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.
OBJECTIVES: To estimate the effect of HCQ to prevent COVID-19 as pre-exposure and as post-exposure prophylaxis by meta-analyzing published randomized trials.
METHODS: A search of PubMed and medRxiv with expert consultation found ten completed randomized trials comparing HCQ as prophylaxis for COVID-19 with a non-active control: 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. We used a fixed effect, the standard random effect, and a modified Hartung-Knapp approaches.
RESULTS: The primary outcome definition varied across trials, with some trials using the presence of symptoms with or without laboratory confirmation, others using laboratory-confirmed symptomatic COVID-19 and others laboratory-confirmed SARS-CoV-2 infection with or without symptoms. One study with moderate risk of bias ("Rob 2" tool by the Cochrane Bias Methods Group) was not included because the effect estimate was reported only as a p-value. Another study was not included because there were zero events in the HCQ arm. The pooled risk ratio estimate of the pre-exposure prophylaxis trials was 0.72 (95% Cl: 0.58-0.91) when using either a fixed effect or a standard random effects approach, and 0.72 (95% Cl: 0.52-1.00) when using a conservative modification of the Hartung-Knapp random effects approach. Sensitivity analyses that used "laboratory-confirmed, symptomatic COVID-19" as the outcome and that analyzed only studies published in peer-reviewed journals did not materially change the results. The corresponding estimates for the post exposure prophylaxis trials were 0.91 (95% Cl: 0.71-1.16) and 0.91 (95% Cl: 0.54-1.55). All trials found a similar rate of serious adverse effects in the HCQ and no HCQ groups.
CONCLUSIONS: 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.
