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Objectives Clinical studies of chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 disease reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin on outcomes of COVID-19 patients. Methods We searched multiple databases, preprints and grey literature up to 17 July 2020. We pooled only adjusted-effect estimates of mortality using a random-effect model. We summarized the effect of CQ or HCQ on viral clearance, ICU admission/mechanical ventilation and hospitalization. Results Seven randomized clinical trials (RCTs) and 14 cohort studies were included (20 979 patients). Thirteen studies (1 RCT and 12 cohort studies) with 15 938 hospitalized patients examined the effect of HCQ on short-term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96–1.15, I2 = 0%). Six cohort studies examined the effect of the HCQ+azithromycin combination with a pooled adjusted OR of 1.32 (95% CI 1.00–1.75, I2 = 68.1%). Two cohort studies and four RCTs found no effect of HCQ on viral clearance. One small RCT demonstrated improved viral clearance with CQ and HCQ. Three cohort studies found that HCQ had no significant effect on mechanical ventilation/ICU admission. Two RCTs found no effect for HCQ on hospitalization risk in outpatients with COVID-19. Conclusions Moderate certainty evidence suggests that HCQ, with or without azithromycin, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19 or risk of hospitalization in outpatients with COVID-19.

Background The antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) show promising SARS-CoV-2 anti-viral activity in vitro; however, clinical studies have reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin (AZ) on outcomes of COVID-19 patients. Methods We performed a systematic review and meta-analysis of studies published through July 7, 2020. We searched Medline, Embase, EBM Reviews, Scopus, Web of Science, preprints and grey literature. We included studies that assessed COVID-19 patients treated with CQ or HCQ, with or without AZ. We pooled only adjusted effect estimates of mortality using a random effect model and estimated between studies heterogeneity using I2 statistic. We summarized the effect of CQ or HCQ on viral clearance and ICU admission/ mechanical ventilation. Results Out of 1463 citations screened for eligibility, five RCTs and 14 cohort studies were included (20,263 patients, all hospitalized but with a variable disease severity spectrum). Thirteen studies (1 RCT and 12 cohorts) with 19,573 patients examined the effect of HCQ on short term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96-1.15, I2=0 %, p=0.647). Six cohort studies examined the effect of HCQ and AZ combination among 3430 patients. After excluding a study that examined only patients with cancers, the pooled adjusted OR was (1.15, 95% CI 0.99-1.34, I2=0.0%). Two cohort studies and three RCTs found no significant effect of HCQ on viral clearance. One RCT with 48 patients demonstrated improved viral clearance in patients treated with CQ and HCQ. Three cohort studies found that HCQ with or without AZ had no significant effect on mechanical ventilation/ ICU admission. Conclusion Moderate certainty evidence suggests that HCQ, with or without AZ, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19. Our findings are consistent with the recommendations from medical societies that HCQ should only be used to treat COVID-19 patients in the context of clinical trials. Trials of HCQ as pre-exposure prophylaxis are ongoing.