Benefits and Risks of Chloroquine and Hydroxychloroquine in The Treatment of Viral Diseases: A Meta-Analysis of Placebo Randomized Controlled Trials

Abstract

Background and Objective:Recently, in the scramble to find drugs to treat COVID-19, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have rapidly gained the public's attention. In this study, we conducted a meta-analysis of randomized clinical trials (RCTs) to evaluate the efficacy and safety of CQ and HCQ in the treatment of viral diseases. Methods:We searched PubMed, EMBASE, Cochrane Central, Web of Science, Clinical Trials Registries, CNKI, Wanfang Data, CQVIP, and Preprint Servers through April 4, 2020, for randomized controlled trials (RCTs) that examined the efficacy and safety of CQ and HCQ against viral infection. We analyzed pooled data on the overall efficacy, the relative risks over the placebo, and the prevalence of adverse events. Trial sequential analysis (TSA) was also performed to evaluate the random errors in the meta-analysis. Potential moderators of drugplacebo efficacy differences were analyzed by meta-regression. Results:The analysis included 11 RCTs with 2613 adult patients. Both the plasma viral load (standard mean difference: 0.29, 95% CI: -1.19 -1.76, P = 0.70) and the improvement of clinical symptoms (odds ratio: 2.36, 95% CI: 0.81 -6.92, P = 0.11) were not different between the intervention and placebo arm. There was significant heterogeneity for the efficacy assessment, which was primarily explained by the mean patients' age and the sample size. Compared to the placebo, CQ and HCQ had increased risk of mild adverse events (risk ratio: 1.51, 95% CI: 1.35 -1.70, P < 0.05, TSA adjusted 95% CI: 1.31 -2.19), which were statistically significant in nervous, integumentary, and gastrointestinal systems. The most common adverse events were observed in the nervous system, with the pooled prevalence of 31.4 % (95% CI: 10.5% -56.7%). Conclusions:Insufficient data were available to support the antiviral efficacy of CQ and HCQ due to the high heterogeneity caused by patients' age. Mild side effects are expected for the current antiviral dose regimens of CQ and HCQ. Treatment outcomes may be enhanced by better-selected patients based on age and well-controlled adverse events.This meta-analysis was registered on OSF (ID: https://osf.io/386aw) P a g e 3 o f 2 1

“Off-label” use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers

“…Yet, HCQ, CQ, AZI and LOPI are frequently used in COVID-19 with its array of inner risk factors. They bear a significant risk of cardiac ADRs [46]. Notwithstanding the need to foster investigation on putative treatments, the safety profile of drugs should not be overlooked.…”

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

“…Hydroxychloroquine compared to control group was found to be associated with a longer time to clinical recovery in both non‐RCTs/cohort study subgroup as well as in the RCT subgroup (Figure S2 in Appendix ). Two recent meta‐analyses conducted by Ren et al and Wang et al found that patients taking chloroquine or hydroxychloroquine had more adverse events compared to patients assigned to placebo group 64,65 . Another meta‐analysis published a couple of months ago by Sarma et al 66 found no association of hydroxychloroquine with virological cure, death or clinical worsening and safety in nCOV‐2019 patients.…”

“…Two recent meta-analyses conducted by Ren et al and Wang et al found that patients taking chloroquine or hydroxychloroquine had more adverse events compared to patients assigned to placebo group. 64,65 Another meta-analysis published a couple of months ago by Sarma et al 66 found no association of hydroxychloroquine with virological cure, death or clinical worsening and safety in nCOV-2019 patients. Similar findings on hydroxychloroquine with or without azithromycin were observed from another meta-analysis of five trials which although did observe a trend but the results were not found to be statistically significant in terms of negative conversion of nCOV-2019 (odds ratio [OR] 1.95; 95%CI 0.19 to 19.73) and reduction in progression rate (OR 0.89 95%CI 0.58 to 1.37).…”

Effect of various treatment modalities on the novel coronavirus (nCOV-2019) infection in humans: a systematic review & meta-analysis

“…A recently published multinational registry analysis on 96,032 nCOV-2019 patients observed that Hydroxychloroquine and Chloroquine were associated with an increased risk of in-hospital mortality (96). Two recent meta-analyses conducted by Ren L et al 2020 and Wang J et al 2020 found that patients taking Chloroquine or Hydroxychloroquine had more adverse events compared to patients assigned to placebo group (97,98). Another meta-analysis published last month by Sarma et al 2020 found no association of Hydroxychloroquine with virological cure, death or clinical worsening and safety in nCOV-2019 patients (99).…”