive even though there may be no viable virus.

There appears to be incorrect data. Table 2, secondary outcomes, control, hospital/vital records shows that 8 of 1042 is 9.7% (we get 0.8%).

Nasopharyngeal viral load analysis issues include test unreliability and temporo-spatial differences in viral shedding [5].

In summary, this study appears positive in the context of very delayed treatment and very small sample sizes, however we have classified it as inconclusive for now pending further analysis and feedback. Preliminary analysis. Supplementary Appendix is not currently available. Please submit any corrections or comments.

Data from this study has been used to show that viral load is the primary factor in transmission: [6].

[1] acpjournals.org/doi/10.7326/M20-1495

[2] mdpi.com/2072-6643/9/7/697

[3] infezmed.it/index.php/article?Anno=2020&numero=2&ArticoloDaVisualizzare=Vol_28_2_2020_192

[4] ncbi.nlm.nih.gov/pmc/articles/PMC7122276/

[5] journal.chestnet.org/article/S0012-3692(20)31718-9/fulltext

[6] medrxiv.org/content/10.1101/2020.10.27.20220277v1

risk of death, 51.7% lower, RR 0.48, p = 0.27, treatment 4 of 1,196 (0.3%), control 9 of 1,301 (0.7%), per supplemental appendix table S7, one treatment death was a patient that did not take any study medication, they have been moved to the control group.

risk of hospitalization, 21.4% lower, RR 0.79, p = 0.59, treatment 13 of 1,196 (1.1%), control 18 of 1,301 (1.4%), per supplemental appendix table S7, one treatment death was a patient that did not take any study medication, they have been moved to the control group.

baseline pcr- risk of cases, 32.0% lower, RR 0.68, p = 0.27, treatment 29 of 958 (3.0%), control 45 of 1,042 (4.3%).

Mitjà et al., 7/26/2020, Randomized Controlled Trial, Spain, Europe, peer-reviewed, 12 authors.

Khurana et al., medRxiv, doi:10.1101/2020.07.21.20159301 (Preprint)

Prevalence and clinical correlates of COVID-19 outbreak among healthcare workers in a tertiary level hospital

Study of hospital health care workers showing HCQ prophylaxis reduces COVID-19 significantly, OR 0.30, p=0.02. 94 positive health care workers with a matched sample of 87 testing negative. Full course prophylaxis was important in this study which used a low dose of 400mg/week HCQ (800mg for week 1), so it may take longer to reach therapeutic levels. Actual benefit of HCQ may be larger because severity of symptoms are not considered here but HCQ may also reduce severity.

risk of case, 51.0% lower, RR 0.49, p = 0.02, treatment 6 of 22 (27.3%), control 88 of 159 (55.3%), OR converted to RR.

Khurana et al., 7/24/2020, retrospective, India, South Asia, preprint, survey, 5 authors.

Cavalcanti et al., NEJM, July 23, 2020, doi:10.1056/NEJMoa2019014 (Peer Reviewed)

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Late stage RCT of 667 hospitalized patients with up to 14 days of symptoms at enrollment and receiving up to 4 liters per minute supplemental oxygen, not finding a significant effect after 15 days.

Authors note: "the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm", sample sizes are too small.

The paper uses the terms mild and moderate, however all patients had serious enough disease to be hospitalized, and 14% were actually randomized in the ICU.

The trial had significant protocol deviations and unusually low medication adherence. Randomization resulted in 64.3% male patients (HCQ) vs. 54.2% (control) which may significantly affect results due to the much higher risk for male patients.

Authors note: "our aim was to exclude patients already receiving longer and potentially therapeutic doses of the study treatments" in explanation for why the study protocol was changed to exclude patients with previous use of the medications >24hrs. Analyzing these patients rather than excluding them may have revealed effectiveness with early use as shown in other studies.

The trial initially required enrollment within 48 hours of admission and was changed to remove this requirement, this change is likely to reduce effectiveness because enrollment was moved later, compared to the time the disease became serious enough for hospitalization. Total HCQ dosage 5.6g.

A correction for 17 errors has been published: [1]

[1] nejm.org/doi/full/10.1056/NEJMx200021

risk of death, 16.0% lower, RR 0.84, p = 0.77, treatment 8 of 331 (2.4%), control 5 of 173 (2.9%), HCQ+HCQ/AZ.

risk of hospitalization, 28.0% higher, RR 1.28, p = 0.30, treatment 331, control 173, HCQ+HCQ/AZ.

Cavalcanti et al., 7/23/2020, Randomized Controlled Trial, Brazil, South America, peer-reviewed, baseline oxygen requirements 41.8%, 14 authors.

Kadnur et al., SSRN, doi:10.2139/ssrn.3622350 (Preprint)

Hydroxychloroquine Pre-Exposure Prophylaxis for COVID-19 Among Healthcare Workers: Initial Experience from India

Prophylaxis study with 334 low-risk healthcare workers in India, showing significantly lower risk of cases with treatment. Symptomatic patients received PCR results, but only some asymptomatic patients did, so there may have been additional asymptomatic cases. There were no severe adverse events.

risk of case, 86.3% lower, RR 0.14, p = 0.03, treatment 2 of 248 (0.8%), control 5 of 86 (5.8%), OR converted to RR, multivariate logistic regression.

Kadnur et al., 7/22/2020, prospective, India, South Asia, preprint, 26 authors.

Ou et al., PLOS Pathogens, doi:10.1371/journal.ppat.1009212 (preprint 7/22) (Peer Reviewed) (In Vitro)

Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2

In Vitro analysis showing that HCQ efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of HCQ and a TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone.

Ou et al., 7/22/2020, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Hoffmann et al., Nature, (2020), doi:10.1038/s41586-020-2575-3 (Peer Reviewed) (In Vitro)

Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2

The title of this paper does not appear to match the results. Fig. 1b @100uM shows CQ results in a ~4.5 fold decrease (on a linear scale) in extracellular virus, p=0.05, after 24 hours (we do not see the supplementary data at this time so this is estimated from the graph). This decrease may continue if examined over longer time periods. Fig. 1a shows a ~45-50% entry inhibition @100uM for HCQ/CQ (p=0.0005/0.0045), ~10-30% @10uM (p=0.13/0.99). Inhibition is significantly better with Vero cells. Note that the safe concentration in practice for different cells is not well known, Keyaerts et al. find CC₅₀ of 261uM [1].

In vitro study of CQ and HCQ inhibition of SARS-CoV-2 into Vero (kidney), Vero-TMPRSS2, and Calu-3 (derived from human lung carcinoma) cells.

Authors reportedly used sodium pyruvate which may inhibit CQ from entering cells [2].

Although there are several theories on how HCQ may help with COVID-19, authors do not consider the most common theory where HCQ functions as a zinc ionophore, facilitating significant intracellular concentrations of zinc. Zinc is known to inhibit SARS-CoV RNA-dependent RNA polymerase activity, and is widely thought to be important for effectiveness with SARS-CoV-2 [3].

Calu-3 is one of many cell lines derived from human lung carcinomas [4]. Calu-3 cells resemble serous gland cells. They do not express 15-lipoxygenase, an enzyme specifically localized to the surface epithelium, but they do express secretory component, secretory leukocyte protease inhibitor, lysozyme, and lactoferrin, all markers of serous gland cells. [5] note that the absence of systemic inflammation, circulatory factors, and other paracrine systemic influences is a potential limitation of the isolated cell system.

RT-PCR is used, we note that nucleic acid may persist even after the virus is no longer viable [6].

It is unclear how the authors conclude "CQ does not block SARS-CoV-2 infection of Calu-3" cells, when the results show statistically significant inhibition at higher concentrations.

Further, it is unclear how the authors go from these results in one specific type of pulmonary adenocarcinoma cells that resemble serous gland cells, in vitro, into the title of the paper which claims no inhibition in lung cells.

Further, it is unclear how another leap is made to "will not be effective against COVID-19" given the multiple theories of HCQ/CQ effectiveness.

[1] c19hcq.com/keyaerts.html

[2] twitter.com/JaclynHord/status/1302680394244947969

[3] infezmed.it/index.php/article?Anno=2020&numero=2&ArticoloDaVisualizzare=Vol_28_2_2020_192

[4] journals.physiology.org/doi/pdf/10.1152/ajplung.1994.266.5.L493

[5] journals.physiology.org/doi/pdf/10.1152/ajplung.1994.266.5.L493

[6] fda.gov/media/136472/download

Hoffmann et al., 7/22/2020, peer-reviewed, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Rivera et al., Cancer Discovery, doi:10.1158/2159-8290.CD-20-0941 (Peer Reviewed)

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

Retrospective cancer patients, showing adjusted OR 1.03 [0.62-1.73] for HCQ. The study reports the number of HCQ+AZ patients but they do not provide results for HCQ+AZ (only HCQ + any other treatment). Significant confounding by indication and compassionate use is likely.

risk of death, 2.4% higher, RR 1.02, p = 0.92, treatment 44 of 179 (24.6%), control 59 of 327 (18.0%), adjusted, OR converted to RR.

Rivera et al., 7/22/2020, retrospective, USA, North America, peer-reviewed, 45 authors.

Kelly et al., British Journal of Clinical Pharmacology, doi:10.1111/bcp.14482 (Peer Reviewed)

Clinical outcomes and adverse events in patients hospitalised with COVID‐19, treated with off‐label hydroxychloroquine and azithromycin

Retrospective 82 hospitalized patients HCQ/AZ, 52 SOC, not finding statistically significant differences. Confounding by indication - authors note that the HCQ/AZ patients were more severely ill, and do not attempt to adjust for confounders.

risk of death, 143.0% higher, RR 2.43, p = 0.03, treatment 23 of 82 (28.0%), control 6 of 52 (11.5%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Kelly et al., 7/22/2020, retrospective, Ireland, Europe, peer-reviewed, 14 authors.

Bernaola et al., medRxiv, doi:10.1101/2020.07.17.20155960 (Preprint)

Observational Study of the Efficiency of Treatments in Patients Hospitalized with Covid-19 in Madrid

HCQ HR 0.83 [0.77-0.89] based on propensity score matched retrospective analysis of 1,645 hospitalized patients. Prednisone HR 0.85 [0.82-0.88], 14 other medications showed either no signicant benefit or a negative effect.

risk of death, 17.0% lower, RR 0.83, p < 0.001, treatment 236 of 1,498 (15.8%), control 28 of 147 (19.0%).

Bernaola et al., 7/21/2020, retrospective, Spain, Europe, preprint, 7 authors.

Krishnan et al., J Clin Anesth., doi:10.1016/j.jclinane.2020.110005 (Peer Reviewed)

Clinical comorbidities, characteristics, and outcomes of mechanically ventilated patients in the State of Michigan with SARS-CoV-2 pneumonia

Retrospective 152 mechanically ventilated patients in the USA showing unadjusted lower mortality with vitamin C, vitamin D, HCQ, and zinc treatment, statistically significant only for vitamin C.

risk of death, 20.4% lower, RR 0.80, p = 0.48, treatment 86 of 144 (59.7%), control 6 of 8 (75.0%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Krishnan et al., 7/20/2020, retrospective, USA, North America, peer-reviewed, 13 authors, dosage not specified.

Desbois et al., Research Square, doi:10.21203/rs.3.rs-41653/v1 (Preprint)

Prevalence and clinical features of COVID-19 in a large cohort of 199 patients with sarcoidosis

Retrospective 199 sarcoidosis patients showing non-statistically significant HCQ RR 0.83, p=1.0.

risk of case, 16.9% lower, RR 0.83, p = 1.00, treatment 3 of 27 (11.1%), control 23 of 172 (13.4%).

Desbois et al., 7/20/2020, retrospective, France, Europe, preprint, mean age 58.8, 13 authors.

Risch, H., American Journal of Epidemiology, July 20, 2020, doi:10.1093/aje/kwaa152 (Peer Reviewed) (meta analysis)

Response to: “Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients” and “Re: Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis”

Updated meta analysis including 7 new studies of high-risk outpatients, for a total of 12 studies, all showing significant benefit.

Risch et al., 7/20/2020, peer-reviewed, 1 author.

Watanabe, M., arXiv.org, arXiv:2007.09477 (Preprint) (meta analysis)

Efficacy of Hydroxychloroquine as Prophylaxis for Covid-19

Secondary analysis of Boulware et al.'s PEP trial and treatment delay-response data, confirming that HCQ is effective when used early, p<0.01.

The effectiveness found is especially notable considering the limitations of the study. Treatment was relatively late, with enrollment up to
4 days after exposure, and an unspecified shipping delay. While the paper does not provide shipping details, the study protocol gives some detail allowing us to estimate the treatment delay as ~70 to 140 hours after exposure on average for the 1-4 days since enrollment specified in the paper (we will update this when authors respond to our request for details). There was only 75% medication adherence, including 16% who did not take the medication at all. The study relies on Internet surveys.

Some issues have been raised with this analysis. 1-tailed vs. 2-tailed tests - this is debatable, an argument can be made for both cases. However, it doesn't affect the conclusion in terms of the delay-response relationship showing statistically significant efficacy. Secondly, the paper projects the "1-4" day results to a day "0" result (in reality about 46 hours later in all cases), while the trend may well continue, we do not know this. However it doesn't change the outcome that the 1-4 day results show a statistically significant delay-response relationship.

Watanabe et al., 7/18/2020, preprint, 1 author.

McGrail et al., medRxiv, doi:10.1101/2020.07.17.20156521 (Preprint)

COVID-19 Case Series at UnityPoint Health St. Luke’s Hospital in Cedar Rapids, IA

HCQ+AZ early in the epidemic had a fairly good success rate with few complications, 86% of HCQ patients survived and 92% of HCQ+AZ patients. Patients not receiving either had 93% survival but were not considered comparable because the treated groups were significantly more ill (100% hypoxic at admission vs. 59%) and this study does not adjust for the differences.

Transition from an early intubation strategy to aggressive utilization of high flow nasal cannula and noninvasive ventilation (i.e, BiPAP) was successful in freeing up ICU resources.

risk of death, 70.0% higher, RR 1.70, p = 0.69, treatment 4 of 33 (12.1%), control 3 of 42 (7.1%).

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

McGrail et al., 7/19/2020, retrospective, USA, North America, preprint, 2 authors.

Lyngbakken et al., Nature Communications, doi:10.1038/s41467-020-19056-6 (Peer Reviewed)

A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics

Small RCT of nasopharyngeal viral load not showing significant differences. The rate of reduction for HCQ was 0.24 [0.03-0.46] RNA copies/mL/24h, and 0.14 [-0.10-0.37] for the control group (71% faster with HCQ but not statistically significant with the small sample size of 27 HCQ and 26 control patients). Analysis only over 96 hours. NCT04316377.

risk of death, 3.7% lower, RR 0.96, p = 1.00, treatment 1 of 27 (3.7%), control 1 of 26 (3.8%).

improvement in viral load reduction rate, 71.0% lower, relative rate 0.29, p = 0.51, treatment 27, control 26.

Lyngbakken et al., 7/17/2020, Randomized Controlled Trial, Norway, Europe, peer-reviewed, median age 62.0, 11 authors.

Hong et al., Infect. Chemother., 2020, doi:10.3947/ic.2020.52.e43 (Peer Reviewed)

Early Hydroxychloroquine Administration for Rapid Severe Acute Respiratory Syndrome Coronavirus 2 Eradication

HCQ 1-4 days from diagnosis was the only protective factor against prolonged viral shedding found, OR 0.111, p=0.001. 57.1% viral clearance with 1-4 days delay vs. 22.9% for 5+ days delayed treatment. Authors report that early administration of HCQ significantly ameliorates inflammatory cytokine secretion and that COVID-19 patients should be administrated HCQ as soon as possible. 42 patients with HCQ 1-4 days from diagnosis, 48 with HCQ 5+ days from diagnosis.

risk of prolonged viral shedding, early vs. late HCQ, 64.9% lower, RR 0.35, p = 0.001, treatment 42, control 48, OR converted to RR.

Hong et al., 7/16/2020, retrospective, South Korea, Asia, peer-reviewed, 7 authors, dosage not specified.

Skipper et al., Annals of Internal Medicine, doi:10.7326/M20-4207 (Peer Reviewed)

Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial

~70 to 140 hour (inc. shipping) delayed outpatient treatment with HCQ showing lower hospitalization/death and faster recovery, but not reaching statistical significance. There was one hospitalized control death and one non-hospitalized HCQ death. It is unclear why there was a non-hospitalized death, external factors such as lack of standard care may be involved. Excluding that case results in one control death and zero HCQ deaths. Details for the hospitalizations and deaths such as medication adherence and treatment delay may be informative but are not provided.

The paper states the end point was changed to symptom severity because they would have required 6,000 participants. However, if the same event rates continued, they would hit 95% significance on the reduction in hospitalization after adding less than 500 patients per arm.

Treatment is relatively late, ~70 to 140 hours after symptoms, including the shipping delay. The paper does not mention the shipping delay but partial details are provided in the study protocol. They are not clear but suggest no shipping on the weekends and a possible 12pm cutoff for same day dispensing and mailing. Assuming that enrollments were evenly distributed between 6am and 12am each day, we get an average of approximately 46 hours shipping delay. We have asked for shipping details and will update with more accurate values when available. In any case the treatment delay is relatively long and there is likely little overlap with the more typical delays used such as 0 - 36 hours for oseltamivir.

The paper compares 0 - 36 hour delayed treatment with oseltamivir (influenza) and ~70 to 140 hour delayed treatment with HCQ (COVID-19), noting that oseltamivir seemed more effective. However, a more comparable study is McLean (2015) who showed that 48 - 119 hour delayed treatment with oseltamivir has no effect. This suggests that HCQ is more effective than oseltamivir, and that HCQ may still have significant effect for some amount of delay beyond the delay where oseltamivir is effective.

6 people were included that enrolled with >4d symptoms, although they do not match the study inclusion criteria. This reduces observed effectiveness. The paper says 56% (236) were enrolled within 1 day of symptoms, but results show only 40% for "<1d", 56% is possibly for <48hrs, we have asked for clarification.

Patients in this study are relatively young and most of them recover without assistance. This reduces the room for a treatment to make improvements. The maximum improvement of an effective treatment would be expected before all patients approach recovery. Authors focus on the end result where most have recovered, but it is more informative to examine the curve and the point of maximum effectiveness. Authors did not collect data for every day but they do have interim results for days 3, 5, 10. The results are consistent with an effective treatment and show a statistically significant improvement, p = 0.05, at day 10 (other unreported days might show increased effectiveness).

Results also show a larger treatment effect for those >50, not statistically significant due to the small sample, but noted as COVID-19 risk dramatically increases with age. The effect may be more visible here because younger patients may on average have more mild cases with less room for improvement. In general patients in this study have relatively mild symptoms on average, limiting the chance to observe improvement.

The study relies on Internet surveys. Known fake surveys were submitted to the similar PEP trial and there could be an unknown number of undetected fake surveys in both trials. The study shows a high incidence of side effects in the placebo arm, which could be in part due to fake entries [1].

The granularity change in the histograms of Figure S4 has raised questions [2]. Data on increasing severity, less affected by the lower bound where everyone has recovered, also supports effectiveness [3].

Research shows the placebo used in the US may be protective for COVID-19 [4] so the true effectiveness of HCQ could be higher than observed. Also see [5].

Treatment delay reporting has changed from the companion PEP trial which reported results for enrollment delays 1, 2, 3, and 4 separately (and from which we can confirm a statistically significant delay-response relationship), while this trial combines 1-2 and 3-4, and adds <1. Since the two trials share reporting (some patients were moved between trials) the reason for the differences are not clear.

RCT of 423 patients with Internet surveys. Medication adherence was only 77% so the true effect of treatment is likely higher. Analysis of primarily low risk patients, authors note the results are not generalizable to the COVID high-risk population. We will update when hearing back on questions asked.

Also see [6] and [7] regarding flaws in this study. NCT04308668.

[1] twitter.com/Covid19Crusher/status/1284515906375356416

[2] twitter.com/Covid19Crusher/status/1284515906375356416

[3] twitter.com/Covid19Crusher/status/1284515906375356416

[4] frontiersin.org/articles/10.3389/fphar.2020.01062/full

[5] acpjournals.org/doi/full/10.7326/L21-0001

[6] drive.google.com/file/d/1NZOJ57fM0RTaHD1t_9w2iua7lUJhOgWT/view

[7] twitter.com/cnpaiva/status/1303324404630388738

risk of death/hospitalization, 36.7% lower, RR 0.63, p = 0.58, treatment 5 of 231 (2.2%), control 8 of 234 (3.4%), COVID-19 adjudicated hospitalization/death.

risk of hospitalization, 49.4% lower, RR 0.51, p = 0.38, treatment 4 of 231 (1.7%), control 8 of 234 (3.4%), COVID-19 adjudicated hospitalization.

risk of death/hospitalization, 49.4% lower, RR 0.51, p = 0.29, treatment 5 of 231 (2.2%), control 10 of 234 (4.3%), all hospitalization/death.

risk of hospitalization, 59.5% lower, RR 0.41, p = 0.17, treatment 4 of 231 (1.7%), control 10 of 234 (4.3%), all hospitalizations.

risk of no recovery at day 14, 20.0% lower, RR 0.80, p = 0.21, treatment 231, control 234.

Skipper et al., 7/16/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 24 authors, dosage 800mg once, followed by 600mg in 6 to 8 hours, then 600mg daily for 4 more days.

Mitjà et al., Clinical Infectious Diseases, ciaa1009, doi:10.1093/cid/ciaa1009 (Peer Reviewed)

Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial

This paper has conflicting values, table S2 shows 12 control hospitalizations, while table 2 shows 11. The original report for this paper had more conflicting values, with values reported in Table 2 and the abstract corresponding to 12 control hospitalizations, while others corresponded to 11 control hospitalizations. The counts in table S2 also do not match - n=290 is given for secondary endpoints but the three groups add up to n=238. The sum of the secondary endpoint counts for the control group in table 2 do not match the group size. One missing patient may be the 12th control hospitalization but there are 2 more missing.

There was a 16% reduction in hospitalization and 34% reduction in the risk of no symptom resolution, without statistical significance due to small samples.

Treatment delay is unknown at this time. They report a delay of up to 120 hours after symptoms plus an additional unspecified delay where medication was provided to patients at the first home visit. We have asked for details of the treatment delay and will update when hearing back. They do not break down results by treatment delay.

The paper does not mention zinc. Zinc deficiency in Spain has been reported at 83% [1], this may significantly reduce effectiveness. HCQ is a zinc ionophore which increases cellular uptake, facilitating significant intracellular concentrations of zinc, and zinc is known to inhibit SARS-CoV RNA-dependent RNA polymerase activity, and is widely thought to be important for effectiveness with SARS-CoV-2 [2].

Undetectable viral load was changed to 3 log10 copies/mL potentially masking effectiveness. For viral load authors use nasopharyngeal swabs, we note that viral activity in the lung may be especially important for COVID-19, and that research has shown HCQ concentrations can be much higher in the lung compared to plasma [3]. We also note that viral detection by PCR does not equate to viable virus [4]. Accuracy of the tests is not provided.

Nasopharyngeal viral load analysis issues include test unreliability and temporo-spatial differences in viral shedding [5].

293 low-risk patients with no deaths. No serious adverse events. We asked for more details on the treatment delay and viral load change but received no response.

Also see this open letter: [6]

[1] mdpi.com/2072-6643/9/7/697

[2] infezmed.it/index.php/article?Anno=2020&numero=2&ArticoloDaVisualizzare=Vol_28_2_2020_192

[3] ncbi.nlm.nih.gov/pmc/articles/PMC7122276/HCQ

[4] ams.edu.sg/view-pdf.aspx?file=media%5c5556_fi_331.pdf&ofile=Period+of+Infectivity+Position+Stateme..

[5] journal.chestnet.org/article/S0012-3692(20)31718-9/fulltext

[6] drive.google.com/file/d/1NZOJ57fM0RTaHD1t_9w2iua7lUJhOgWT/view

risk of hospitalization, 16.0% lower, RR 0.84, p = 0.64, treatment 8 of 136 (5.9%), control 11 of 157 (7.0%).

risk of no recovery, 34.0% lower, RR 0.66, p = 0.38, treatment 8 of 136 (5.9%), control 14 of 157 (8.9%).

relative change in viral load from baseline, 2.0% lower, RR 0.98, treatment 136, control 157, day 7.

Mitjà et al., 7/16/2020, Randomized Controlled Trial, Spain, Europe, peer-reviewed, 45 authors, dosage 800mg day 1, 400mg days 2-7.

Gupta et al., JAMA Intern. Med., doi:10.1001/jamainternmed.2020.3596 (Peer Reviewed)

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US

Analysis of 2215 intensive care unit patients showing no significant differences with this very late stage use of HCQ. HCQ+AZ mortality relative risk RR 0.96, p=0.53, HCQ and HCQ+AZ combined RR 1.06, p=0.409.

risk of death, 6.0% higher, RR 1.06, p = 0.41, treatment 631 of 1,761 (35.8%), control 153 of 454 (33.7%).

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline.

Gupta et al., 7/15/2020, retrospective, USA, North America, peer-reviewed, baseline oxygen requirements 87.1%, 34 authors.

Kavanagh et al., Med. Hypotheses, doi:10.1016/j.mehy.2020.110110 (Peer Reviewed)

Inhaled hydroxychloroquine to improve efficacy and reduce harm in the treatment of COVID-19

Proposal to use an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma. Authors advocate for early treatment or prophylaxis of COVID-19, using HCQ as an inhaled aerosol, to deliver the drug directly to the lungs at a lower dose than that required for oral systemic delivery.

Kavanagh et al., 7/15/2020, peer-reviewed, 9 authors.

Trullàs et al., Research Square, doi:10.21203/rs.3.rs-39421/v1 (Preprint)

High in-hospital mortality due to COVID-19 in a community hospital in Spain: a prospective observational study

Retrospective 100 hospitalized patients in Spain showing lower mortality with HCQ+AZ.

risk of death, 35.6% lower, RR 0.64, p = 0.12, treatment 20 of 66 (30.3%), control 16 of 34 (47.1%).

Trullàs et al., 7/14/2020, retrospective, Spain, Europe, preprint, median age 75.0, 8 authors.

Chowdhury et al., Eurasian Journal of Medicine and Oncology, doi:10.14744/ejmo.2021.16263 (Peer Reviewed)

A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients

Small 116 patient RCT comparing ivermectin+doxycycline and HCQ+AZ, not showing a significant difference in time to PCR negative or symptom resolution. Time to symptomatic recovery was 5.93 days for ivermectin+doxycycline vs. 6.99 days for HCQ+AZ. Given the long half-life of HCQ and the lack of a loading dose, it may take several days for HCQ to reach therapeutic levels. 10% of HCQ+AZ patients were lost to followup (2x ivermectin+doxycycline). There is no comparison with a control group. NCT04434144.

Chowdhury et al., 7/14/2020, peer-reviewed, 6 authors.

Lecronier et al., Critical Care, 24:418, 2020, doi:10.1186/s13054-020-03117-9 (Peer Reviewed)

Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis

Retrospective 80 ICU patients, 22 SOC, 20 lopinavir/ritonavir, 38 HCQ. 28 day mortality 24% (HCQ) versus 41% (SOC), a 41% decrease, but not statistically significant due to very small sample sizes. No statistically significant differences found for treatment escalation, ventilator-free days, viral load, or mortality. Authors consider treatment escalation more important than mortality, for unknown reasons.

risk of death, 42.0% lower, RR 0.58, p = 0.24, treatment 9 of 38 (23.7%), control 9 of 22 (40.9%).

risk of treatment escalation, 6.0% lower, RR 0.94, p = 0.73, treatment 15 of 38 (39.5%), control 9 of 22 (40.9%).

risk of viral+ at day 7, 15.0% lower, RR 0.85, p = 0.61, treatment 19 of 26 (73.1%), control 12 of 14 (85.7%).

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline.

Lecronier et al., 7/11/2020, retrospective, France, Europe, peer-reviewed, baseline oxygen requirements 100.0%, 25 authors, HCQ vs. control.

Cravedi et al., American Journal of Transplantation, doi:10.1111/ajt.16185 (Peer Reviewed)

COVID‐19 and kidney transplantation: Results from the TANGO International Transplant Consortium

Analysis of 144 hospitalized kidney transplant patients showing HCQ mortality HR 1.53, p = 0.17. Subject to confounding by indication.

risk of death, 53.0% higher, RR 1.53, p = 0.17, treatment 36 of 101 (35.6%), control 10 of 43 (23.3%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Cravedi et al., 7/10/2020, retrospective, USA, North America, peer-reviewed, mean age 60.0, 25 authors.

Chen et al., PLoS ONE, doi:10.1371/journal.pone.0242763 (Peer Reviewed)

A Multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate Coronavirus disease 2019 (COVID-19)

2 very small studies with hospitalized patients in Taiwan.

RCT with 21 treatment and 12 SOC patients. No mortality, or serious adverse effects. Median time to negative RNA 5 days versus 10 days SOC, p=0.4. Risk of PCR+ at day 14, RR 0.76, p = 0.71.

This paper also reports on a small retrospective study with 12 of 28 HCQ patients and 5 of 9 in the control group being PCR- at day 14, RR 1.29, p = 0.7.

risk of no virological cure, 24.0% lower, RR 0.76, p = 0.71, treatment 4 of 21 (19.0%), control 3 of 12 (25.0%), day 14.

median time to PCR-, 50.0% lower, relative time 0.50, p = 0.40, treatment 21, control 12.

Chen et al., 7/10/2020, Randomized Controlled Trial, Taiwan, Asia, peer-reviewed, 19 authors.

Rivera-Izquierdo et al., Medicina Clínica, doi:10.1016/j.medcli.2020.06.025 (Peer Reviewed)

Agentes terapéuticos utilizados en 238 pacientes hospitalizados por COVID-19 y su relación con la mortalidad

Retrospective 238 hospitalized patients in Spain showing lower mortality with HCQ, adjusted hazard ratio aHR 0.81 [0.24-2.76].

risk of death, 19.0% lower, RR 0.81, p = 0.75, treatment 215, control 23.

Rivera-Izquierdo et al., 7/9/2020, retrospective, Spain, Europe, peer-reviewed, 21 authors.

Raoult et al., Preprint (Preprint) (meta analysis)

Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial: Response to David Spencer (Elsevier)

Updated meta analysis showing significant reductions in mortality and viral shedding. Mortality OR 0.53 [0.4-0.71] for clinical studies, 0.92 big data studies, 18,211 patients. Persistent viral shedding OR 0.47 [0.28-0.79], 4,540 patients.

Raoult et al., 7/9/2020, preprint, 7 authors.

Marzolini et al., Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.01177-20 (Peer Reviewed)

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Study of Lopinivar and HCQ plasma concentrations and CRP levels in late stage (treatment initiation median 8 days from onset) COVID-19 patients. The median HCQ plasma concentration was 171 ng/ml, which authors suggest indicates that HCQ levels achieved in vivo do not result in adequate clinical activity for COVID-19, however this is incorrect as tissue concentration can be many times higher [1].

[1] c19hcq.com/ruiz.html

Marzolini et al., 7/8/2020, peer-reviewed, 18 authors.

Li et al., Cell Death & Disease volume 11, doi:10.1038/s41419-020-2721-8 (Review) (Peer Reviewed)

Is hydroxychloroquine beneficial for COVID-19 patients?

Review of the anti-inflammatory, antiviral, and protective vascular effects of CQ and HCQ, noting that HCQ may be preferable for COVID-19 due to fewer side effects.

Li et al., 7/8/2020, peer-reviewed, 8 authors.

Goldstein, L., Preprint, July 7, 2020 (Review) (Preprint)

Hydroxychloroquine-based COVID-19 Treatment, A Systematic Review of Clinical Evidence and Expert Opinion from Physicians’ Surveys

85% of globally surveyed physicians recognized HCQ as at least partially effective in treating COVID-19, according to Sermo W3. More than half of the surveyed US physicians would take the drug or give it to family members early or even before onset of symptoms, according to JC.

Aside from the rarely used plasma, HCQ / HCQ+AZ based treatments are preferred by physicians by wide margin over other drugs. HCQ / HCQ+AZ based treatments are the most used, most recommended, and most highly rated by physicians treating COVID-19 at an early stage.

Goldstein et al., 7/7/2020, preprint, 1 author.

An et al., medRxiv, doi:10.1101/2020.07.04.20146548 (Preprint)

Treatment Response to Hydroxychloroquine and Antibiotics for mild to moderate COVID-19: a retrospective cohort study from South Korea

Retrospective of hospitalized patients with 31 HCQ patients and 195 standard treatment patients, not showing a significant difference in terms of viral clearance or recovery. There was no mortality in either group.

"It is notable that HQ plus antibiotics group had worse baseline clinical profiles (i.e. higher percentage of moderate severity patients, more patients with fever >=37.5C, higher average body temperature) and prognostic indicators such as age, LDH, lymphocyte count, and CRP".

We note that propensity score matching removed almost all of the male patients in the control group (40% -> 5%) but increased the percentage of male patients in the treatment group. This provides a large advantage to the control group because there is a very large difference in severity and mortality based on gender [1].

In terms of viral RNA clearance we note that other research has found that "active viral replication drops quickly after the first week, and viable virus was not found after the second week of illness despite the persistence of PCR detection of RNA” [2].

[1] ncbi.nlm.nih.gov/pmc/articles/PMC7247289/

[2] ams.edu.sg/view-pdf.aspx?file=media%5c5556_fi_331.pdf&ofile=Period+of+Infectivity+Position+Stateme..

time to viral clearance, 3.0% lower, RR 0.97, p = 0.92, treatment 31, control 195.

An et al., 7/7/2020, retrospective, South Korea, Asia, preprint, 12 authors.

Derwand et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106214 (preprint 7/3) (Peer Reviewed)

COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

79% lower mortality and 82% lower hospitalization with early HCQ+AZ+Z. No cardiac side effects. Retrospective 518 patients (141 treated, 377 control).

risk of death, 79.4% lower, RR 0.21, p = 0.12, treatment 1 of 141 (0.7%), control 13 of 377 (3.4%), OR converted to RR.

risk of hospitalization, 81.6% lower, RR 0.18, p < 0.001, treatment 4 of 141 (2.8%), control 58 of 377 (15.4%), OR converted to RR.

Derwand et al., 7/3/2020, retrospective, USA, North America, peer-reviewed, 3 authors, dosage 200mg bid days 1-5, this trial uses multiple treatments in the treatment arm (combined with zinc and azithromycin) - results of individual treatments may vary.

Zhong et al., Lancent Rheumatology, doi:10.1016/S2665-9913(20)30227-7 (Peer Reviewed)

COVID-19 in patients with rheumatic disease in Hubei province, China: a multicentre retrospective observational study

Rheumatic disease patients on HCQ had a lower risk of COVID-19 than those on other disease-modifying anti-rheumatic drugs, OR 0.09 (0.01–0.94), p=0.044 after adjusting for age, sex, smoking, systemic lupus erythematosus, infection in other family members, and comorbidities. 43 patients with rheumatic disease and COVID-19 exposure.

risk of case, 91.0% lower, RR 0.09, p = 0.04, treatment 7 of 16 (43.8%), control 20 of 27 (74.1%), adjusted.

Zhong et al., 7/3/2020, retrospective, database analysis, China, Asia, peer-reviewed, 20 authors.

Arshad et al., Int. J. Infect. Dis., July 1 2020, doi:10.1016/j.ijid.2020.06.099 (Peer Reviewed)

Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19

HCQ decreases mortality from 26.4% to 13.5% (HCQ) or 20.1% (HCQ+AZ). Propensity matched HCQ HR 0.487, p=0.009. Michigan 2,541 patients retrospective. Before propensity matching the HCQ group average age is 5 years younger and the percentage of male patients is 4% higher which is likely to favor the treatment and the control respectively in the before-propensity matching results.

Some reported limtiations of this study are inaccurate [1]. Corticosteroids were controlled for in the multivariate and propensity analyses as were age and comorbidities including cardiac disease and severity of illness. Age was an independent risk factor associated with mortality. HCQ was independently associated with decreased mortality, distinct from the steroid effect. 91% of all patients began treatment within two days of admission. HCQ was used throughout the study period, limiting time bias. Patients assigned to HCQ group had moderate and severe illness at presentation, which would favor worse outcome with HCQ.

[1] ijidonline.com/article/S1201-9712(20)30604-4/fulltext

risk of death, 51.3% lower, RR 0.49, p = 0.009, treatment 162 of 1,202 (13.5%), control 108 of 409 (26.4%).

Arshad et al., 7/1/2020, retrospective, USA, North America, peer-reviewed, 12 authors.

Samuel et al., Heart Rhythm, doi:10.1016/j.hrthm.2020.06.033 (Peer Reviewed)

Incidence of arrhythmias and electrocardiographic abnormalities in symptomatic pediatric patients with PCR positive SARS-CoV-2 infection including drug induced changes in the corrected QT interval (QTc)

In pediatric patients with PCR positive active COVID-19 infection, significant arrhythmias are infrequent, but occur at an incidence higher than expected in a general pediatric population. Comorbidities are not more common in patients with arrhythmias than in patients without arrhythmias. However, providers still need to be vigilant for comorbidities that may independently place patients at risk for arrhythmias. COVID-19 treatment using HCQ leads to significant QTc prolongation, but was not associated with arrhythmias in pediatric patients. The long term sequelae of arrhythmia development in this population and their impact on outcome needs to be studied.

Samuel et al., 7/1/2020, peer-reviewed, 7 authors.

Martinez-Lopez et al., Blood Cancer Journal, doi:10.1038/s41408-020-00372-5 (Peer Reviewed)

Multiple Myeloma and SARS-CoV-2 Infection: Clinical Characteristics and Prognostic Factors of Inpatient Mortality

Retrospective 167 multiple myeloma patients in Spain.

risk of death, 33.0% lower, RR 0.67, p = 0.20, treatment 47 of 148 (31.8%), control 9 of 19 (47.4%).

Martinez-Lopez et al., 6/30/2020, retrospective, Spain, Europe, peer-reviewed, median age 71.0, 25 authors.

Mikami et al., J. Gen. Intern. Med., doi:10.1007/s11606-020-05983-z (Peer Reviewed)

Risk Factors for Mortality in Patients with COVID-19 in New York City

HCQ decreases mortality, HR 0.53 (CI 0.41–0.67). IPTW adjustment does not significantly change HR 0.53 (0.41-0.68). Retrospective 6,000 patients in New York City.

risk of death, 47.0% lower, RR 0.53, p < 0.001, treatment 575 of 2,077 (27.7%), control 231 of 743 (31.1%), adjusted.

Mikami et al., 6/30/2020, retrospective, USA, North America, peer-reviewed, 7 authors.

Komissarov et al., medRxiv, doi:10.1101/2020.06.30.20143289 (Preprint)

Hydroxychloroquine has no effect on SARS-CoV-2 load in nasopharynx of patients with mild form of COVID-19

Small late stage (7-10 days post symptoms) study of nasal swab RNA with 12 control and 33 patients, showing no significant differences (significant reduction in viral load is seen in both groups).

The groups are not comparable, with significant differences seen between hospitalized and non-hospitalized patients. 9 of 10 hospitalized patients were in the HCQ group and only one in the control group. 2 additional control patients were added between the first and second version of this preprint (including the only hospitalized control patient).

risk of viral load, 25.0% higher, RR 1.25, p = 0.45, treatment 26, control 10.

Komissarov et al., 6/30/2020, retrospective, Russia, Europe, preprint, 8 authors.

Sosa-García et al., Cir Cir. 2020, 88:5, 569-575, doi:10.24875/CIRU.20000675 (Peer Reviewed)

Experience in the management of severe COVID-19 patients in an intensive care unit

Small retrospective study of 56 ICU patients in Mexico showing HCQ RR 1.1, p = 1.0.

risk of death, 10.5% higher, RR 1.11, p = 1.00, treatment 7 of 38 (18.4%), control 3 of 18 (16.7%).

Excluded in after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline, substantial unadjusted confounding by indication likely.

Sosa-García et al., 6/29/2020, retrospective, Mexico, North America, peer-reviewed, baseline oxygen requirements 100.0%, 6 authors.

Ferreira et al., J. Medical Virology, July 9, 2020, doi:10.1002/jmv.26286 (preprint 6/29) (Peer Reviewed)

Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection

Chronic treatment with HCQ provides protection against COVID, odds ratio 0.51 (0.37-0.70).

The actual benefit is likely to be larger becasue research shows that the risk of COVID-19 for systemic autoimmune disease patients is much higher overall. Ferri et al. show OR 4.42, p<0.001 [1], which is the observed real-world risk, taking into account factors such as these patients potentially being more careful to avoid exposure.

[1] c19hcq.com/ferri.html

risk of case, 47.1% lower, RR 0.53, p < 0.001, adjusted, OR converted to RR.

Ferreira et al., 6/29/2020, retrospective, population-based cohort, database analysis, Portugal, Europe, peer-reviewed, 3 authors.

Mfeukeu-Kuate et al. (Preprint)

Electrocardiographic safety of daily Hydroxychloroquine 400mg plus Azithromycin 250mg as an ambulatory treatment for COVID-19 patients in Cameroon

No life-threatening modifications of the QT interval was observed in non-severe COVID-19 patients treated ambulatory with HCQ+AZ. 51 relatively young patients 39 +/- 11.

Mfeukeu-Kuate et al., 6/29/2020, preprint, 29 authors.

Gendebien et al., Annals of the Rheumatic Diseases, doi:10.1136/annrheumdis-2020-218244 (Letter)

Systematic analysis of COVID-19 infection and symptoms in a systemic lupus erythematosus population: correlation with disease characteristics, hydroxychloroquine use and immunosuppressive treatments

Small study of 152 SLE patients taking HCQ with a phone survey for COVID-19 suggestive symptoms. There was 2 hospitalizations (group not identified) and no ICU or death cases. A similar percentage of suspected infections were reported for HCQ users and non-HCQ users, RR 0.96, p = 0.93.

There was no mortality and severity was not analyzed to determine if HCQ treated patients fared better. No adjustment for concomitant medications or severity of SLE. Only 5 cases were PCR confirmed.

risk of case, 3.9% lower, RR 0.96, p = 0.93, treatment 12 of 152 (7.9%), control 6 of 73 (8.2%).

Excluded in after exclusion results of meta analysis: not fully adjusting for the baseline risk differences within systemic autoimmune patients.

Gendebien et al., 6/25/2020, retrospective, Belgium, Europe, preprint, survey, 9 authors.

Lagier et al., Travel Med. Infect. Dis. 101791, Jun 25, 2020, doi:10.1016/j.tmaid.2020.101791 (Peer Reviewed)

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis

Early treatment leads to significantly better clinical outcome and faster viral load reduction. Matched sample mortality HR 0.41 p-value 0.048. Retrospective 3,737 patients. This study includes both outpatients and hospitalized patients.

risk of death, 59.0% lower, RR 0.41, p = 0.05, treatment 35 of 3,119 (1.1%), control 58 of 618 (9.4%), adjusted.

Lagier et al., 6/25/2020, retrospective, France, Europe, peer-reviewed, 22 authors, dosage 200mg tid days 1-10.

Bousquet et al., Aging, 12:12, 11306-11313, doi:10.18632/aging.103583 (Peer Reviewed)

ADL-dependency, D-Dimers, LDH and absence of anticoagulation are independently associated with one-month mortality in older inpatients with Covid-19

Observational prospective 108 hospitalized patients 65 and older, showing HCQ mortality OR 0.49, p = 0.15.

risk of death, 42.8% lower, RR 0.57, p = 0.15, treatment 5 of 27 (18.5%), control 23 of 81 (28.4%), adjusted, OR converted to RR.

Bousquet et al., 6/23/2020, prospective, France, Europe, peer-reviewed, 10 authors.

Isaksen et al., medRxiv, doi:10.1101/2020.06.19.20135475 (Preprint)

Chloroquine, but not hydroxychlorquine, prolongs the QT interval in a primary care population

Safety analysis in patients without COVID-19, finding a small increase in QTc associated with use of CQ, but not HCQ. Authors also study mortality (n=3,368), with HCQ hazard ratio 0.67 [0.43-1.05].

Isaksen et al., 6/22/2020, preprint, 5 authors.

Fontana et al., Clinical Kidney Journal, 13:3, 334–339, doi:10.1093/ckj/sfaa084 (Peer Reviewed)

SARS-CoV-2 infection in dialysis patients in northern Italy: a single-centre experience

Very small observational study of 15 dialysis patients showing HCQ mortality RR 0.50, p = 0.53.

risk of death, 50.0% lower, RR 0.50, p = 0.53, treatment 4 of 12 (33.3%), control 2 of 3 (66.7%).

Fontana et al., 6/22/2020, retrospective, Italy, Europe, peer-reviewed, 8 authors.

Chen et al., medRxiv, doi:10.1101/2020.06.19.20136093 (Preprint)

Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study

Significantly faster clinical recovery and shorter time to RNA negative (from 7.0 days to 2.0 days (HCQ), p=0.01. 67 patients with mild/moderate cases.

median time to PCR-, 72.0% lower, relative time 0.28, p = 0.01, treatment 18, control 12.

Chen et al., 6/22/2020, Randomized Controlled Trial, China, Asia, preprint, 19 authors, dosage 200mg bid days 1-10.

Faíco-Filho et al., Braz J Microbiol, doi:10.1007/s42770-020-00395-x (preprint 6/21) (Peer Reviewed)

No benefit of hydroxychloroquine on SARS-CoV-2 viral load reduction in non-critical hospitalized patients with COVID-19

Viral load comparison for 34 HCQ and 32 control patients hospitalized with moderate COVID-19. All patients recovered limiting the room for beneficial effects.

While not achieving statistical significance, results show faster recovery with HCQ. The greatest benefit is seen mid-recovery as expected for an effective treatment:

Δt7-12: 81% improvement with HCQ
Δt<7: 24% improvement with HCQ

For Δt>12, everyone has recovered so there is no room for improvement. Since the HCQ group started slightly higher the improvement is slightly less. Most participants have also dropped out by this test, with only 6 HCQ and 9 control remaining (also suggesting HCQ patients recovered faster).

Δt7-12 ΔCt improvement, 80.8% lower, relative rate 0.19, p = 0.40, treatment 34, control 32.

Δt<7 ΔCt improvement, 24.0% lower, relative rate 0.76, p = 0.36, treatment 34, control 32.

Δt>12 ΔCt improvement, 15.0% higher, relative rate 1.15, p = 0.52, treatment 34, control 32.

Faíco-Filho et al., 6/21/2020, prospective, Brazil, South America, peer-reviewed, median age 58.0, 6 authors.

SMSH Sawai Man Singh Hospital, India (News)

HCQ beneficial as preventive drug: SMS doctors told ICMR

PrEP with 4,300 very high risk healthcare workers in a hospital with up to 500+ COVID patients at a time, only 1% cases, all recovered.

SMSH et al., 6/19/2020, preprint, 1 author.

NIH, study not available yet (News)

NIH halts clinical trial of hydroxychloroquine

NIH halts late stage trial reporting no harm and no benefit. 470 patients.

NIH et al., 6/19/2020, preprint, 1 author.

Sbidian et al., medRxiv, doi:10.1101/2020.06.16.20132597 (Preprint)

Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France

Retrospective of 4,642 hospitalized patients in France showing significantly faster discharge with HCQ and HCQ+AZ. No significant effect is seen on 28-day mortality, however many more control patients are still in hospital at 28 days. Other studies show faster resolution for HCQ, suggesting there will be a significant improvement when extending past 28 days. Hopefully authors will extend the analysis. Note that the median age is higher in the group not treated with HCQ or AZ.

For other issues with the adjustments see [1]. Also see the analysis here [2].

[1] medrxiv.org/content/10.1101/2020.06.16.20132597v1#disqus_thread

[2] twitter.com/Covid19Crusher/status/1274668697408471040

risk of death, 5.0% higher, RR 1.05, p = 0.74, treatment 111 of 623 (17.8%), control 830 of 3,792 (21.9%), adjusted, whole population HCQ AIPTW adjusted.

risk of no hospital discharge, 20.0% lower, RR 0.80, p = 0.002, treatment 623, control 3,792, adjusted, whole population HCQ AIPTW adjusted.

Excluded in after exclusion results of meta analysis: significant issues found with adjustments.

Sbidian et al., 6/19/2020, retrospective, database analysis, France, Europe, preprint, 21 authors.

Kaptein et al., bioRxiv, doi:10.1101/2020.06.19.159053 (Peer Reviewed)

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity

Animal study with Syrian hamsters, showing treatment of SARS-CoV-2-infected hamsters with favipiravir or HCQ (with and without AZ). Treatment with HCQ alone resulted in a very modest reduction of 0.3 log10 viral RNA copies/mg lung, and no reduction in viral RNA load in the ileum or stool.

Therapeutic levels of HCQ may not have been reached. Cytosolic concentrations in the lung were far below the EC90 target.

A number of issues have reportedly been raised, including the following, for which the authors did not respond:

- HCQ was administered with DMSO and Cremophor - why were non-neutral carriers chosen? DMSO has anti-inflammatory properties and Cremophor has a range of side effects [1]: "use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy". Why weren't the same amounts of solvent applied to the non-treated animals? Shouldn't favipiravir have been dissolved in the same way to avoid bias?

- Why is the method of administration different for both products (oral gavage/intraperitoneal injection)?

- One of the HCQ protocols used in France (IHU Marseille) prescribes 600mg of HCQ per day to patients. For a body weight of 60kg, this corresponds to a dose of 10mg/kg. How is a dose of 50 mg/kg in this study justified, i.e. 5 times more, with possible systemic effects on the animals and possible influence on the results?

- Why were the animals killed after 4/5 days and did the treatment not continue? Unfortunately, this does not allow us to know the real course of the disease or the mortality of the animals beyond day 4. Is it because the animals spontaneously improve without treatment as Professor Neyts seems to say in his webinar for the GVN? And if this is indeed the case, isn't the use of these hamsters exactly an objection as a model for COVID-19 research?

[1] sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cremophor

Kaptein et al., 6/19/2020, peer-reviewed, 35 authors.

Paccoud et al., Clinical Infectious Diseases, doi:10.1093/cid/ciaa791 (Peer Reviewed)

Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe Covid-19 in a French university hospital

Retrospective of 89 hospitalized patients, survival HR 0.89 [0.23-3.47], not statistically significant. Authors note that unmeasured confounders may have persisted and the study may be underpowered.

risk of death, 11.0% lower, RR 0.89, p = 0.88, treatment 21 of 38 (55.3%), control 26 of 46 (56.5%), adjusted.

Paccoud et al., 6/18/2020, retrospective, France, Europe, peer-reviewed, 20 authors.

Capucci et al., J. Cardiovasc. Med. 21, 922–923, doi:10.2459/JCM.0000000000001061 (Peer Reviewed)

Low hospitalization rate without severe arrhythmias: a prospective survey on 350 patients early home treated with hydroxychloroquine during COVID-19 pandemic

Prospective analysis of early treatment of 350 patients in Italy (without waiting for PCR results), showing low hospitalization rates and no serious adverse events.

From 274 patients treated with HCQ, 16 required hospitalization (5.8%). Minor complications (mainly gastrointestinal, diarrhoea) were found in eight patients (2.9%), none of whom had to interrupt treatment. No major cardiac complications were found.

Of the 76 patients treated with HCQ+AZ, 4 were hospitalized (5.2%). Minor complications occurred in two patients (2.6%). There were no reports of any major arrhythmias, syncope or sudden death.

Capucci et al., 6/17/2020, peer-reviewed, 7 authors.

Xue et al., J. Med. Virology, June 17, 2020, doi:10.1002/jmv.26193 (Peer Reviewed)

Hydroxychloroquine treatment in COVID-19: a descriptive observational analysis of 30 cases from a single center in Wuhan, China

30 hospitalized patients. Early use of HCQ is more effective, 43% reduction in progression from moderate to severe. "Early" is relative here, within 7 days of hospitalization.

Xue et al., 6/17/2020, peer-reviewed, 7 authors.

Luo et al., Annals of Oncology, 31:10, 1386-1396, doi:10.1016/j.annonc.2020.06.007 (Peer Reviewed)

COVID-19 in patients with lung cancer

Analysis of hospitalized lung cancer patients with 35 of 48 taking HCQ, mortality OR 1.03, p = 0.99.

risk of death, 2.2% higher, RR 1.02, p = 0.99, treatment 11 of 35 (31.4%), control 4 of 13 (30.8%), OR converted to RR.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Luo et al., 6/17/2020, retrospective, USA, North America, peer-reviewed, 31 authors.

Kim et al., Korean J Intern Med, doi:10.3904/kjim.2020.224 (Peer Reviewed)

Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019

Small retrospective study of hospitalized patients with 31 lopinavir-ritonavir and 34 HCQ patients, HCQ 400mg once per day, finding no significant difference in clinical response, but more rapid viral clearance with lopinavir-ritonavir.

Kim et al., 6/16/2020, retrospective, South Korea, Asia, peer-reviewed, 7 authors.

WHIP COVID-19 (News)

Henry Ford Health System still moving forward with hydroxychloroquine study

Ongoing WHIP COVID-19 HCQ PrEP study reports analyzing their data and seeing a significantly improved outcome in a group of COVID-19 patients who received HCQ. For more details on the study see [1].

[1] henryford.com/whip-covid-19

WHIP et al., 6/16/2020, preprint, 1 author.

Huang et al., Annals of the Rheumatic Diseases 2020:79, 1163-1169, doi:10.1136/annrheumdis-2020-217425 (Peer Reviewed)

Clinical characteristics of 17 patients with COVID-19 and systemic autoimmune diseases: a retrospective study

Analysis of 1255 COVID-19 patients in Wuhan Tongji Hospital finding 0.61% with systemic autoimmune diseases, much lower than authors expected (3%–10%). Authors hypothesise that protective factors, such as CQ/HCQ use, reduce hospitalization.

risk of hospitalization, 80.0% lower, RR 0.20, p < 0.001, treatment 8, control 1,247.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Huang et al., 6/16/2020, retrospective, China, Asia, peer-reviewed, 15 authors.

Scherrmann, AAPS J 22, 86 (2020), doi:10.1208/s12248-020-00465-w (Peer Reviewed) (Theory)

Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy

Theory paper, not included in the study count or percentages. Proposes a new mechanism supporting the synergistic interaction between HCQ+AZ.

Scherrmann et al., 6/12/2020, peer-reviewed, 1 author.

Giacomelli et al., Journal of Medical Virology, doi:10.1002/jmv.26407 (preprint 6/12) (Peer Reviewed)

Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-CoV-2 infection: a retrospective cohort study

Late stage study of hospitalized patients comparing treatment starting within 5 days versus later. Note that "early" here is only relative - all patients are hospitalized so this is "late" and "very late". The "early" treatment group is significantly older. Severe adverse events attributed by authors to concurrent administration of LPV, making it difficult to make conclusions about HCQ.

Giacomelli et al., 6/12/2020, peer-reviewed, 20 authors.

Wang et al., medRxiv, doi:10.1101/2020.06.11.20128926 (Preprint)

Comorbidity and Sociodemographic determinants in COVID-19 Mortality in an US Urban Healthcare System

Database analysis of 7,592 patients in NYC, showing adjusted HCQ mortality odds ratio OR 0.96, p = 0.82, and HCQ+AZ OR 0.94, p = 0.63

risk of death, 5.8% lower, RR 0.94, p = 0.63, treatment 1,866, control 5,726, OR converted to RR.

Excluded in after exclusion results of meta analysis: confounding by indication is likely and adjustments do not consider COVID-19 severity.

Wang et al., 6/10/2020, retrospective, database analysis, USA, North America, preprint, 3 authors.

Otea et al., medRxiv, doi:10.1101/2020.06.10.20101105 (Preprint)

A short therapeutic regimen based on hydroxychloroquine plus azithromycin for the treatment of COVID-19 in patients with non-severe disease. A strategy associated with a reduction in hospital admissions and complications.

80 moderate cases, HCQ+AZ appears to reduce serious complications and death. Moderate treated cases resulted in hospitalization at the same rate as mild untreated cases suggesting efficacy.

Otea et al., 6/10/2020, preprint, 6 authors.

Pirnay et al., Hosp. Pharm. and Clinician, doi:10.1016/j.phclin.2020.06.001 (Peer Reviewed)

Beneficial effect of Hydroxychloroquine-Azithromycin combination in the treatment of elderly patients with Covid-19: results of an observational study

68 very high risk nursing home residents, median age 86, HCQ+AZ early treatment within 2.5 days onset, 2 stopped due to QTc. Only 7 died, significantly less than other nursing homes in France and the same as the median death for the same period in 2019/2018.

Pirnay et al., 6/9/2020, peer-reviewed, 13 authors.

Bhattacharya et al., medRxix, doi:10.1101/2020.06.09.20116806 (Preprint)

Pre exposure Hydroxychloroquine use is associated with reduced COVID19 risk in healthcare workers

HCQ reduced cases from 38% to 7%. 106 people. No serious adverse effects.

risk of case, 80.7% lower, RR 0.19, p = 0.001, treatment 4 of 54 (7.4%), control 20 of 52 (38.5%).

Bhattacharya et al., 6/9/2020, retrospective, India, South Asia, preprint, 7 authors.

Roussel et al., New Microbes and New Infections, Volume 38, doi:10.1016/j.nmni.2020.100710 (Review) (Peer Reviewed)

Influence of conflicts of interest on public positions in the COVID-19 era, the case of Gilead Sciences

Shows a correlation (Spearman test, p = 0.017) between the amount received from Gilead Sciences and public opposition to the use of HCQ in France.

Roussel et al., 6/6/2020, peer-reviewed, 2 authors.

Million et al., New Microbes and New Infections, doi:10.1016/j.nmni.2020.100709 (Peer Reviewed) (meta analysis)

Clinical Efficacy of Chloroquine derivatives in COVID-19 Infection: Comparative metaanalysis between the Big data and the real world

[H]CQ effective and reduces mortality by a factor 3. Meta analysis of 20 studies.

Million et al., 6/6/2020, peer-reviewed, 14 authors.

RECOVERY Collaborative Group, NEJM, doi:10.1056/NEJMoa2022926 (press release 6/5) (Preprint)

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial

RECOVERY trial finds no significant benefit for very late stage (9 days after symptom onset) very sick patients. Results may be due to the unusually high dosage used (9.2g total over 10 days) [1, 2].

The overall dosage used is only 23% less than the high dosage that Borba et al. show greatly increases risk (OR 2.8) [3].

Authors do not report results based on weight, BMI, or related conditions such as diabetes, which may provide additional evidence of toxic dosages. Authors do not adjust dosage based on patient weight, so toxicity may be higher in patients of lower weight.

KM curves show a spike in HCQ mortality days 5-8, corresponding to ~85% of the total excess seen at day 28 (a similar spike is seen in the SOLIDARITY trial).

Authors will not release the data until Jan 8, 2021.

Authors note: "we did not observe excess mortality in the first 2 days of treatment ... when early effects of dose-dependent toxicity might be expected", but they are ignoring the very long half-life of HCQ and the dosing regimen - much higher levels of HCQ will be reached later. Increased mortality in Borba et al. occurred after 2 days.

Patients were extremely sick (median 9 days post symptoms, 60% requiring oxygen and an additional 17% requiring ventilation/ECMO), and an unusually high death rate was seen in both arms. 1,561 HCQ patients, 3,155 SOC.

A secondary analysis has found several inconsistencies in the data: [4]. Hypoxia may inhibit HCQ entering cells [5], making it less effective for late stage use.

For more on the dosing problems see [6], also noting that concentrations vary substantially in different tissues and lung concentration may be >30x plasma concentration.

[1] twitter.com/JamesTodaroMD/status/1272661099985481733

[2] twitter.com/JamesTodaroMD/status/1276245669372723200

[3] c19hcq.com/borba.html

[4] francesoir.fr/politique-monde/oxford-etude-recovery-ou-sont-les-morts

[5] twitter.com/JaclynHord/status/1302704076573077507

[6] kristianfranciscomillanielsen.medium.com/analysis-of-the-hydroxychloroquine-dosing-regimen-in-reco..

risk of death, 9.0% higher, RR 1.09, p = 0.15, treatment 421 of 1,561 (27.0%), control 790 of 3,155 (25.0%).

Excluded in after exclusion results of meta analysis: excessive dosage in late stage patients, results do not apply to typical dosages.

RECOVERY et al., 6/5/2020, Randomized Controlled Trial, United Kingdom, Europe, preprint, 29 authors.

Boulware et al., NEJM, June 3 2020, doi:10.1056/NEJMoa2016638 (Peer Reviewed)

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

COVID-19 cases are reduced by [49%, 29%, 16%] respectively when taken within ~[70, 94, 118] hours of exposure (including shipping delay). The treatment delay-response relationship is significant at p=0.002. PEP delayed treatment RCT.

For more detailed analysis, see [1].

6 independent analyses of the data in this study confirm efficacy: [2, 3, 4, 5, 6, 7, 8].

Regarding the use of folic acid, see [9].

[1] c19hcq.com/boulware.html

[2] drive.google.com/file/d/1NZOJ57fM0RTaHD1t_9w2iua7lUJhOgWT/view

[3] arxiv.org/abs/2007.09477

[4] medrxiv.org/content/10.1101/2020.08.19.20178376v1

[5] researchgate.net/publication/344369617_Hydroxychloroquine_as_Post-Exposure_Prophylaxis_for_Covid-1..

[6] blog.philbirnbaum.com/2020/08/the-nejm-hydroxychloroquine-study-fails.html

[7] longdom.org/open-access/hydroxychloroquine-and-interferons-for-the-prophylaxis-and-early-treatment..

[8] osf.io/vz8a7/

[9] sciencedirect.com/science/article/abs/pii/S0306987721000578

risk of case, 17.0% lower, RR 0.83, p = 0.35, treatment 49 of 414 (11.8%), control 58 of 407 (14.3%).

risk of case, 25.1% lower, RR 0.75, p = 0.22, treatment 32 of 414 (7.7%), control 42 of 407 (10.3%), probable COVID-19 cases.

Boulware et al., 6/3/2020, Randomized Controlled Trial, USA, North America, peer-reviewed, 24 authors.

Al-Kofahi et al., Clin. Pharmacol. Ther., Jun 1, 2020, doi:10.1002/cpt.1874 (Peer Reviewed)

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness

Analysis of HCQ dosing regimens, recommending:

PrEP: 800mg loading dose followed by 400mg 2 or 3 times weekly to maintain weekly troughs above EC₅₀ in >50% of patients at steady-state.

PEP: 800mg loading dose followed in 6 hours by 600mg, then 600mg daily for 4 more days to achieve daily troughs above EC₅₀ in >50% subjects.

Al-Kofahi et al., 6/1/2020, peer-reviewed, 9 authors.

Guérin et al., Asian J. Medicine and Health, July 15, 2020, doi:10.9734/ajmah/2020/v18i730224 (preprint 5/31) (Peer Reviewed)

Azithromycin and Hydroxychloroquine Accelerate Recovery of Outpatients with Mild/Moderate COVID-19

Mean clinical recovery time reduced from 26 days (SOC) to 9 days, p<0.0001 (HCQ+AZ) or 13 days, p<0.0001 (AZ). No cardiac toxicity. Small retrospective study of 88 patients with case control analysis with matched patients.

risk of death, 61.4% lower, RR 0.39, p = 1.00, treatment 0 of 20 (0.0%), control 1 of 34 (2.9%), relative risk is not 0 because of continuity correction due to zero events.

recovery time, 65.0% lower, relative time 0.35, p < 0.001, treatment 20, control 34.

Guérin et al., 5/31/2020, retrospective, France, Europe, peer-reviewed, 8 authors, dosage 600mg days 1-10, 7-10 days.

Rogado et al., Lung Cancer, doi:10.1016/j.lungcan.2020.05.034 (Peer Reviewed)

Covid-19 and lung cancer: A greater fatality rate?

Retrospective 17 hospitalized lung cancer patients showing lower mortality with HCQ+AZ treatment.

risk of death, 91.6% lower, RR 0.08, p = 0.02, treatment 1 of 8 (12.5%), control 7 of 9 (77.8%), OR converted to RR, multivariate logistic regression.

Rogado et al., 5/29/2020, retrospective, Spain, Europe, peer-reviewed, 9 authors.

Chamieh et al., medRxiv 2020.05.28.20114835, doi:10.1101/2020.05.28.20114835 (Preprint)

Viral Dynamics Matter in COVID-19 Pneumonia: the success of early treatment with hydroxychloroquine and azithromycin in Lebanon

HCQ+AZ potentially explains 94.7% success in treating a fairly complex cohort.

Chamieh et al., 5/28/2020, preprint, 10 authors.

Chatterjee et al., Indian J. Med. Res., June 20, 2020, doi:10.4103/ijmr.IJMR_2234_20 (Peer Reviewed)

Healthcare workers & SARS-CoV-2 infection in India: A case-control investigation in the time of COVID-19

4+ doses of HCQ associated with a significant decline in the odds of getting infected, dose-response relationship exists.

risk of case, 66.8% lower, RR 0.33, p < 0.001, treatment 12 of 68 (17.6%), control 206 of 387 (53.2%), full course vs. unused.

Chatterjee et al., 5/28/2020, retrospective, India, South Asia, peer-reviewed, survey, 11 authors.

Huang et al., National Science Review, nwaa113, doi:10.1093/nsr/nwaa113 (Peer Reviewed)

Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19

197 CQ patients, 176 control. Mean time to undetectable viral RNA and duration of fever significantly reduced. No serious adverse events.

time to viral-, 67.0% lower, relative time 0.33, p < 0.001, treatment 197, control 176.

time to viral-, 59.1% lower, relative time 0.41, p < 0.001, treatment 32, control 37, early treatment.

Huang et al., 5/28/2020, prospective, China, Asia, peer-reviewed, 36 authors.

Goldman et al., NEJM, doi:10.1056/NEJMoa2015301 (Peer Reviewed)

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Study focused on remdesivir but with results for HCQ in the supplementary appendix, showing 9% death with HCQ versus 12% control, unadjusted relative risk uRR 0.78, p = 0.46.

risk of death, 22.3% lower, RR 0.78, p = 0.46, treatment 10 of 109 (9.2%), control 34 of 288 (11.8%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Goldman et al., 5/27/2020, retrospective, multiple countries, multiple regions, peer-reviewed, 26 authors.

Kuderer et al., Lancet, June 20, 2020, doi:10.1016/S0140-6736(20)31187-9 (preprint 5/28) (Peer Reviewed)

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

Retrospective 928 cancer patients, showing HCQ OR 1.06 [0.51-2.20]. HCQ+AZ OR 2.93 [1.79-4.79]. The relative risks of different therapies suggest that the results are overly affected by confounding by indication. Authors note: HCQ+AZ might not be the cause of increased mortality, but instead these were given to patients with more severe COVID-19.

risk of death, 134.2% higher, RR 2.34, p < 0.001, treatment 45 of 181 (24.9%), control 121 of 928 (13.0%), OR converted to RR, HCQ+AZ.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Kuderer et al., 5/28/2020, retrospective, USA, North America, peer-reviewed, 73 authors.

Gianfrancesco et al., Annals of the Rheumatic Diseases, 79:7, 859-866, doi:10.1136/annrheumdis-2020-217871 (Peer Reviewed)

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry

Analysis of rheumatic disease patients showing no significant association between antimalarial therapy and hospitalisation, OR=0.94 [0.57-1.57], p=0.82 after adjustments.

risk of hospitalization, 3.3% lower, RR 0.97, p = 0.82, treatment 58 of 130 (44.6%), control 219 of 470 (46.6%), OR converted to RR.

Excluded in after exclusion results of meta analysis: not fully adjusting for the baseline risk differences within systemic autoimmune patients.

Gianfrancesco et al., 5/28/2020, retrospective, database analysis, multiple countries, multiple regions, peer-reviewed, 28 authors.

Risch, American Journal of Epidemiology, kwaa093, 27 May 2020, doi:10.1093/aje/kwaa093 (Peer Reviewed) (meta analysis)

Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis

Five studies, including two controlled clinical trials, have demonstrated significant outpatient treatment efficacy.

Risch et al., 5/27/2020, peer-reviewed, 1 author.

Ip et al., PLoS ONE, doi:10.1371/journal.pone.0237693 (Peer Reviewed)

Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients - An Observational Study

Retrospective study of late stage use on 2,512 hospitalized patients showing no significant differences in associated mortality for patients receiving any HCQ during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), HCQ alone (HR, 1.02 [95% CI, 0.83-1.27]), or HCQ+AZ (HR, 0.98 [95% CI, 0.75-1.28]). Misclassification is possible due to manual abstraction of EHR data. They observed a change in the prescribing patterns of HCQ during the study timeframe. Confounding by indication.

risk of death, 1.0% lower, RR 0.99, p = 0.93, treatment 432 of 1,914 (22.6%), control 115 of 598 (19.2%), adjusted.

Ip et al., 5/25/2020, retrospective, database analysis, USA, North America, peer-reviewed, 32 authors.

Hraiech et al., Ann. Intensive Care, doi:10.1186/s13613-020-00678-4 (Peer Reviewed)

Lack of viral clearance by the combination of hydroxychloroquine and azithromycin or lopinavir and ritonavir in SARS-CoV-2-related acute respiratory distress syndrome

Retrospective 45 ICU patients, 17 treated with HCQ+AZ, showing no significant difference in viral clearance after 6 days, or mortality 6 days from ARDS.

risk of death, 64.7% lower, RR 0.35, p = 0.21, treatment 2 of 17 (11.8%), control 5 of 15 (33.3%), day 38 +- 7.

risk of death, 376.5% higher, RR 4.76, p = 0.49, treatment 2 of 17 (11.8%), control 0 of 15 (0.0%), continuity correction due to zero event, day 6 from ARDS.

risk of no virological cure, 2.9% higher, RR 1.03, p = 1.00, treatment 14 of 17 (82.4%), control 8 of 10 (80.0%), day 6 from treatment.

Excluded in after exclusion results of meta analysis: very late stage, ICU patients.

Hraiech et al., 5/24/2020, retrospective, France, Europe, peer-reviewed, 8 authors.

ICMR, Indian Council of Medical Research (Advisory)

Revised advisory on the use of Hydroxychloroquine (HCQ) as prophylaxis for SARS-CoV-2 infection

Healthcare workers on HCQ prophylaxis less likely to get COVID. Significant dose-response relationship. Extends recommended HCQ prophylaxis to asymptomatic household contacts of cases and frontline workers. Degree of benefit not quantified.

ICMR et al., 5/22/2020, preprint, 1 author.

Mehra et al., The Lancet, May 22, 2020, doi: 10.1016/S0140-6736(20)31180-6 (Peer Reviewed)

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Incorrect at first read (implausible death, ventilation, and population numbers). This paper was retracted.

Mehra et al., 5/22/2020, peer-reviewed, 4 authors.

Luo et al., The American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.20-0375 (Peer Reviewed)

Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis

Retrospective 283 COVID-19+ diabetes patients in China, showing non-statistically significant lower mortality with HCQ/CQ treatment.

risk of death, 32.4% lower, RR 0.68, p = 0.72, treatment 19, control 264, multivariate, RR approximated with OR.

Luo et al., 5/21/2020, retrospective, China, Asia, peer-reviewed, 9 authors.

Singh et al., medRxiv, doi:10.1101/2020.05.12.20099028 (Preprint)

Outcomes of Hydroxychloroquine Treatment Among Hospitalized COVID-19 Patients in the United States- Real-World Evidence From a Federated Electronic Medical Record Network

EHR analysis of 3,372 hospitalized COVID-19 patients not showing a significant difference for mortality or the risk of mechanical ventilation. Subject to the limitations of EHR analysis. Misclassification is possible. Confounding by indication is likely.

risk of death, 5.0% lower, RR 0.95, p = 0.72, treatment 104 of 910 (11.4%), control 109 of 910 (12.0%).

risk of mechanical ventilation, 19.0% lower, RR 0.81, p = 0.26, treatment 46 of 910 (5.1%), control 57 of 910 (6.3%).

Excluded in after exclusion results of meta analysis: confounding by indication is likely and adjustments do not consider COVID-19 severity.

Singh et al., 5/19/2020, retrospective, database analysis, USA, North America, preprint, 4 authors.

Kim et al., medRxiv, doi:10.1101/2020.05.13.20094193 (Preprint)

Treatment Response to Hydroxychloroquine, Lopinavir/Ritonavir, and Antibiotics for Moderate COVID 19: A First Report on the Pharmacological Outcomes from South Korea

Retrospective of 97 moderate cases. Time to viral clearance significantly shorter for HCQ+antibiotic. Preprint withdrawn pending peer review.

hospitalization time, 51.0% lower, relative time 0.49, p = 0.01, treatment 22, control 40.

time to viral-, 56.0% lower, relative time 0.44, p = 0.005, treatment 22, control 40.

Kim et al., 5/18/2020, retrospective, South Korea, Asia, preprint, 11 authors.

Ahmad et al., doi:10.1101/2020.05.18.20066902 (Preprint)

Doxycycline and Hydroxychloroquine as Treatment for High-Risk COVID-19 Patients: Experience from Case Series of 54 Patients in Long-Term Care Facilities

54 patients in long term care facilities. 6% death with HCQ+AZ compared to 22% using a naive indirect comparison.

Ahmad et al., 5/18/2020, preprint, 5 authors.

Macias et al., medRxiv, 10.1101/2020.05.16.20104141 (Preprint)

Similar incidence of Coronavirus Disease 2019 (COVID-19) in patients with rheumatic diseases with and without hydroxychloroquine therapy

Very small retrospective study of rheumatic disease patients, sample size is too small for statistical significance (HCQ 0.5-4.0%, no-HCQ 0.4-2.7%). Confirmed cases were 1 HCQ and 2 no-HCQ, confirmed+likely cases were 1 HCQ and 3 no-HCQ. 1 HCQ and 2 no-HCQ patients were admitted to hospital. We do not think a conclusion can be drawn based on these sample sizes.

There are very significant differences between the groups, for example 30% of the HCQ group have SLE vs. 2.5% of the no-HCQ group. SLE patients have a 5.7 times relative risk of pneumonia according to [1], whereas the relative risk with glucocorticoids and TNF-α inhibitors is significantly lower [2]. Two more recent studies with rheumatic disease/autoimmune condition patients provide higher confidence.

[1] ncbi.nlm.nih.gov/pmc/articles/PMC4516647/

[2] academic.oup.com/rheumatology/article/52/1/53/1830871

risk of hospitalization, 25.5% lower, RR 0.74, p = 1.00, treatment 1 of 290 (0.3%), control 2 of 432 (0.5%).

risk of case, 49.0% higher, RR 1.49, p = 0.53, treatment 5 of 290 (1.7%), control 5 of 432 (1.2%).

Excluded in after exclusion results of meta analysis: not fully adjusting for the baseline risk differences within systemic autoimmune patients.

Macias et al., 5/16/2020, retrospective, database analysis, Spain, Europe, preprint, 12 authors.

Yu et al., Science China Life Sciences, 2020 May 15, 1-7, doi:10.1007/s11427-020-1732-2 (Peer Reviewed)

Low Dose of Hydroxychloroquine Reduces Fatality of Critically Ill Patients With COVID-19

Retrospective, 550 critically ill patients. 19% fatality for HCQ versus 47% for non-HCQ, RR 0.395, p=0.002.

The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 pg/mL to 5.2 pg/mL (p<0.05) at the end of the treatment in the HCQ group but there was no change in the control group.

risk of death, 60.5% lower, RR 0.40, p = 0.002, treatment 9 of 48 (18.8%), control 238 of 502 (47.4%).

Yu et al., 5/15/2020, retrospective, China, Asia, peer-reviewed, 8 authors.

Mahévas et al., BMJ 2020, 369, doi: https://doi.org/10.1136/bmj.m1844 (Peer Reviewed)

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Observational study of 181 patients with advanced disease requiring oxygen showing no benefit for HCQ. Power of study appears too low to support conclusions [1].

None of the 15 patients receiving HCQ+AZ were transferred to intensive care or died compared to 23% overall.

[1] bmj.com/content/369/bmj.m1844/rapid-responses

risk of death, 20.0% higher, RR 1.20, p = 0.75, treatment 9 of 84 (10.7%), control 8 of 89 (9.0%), adjusted.

Mahévas et al., 5/14/2020, retrospective, France, Europe, peer-reviewed, 34 authors.

Okour et al., Journal of Pharmacokinetics and Pharmacodynamics, May 13, 2020, doi:10.1007/s10928-020-09689-x (Peer Reviewed)

Hydroxychloroquine and azithromycin as potential treatments for COVID-19; clinical status impacts the outcome

Odds of PCR-positive decrease by 53% for each unit increase in HCQ log-concentration. Similarly, the odds decrease by 61%, and by 12% for each day increase, and for azithromycin co-treatment, respectively. Computes the minimum HCQ concentration needed based on severity, and corresponding dosage regimens. A loading dose is found to be important. For LRTI and URTI patients the addition of AZ is needed. Extended analysis of Gautret et al. using the observed HCQ concentrations and pharmacokinetic analysis to compute concentrations for all days.

Okour et al., 5/13/2020, peer-reviewed, 3 authors.

Cassione et al., Annals of the Rheumatic Diseases, doi:10.1136/annrheumdis-2020-217717 (Letter)

COVID-19 infection in a northern-Italian cohort of systemic lupus erythematosus assessed by telemedicine

Survey of 165 SLE patients, 127 on HCQ. 8 patients with suspected COVID-19 and 4 confirmed cases. No mortality, one ICU case. 7 patients had no symptoms despite contact with a COVID-19 patient.

No adjustment for concomitant medications or severity of SLE. Confounding by indication.

risk of case, 49.6% higher, RR 1.50, p = 0.59, treatment 10 of 127 (7.9%), control 2 of 38 (5.3%).

Excluded in after exclusion results of meta analysis: not fully adjusting for the different baseline risk of systemic autoimmune patients.

Cassione et al., 5/12/2020, retrospective, Italy, Europe, preprint, survey, median age 52.5, 6 authors.

Shabrawishi et al., medRxix, doi:10.1101/2020.05.08.20095679 (Preprint)

Negative nasopharyngeal SARS-CoV-2 PCR conversion in response to different therapeutic interventions

Retrospective 93 hospitalized patients in Saudi Arabia showing a non-statistically significant 15% reduction in PCR positive results at day 5, RR 0.85, p = 0.65. The treatment group had significantly more severe illness and significantly more male patients.

risk of no virological cure at day 5, 14.7% lower, RR 0.85, p = 0.66, treatment 12 of 45 (26.7%), control 15 of 48 (31.2%).

Shabrawishi et al., 5/11/2020, retrospective, Saudi Arabia, Middle East, preprint, mean age 43.9, 5 authors.

Rosenberg et al., JAMA, May 11, 2020, doi:10.1001/jama.2020.8630 (Peer Reviewed)

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Restrospective observational late stage study showing no significant differences but calling for clinical trials.

Zervos et al. [1] point out serious limitations that they say should be corrected on the record: patients receiving HCQ with or without AZ were overall sicker on presentation and had multiple other risk factors including much higher risk based on ethnicity; patients receiving HCQ were more likely to be obese, diabetic, have chronic lung disease, and cardiovascular conditions; yet these sicker patients had approximately the same mortality rates compared to patients with a milder course of the disease and less risk factors. However, the authors conclude that "there are no significant benefits." It is noteworthy that HCQ was associated with a significant survival benefit in a larger cohort of patients from New York City as reported by Mikami et al [2].

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychloro..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption