A meta-review of systematic reviews and an updated meta-analysis on the efficacy of chloroquine and hydroxychloroquine in treating COVID19 infection

BACKGROUND: There is an urgent need for an efficacious and safe treatment for COVID19. Several trials testing a variety of therapeutics are on-going. Some in-vitro studies found the anti-malarial drug chloroquine (CQ), and its derivative, hydroxychloroquine (HCQ), are effective against COVID19. However, systematic reviews and meta-analyses of clinical trials in humans have produced conflicting findings on the efficacy and safety of these drugs. Guidelines vary considerably and are hotly debated at political and scientific levels. Therefore, it has become necessary to provide a summary of the effectiveness and safety of these drugs in treating COVID19 infection, using an overview of the existing systematic reviews and meta-analyses. 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 COVID19 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 COVID19 treatment. Manual searches of the reference list of all included studies and a citation search of the top 20 papers supplemented the search. Findings from the systematic reviews and meta-analyses were reported using a structured summary including tables and forest plots. The updated meta-analysis 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 outcomes for both the meta-review and the updated meta-analysis were; mortality, transfer to the intensive care unit (ICU), intubation or the need for 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 meta-analyses reported contradictory results with two reporting a high risk of mortality (OR ~ 2.2 to 3.0) 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 quasi-experimental 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 (RR 5.7, 95%CI 2.4-13.7, I2 =55%, n = 5 studies). HCQ was not effective in reducing mortality (RR 1.0, 95%CI 1.0-1.2, I2 =0%, n=6 studies), transfer to the ICU, intubation or need for mechanical ventilation (RR 1.1, 95%CI 0.9-1.4, I2 =0%, n=3 studies) 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.