Systematic review and meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19

Background Recruitment into randomized trials of hydroxychloroquine (HCQ) for prevention of COVID-19 has been adversely affected by a widespread conviction that HCQ is not effective for prevention. In the absence of an updated systematic review, we conducted a meta-analysis of randomized trials that study the effectiveness of HCQ to prevent COVID-19. Methods A search of PubMed and medRxiv with expert consultation found ten completed randomized trials: seven pre-exposure prophylaxis trials and three post-exposure prophylaxis trials. We obtained or calculated the risk ratio of COVID-19 diagnosis for assignment to HCQ versus no HCQ (either placebo or usual care) for each trial, and then pooled the risk ratio estimates. Results The pooled risk ratio estimate of the pre-exposure prophylaxis trials was 0.72 (95% CI: 0.58-0.91) when using either a fixed effect or a standard random effects approach, and 0.72 (95% CI: 0.52-1.00) when using a conservative modification of the Hartung-Knapp random effects approach. The corresponding estimates for the post-exposure prophylaxis trials were 0.91 (95% CI: 0.71-1.16) and 0.91 (95% CI: 0.54-1.55). All trials found a similar rate of serious adverse effects in the HCQ and no HCQ groups. Discussion A benefit of HCQ as prophylaxis for COVID-19 cannot be ruled out based on the available evidence from randomized trials. However, the “not statistically significant” findings from early prophylaxis trials were widely interpreted as definite evidence of lack of effectiveness of HCQ. This interpretation disrupted the timely completion of the remaining trials and thus the generation of precise estimates for pandemic management before the development of vaccines.