A Meta-Review of Meta-Analyses and an Updated Meta-Analysis on the Efficacy of Chloroquine and Hydroxychloroquine in treating COVID-19 Infection

Objective: To synthesize the findings presented in systematic reviews and meta-analyses as well as to update the evidence using a meta-analysis in evaluating the efficacy and safety of CQ and HCQ with or without Azithromycin for the treatment of COVID-19 infection. Methods: The design of this meta-review followed the preferred reporting items for overviews of systematic reviews including harms checklist (PRIO-harms). A comprehensive search included several electronic databases in identifying all systematic reviews and meta-analyses as well as experimental studies which investigated the efficacy and safety of CQ, HCQ with or without antibiotics as COVID-19 treatment. Findings from the systematic reviews and metaanalyses were reported using a structured summary including tables and forest plots. The updated metaanalyses of experimental studies was carried out using the distributional assumption-free quality effects model. Risk of bias was assessed using the assessing the methodological quality of systematic reviews (AMSTAR) tool for reviews and the methodological standard for epidemiological research (MASTER) scale for the experimental studies. The main outcome for both the meta-review and the updated metaanalyses was mortality. Secondary outcomes included transfer to the intensive care unit (ICU) or mechanical ventilation, worsening of illness, viral clearance and the occurrence of adverse events. Results: A total of 13 reviews with 40 primary studies comprising 113,000 participants were included. Most of the primary studies were observational (n=27) and the rest were experimental studies. Two meta-analyses reported a high risk of mortality with similar ORs of 2.5 for HCQ with Azithromycin. However, four other metaanalyses reported contradictory results with two reporting a high risk of mortality and the other two reporting no significant association between HCQ with mortality. Most reviews reported that HCQ with or without Azithromycin had no significant effect on virological cure, disease exacerbation or the risk of transfer to the ICU, need for intubation or mechanical ventilation. After exclusion of studies that did not meet the eligibility criteria, the updated meta-analysis contained eight experimental studies (7 RCTs and 1 quasiexperimental trial), with a total of 5279 participants of whom 1856 were on either CQ/HCQ or combined with Azithromycin. CQ/HCQ with or without Azithromycin was significantly associated with a higher risk of adverse events. HCQ was not effective in reducing mortality transfer to the ICU, intubation or need for mechanical ventilation virological cure (RR 1.0, 95%CI 0.9-1.2, I2 =55%, n=5 studies) nor disease exacerbation (RR 1.2, 95%CI 0.3-5.0, I2 =29%, n=3 studies). Conclusion: There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation.