HCQ for COVID-19: real-time analysis of all 364 studies

Covid Analysis (Preprint) (meta analysis)

HCQ for COVID-19: real-time meta analysis of 298 studies

• 97% of the 33 early treatment studies report a positive effect (14 statistically significant in isolation).

• 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.

• Late treatment is less successful, with only 68% of the 201 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 this happening for an ineffective treatment is 0.0038.

• There is evidence of bias towards publishing negative results. 76% of prospective studies report positive effects, compared to 72% 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 = 0.0000000277. The probability that an ineffective treatment generated results as positive as the 298 studies is estimated to be 1 in 1 quadrillion.

• 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	298 studies	4,772 authors	413,756 patients
Positive effects	217 studies	3,380 authors	291,466 patients

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

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, 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, 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.

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 any difference in the probability of a serious enough case to be 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 combined intubation/death, 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 combined intubation/death, 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 combined 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 disease 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 disease 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 disease 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 disease 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 combined intubation/death, 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 disease 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.

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., 10/26/2020, 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.

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 combined 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 combined 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].

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