Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis

Abstract

Background Hydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat COVID-19 following early in vitro antiviral effects against SARS-CoV-2 Objective The aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared to the standard of care. Data sources Pubmed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched until 25 July 2020. Study eligibility criteria We included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care. Participants Patients ≥18 years old with confirmed COVID-19. Interventions Chloroquine or hydroxychloroquine with or without azithromycin. Methods Effect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess the drug safety. Results The initial search yielded 839 articles, of which 29 articles met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, 3 were randomized controlled trials (RCT), one was a non-randomized trial and 25 were observational studies, including 10 with a critical risk of bias and 15 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11,932 participants for the hydroxychloroquine group, 8,081 for the hydroxychloroquine with azithromycin group and 12,930 for the control group. Hydroxychloroquine was not significantly associated with mortality: pooled Relative Risk RR=0.83 (95% CI: 0.65-1.06, n=17 studies) for all studies and RR=1.09 (95% CI: 0.97-1.24, n=3 studies) for RCTs. Hydroxychloroquine with azithromycin was associated with an increased mortality: RR=1.27 (95% CI: 1.04-1.54, n=7 studies). We found similar results with a Bayesian meta-analysis. Conclusion Hydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.