Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis

Abstract

Background: Hydroxychloroquine or chloroquine with or without azithromycin have been widely pro-moted to treat coronavirus disease 2019 (COVID-19) following earlyin vitroantiviral effects against se-vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Objective:The aim of this systematic review and meta-analysis was to assess whether chloroquine orhydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with thestandard of care.Data sources:PubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv weresearched up to 25 July 2020.Study eligibility criteria:We included published and unpublished studies comparing the mortality ratebetween patients treated with chloroquine or hydroxychloroquine with or without azithromycin andpatients managed with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 wereconducted to assess drug safety.Results:The initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies exceptone were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with orwithout azithromycin. Among the 29 articles, three were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysisincluded 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine withazithromycin group and 12 930 for the control group. Hydroxychloroquine was not significantly asso-ciated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65e1.06,n¼17 studies) for all studies andRR¼1.09 (95% CI 0.97e1.24,n¼3 studies) for randomized controlled trials. Hydroxychloroquine withazithromycin was associated with an increased mortality (RR¼1.27; 95% CI 1.04e1.54,n¼7 studies). Wefound 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.