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Safety and efficacy of hydroxychloroquine as prophylactic against COVID-19 in healthcare workers: a meta-analysis of randomised clinical trials

Hong et al., BMJ Open, doi:10.1136/bmjopen-2022-065305, PROSPERO CRD42021285093
Jun 2023  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Study does not match registration: outcomes, search sources, exclusions, statistical analysis, and the cutoff date have changed. Efficacy seen without the post-hoc HCW restriction.
Meta analysis of 10 RCTs showing lower COVID-19 cases with HCQ, without statistical significance.
This analysis is missing Nasri, Seet. Statistically significant efficacy is seen with analysis of all PrEP studies at the time. There are now 13 PrEP RCTs, showing significant efficacy with p = 0.00023
Authors include only studies with healthcare workers, which excludes Seet. This is a protocol violation - the pre-registered protocol has no restriction or mention of healthcare workers.
Authors report a 67% probability of efficacy for the lab-confirmed analysis (Bayesian posterior probability of OR<1). Notably authors do not report the probability for the suspected COVID-19 analysis, which is higher.
All PEP studies are not included Barnabas, Boulware, Dhibar, Mitjà.
Authors claim Seet has moderate risk of bias, however trials with more significant issues were included. Authors state: "HCQ does not reduce the risk of confirmed or probable SARS-CoV-2 infection". This is false, authors found reduced risk, just without statistical significance due to the exclusion of studies.
Author's bayesian analysis, with details unspecified in the pre-registration, provides flexibility to alter the results. Notably, a standard DerSimonian and Laird random effects analysis is much closer to statistical significance - 0.78 [0.59-1.02] p=0.07 for suspected COVID-19.
This study includes authors with extreme conflicts of interest that have coauthored other COVID-19 trials with many critical issues, including impossible and inconsistent data. For example see issues with Boulware, Naggie, Reis.
7 meta analyses show significant improvements with hydroxychloroquine for mortality Landsteiner de Sampaio Amêndola, Risch, Risch (B), Stricker, hospitalization Landsteiner de Sampaio Amêndola, recovery Prodromos, combined death/hospitalization/cases Ladapo, and cases García-Albéniz.
Currently there are 39 HCQ for COVID-19 early treatment studies, showing 76% lower mortality [61‑85%], 67% lower ventilation [-710‑99%], 31% lower ICU admission [1‑53%], and 41% lower hospitalization [28‑51%].
Hong et al., 16 Jun 2023, peer-reviewed, 15 authors, trial PROSPERO CRD42021285093.
This PaperHCQAll
Safety and efficacy of hydroxychloroquine as prophylactic against COVID-19 in healthcare workers: a meta-analysis of randomised clinical trials
Hwanhee Hong, Anne Friedland, Mengyi Hu, Kevin J Anstrom, Susan Halabi, John E Mckinnon, Ravi Amaravadi, Jorge Rojas-Serrano, Benjamin S Abella, Angélica Margarita Portillo-Vázquez, Christopher W Woods, Adrian F Hernandez, David R Boulware, Susanna Naggie, Radha Rajasingham
BMJ Open, doi:10.1136/bmjopen-2022-065305
Objective We studied the safety and efficacy of hydroxychloroquine (HCQ) as pre-exposure prophylaxis for COVID-19 in healthcare workers (HCWs), using a metaanalysis of randomised controlled trials (RCTs). Data sources PubMed and EMBASE databases were searched to identify randomised trials studying HCQ. Study selection Ten RCTs were identified (n=5079 participants). Data extraction and synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this systematic review and metaanalysis between HCQ and placebo using a Bayesian random-effects model. A pre-hoc statistical analysis plan was written. Main outcomes The primary efficacy outcome was PCRconfirmed SARS-CoV-2 infection and the primary safety outcome was incidence of adverse events. The secondary outcome included clinically suspected SARS-CoV-2 infection. Results Compared with placebo, HCWs randomised to HCQ had no significant difference in PCR-confirmed SARS-CoV-2 infection (OR 0.92, 95% credible interval (CI): 0.58, 1.37) or clinically suspected SARS-CoV-2 infection (OR 0.78, 95% CI: 0.57, 1.10), but significant difference in adverse events (OR 1.35, 95% CI: 1.03, 1.73). Conclusions and relevance Our meta-analysis of 10 RCTs investigating the safety and efficacy of HCQ as preexposure prophylaxis in HCWs found that compared with placebo, HCQ does not significantly reduce the risk of confirmed or clinically suspected SARS-CoV-2 infection, while HCQ significantly increases adverse events. PROSPERO registration number CRD42021285093.
Competing interests All authors except BSA reported no financial relationship with commercial interest. BSA has received NIH funds for COVID-19-related research and holds equity in VOC Health, a start-up company that is developing novel COVID-19 testing. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Patient consent for publication Not required. Ethics approval Ethics approval was not required because this study used publicly available aggregate data that were not involved with patients' information or prospective data collection. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or..
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