Efficacy and Safety of Anti-malarial Drugs (Chloroquine and Hydroxy-Chloroquine) in Treatment of COVID-19 Infection: A Systematic Review and Meta-Analysis

Abstract

Background: Anti-malarial drugs inhibit coronaviruses in-vitro. Few published studies have evaluated the safety and efficacy of these drugs in the treatment of COVID-19 infection. Materials and Methods: This is a systematic review and meta-analysis of clinical trials and observational studies. Major database searches were carried out up until June 5, 2020. Participants admitted with RT-PCR-confirmed SARS Cov-2 (COVID-19) infection were included. The "Intervention group" received anti-malarial drugs with or without other drugs (Azithromycin) administered as an adjunct to the standard treatment/care. The "Control group" received treatment except anti-malarial drugs. The primary outcome is "all-cause mortality." Secondary outcome measures were effects on clinical and laboratory parameters and adverse events. Results: Of 3,472 citations, 17 (six clinical trials and 11 observational studies) studies provided data of 8,071 participants. Compared to the control, Hydroxy-chloroquine (HCQ) has no significant effect on mortality [(OR 0.87; 95% CI 0.46-1.64); eight observational studies; N = 5,944]. Data from a single, small non-randomized trial (N = 42) also reached a similar conclusion (OR 1.94; 95% CI 0.07-50.57; p = 0.69). Compared to the control, HCQ plus Azithromycin (AZM) significantly increased mortality [(OR 2.84; 95% CI 2.19-3.69); four observational studies; N = 2,310]. Compared to the control, risk of any adverse event was significantly increased in HCQ group [(OR 3.35; 95% CI 1.58-7.13); four clinical trials; N = 263]. Compared to control, risk of adverse cardiac events (abnormal ECG, arrhythmia, or QT prolongation) were not significantly increased in HCQ group (but significantly increased in the HCQ plus AZM group). The GRADE evidence generated for all the outcomes was of "very low-quality." Conclusions: As very low quality evidence suggests an increased risk of mortality and adverse event with HCQ plus Azithromycin combination (not HCQ alone), caution should Das et al. Anti-malarial Drugs as a Treatment of COVID-19 be exercised while prescribing this combination for treatment of hospitalized adults with COVID-19 infection. Good quality, multi-centric RCTs (including both hospitalized and non-hospitalized patients) are required for any firm recommendation to be made during the ongoing pandemic. OSF Protocol Registration Link: https://osf.io/6zxsu.

Rationale for azithromycin in COVID-19: an overview of existing evidence

“…However, as they are largely based on the sometimes heavily biased data of the studies discussed above, one might still doubt a causal inference. The data of azithromycin monotherapy have not been pooled, and of the three meta-analyses that directly compared hydroxychloroquine with azithromycin versus hydroxychloroquine alone, only Das et al 77 found a significantly increased mortality with the addition of azithromycin. Interestingly, not cardiac adverse events but rather the development of severe disease was an outcome associated with the addition of azithromycin to hydroxychloroquine.…”

Chloroquine and hydroxychloroquine in the treatment of COVID-19: the never-ending story

“…Nowadays, there are increasing data reporting evidence of the ineffectiveness of CQ and HCQ in improving the prognosis or shorten the clinical course of COVID-19 (Gao et al 2020a;Horby et al 2020;Kashour et al 2020;Lammers et al 2020). Also, some reports highlight the severe risks, including death, when CQ is used in high dose and the potentially detrimental consequences of rapid dissemination of over-interpreted data of its efficacy (Das et al 2020;Ektorp 2020;Kim et al 2020;Touret and de Lamballerie 2020). In a recent report, Junqueira and Rowe highlighted the heterogeneous and insufficient approaches of early randomized control trials (RCTs) of the COVID-19 pandemic to measure CQ or HQ's effectiveness and safety relevant to patients and clinical practice and the urgent need for well-designed high-quality RCTs (Junqueira and Rowe 2020).…”

SARS-CoV-2 and Systemic Lupus Erythematosus

“…Supply issues of HCQ for SLE patient have since luckily resolved, following clinical trials in hospitalized COVID-19 patients, including a randomized controlled trial and three large observational studies, that failed to demonstrate benefit [ 58 ]. Furthermore, HCQ use in combination with azithromycin was associated with increased mortality due to cardiac arrhythmias in this population [ 58 , 59 ]. Congruent to those results, observational studies in patients with SLE and other AIRDs and concurrent COVID-19 did not support a protective effect of HCQ against COVID-19 infection or hospitalization [ 28 , 30 , 32 , 35 •, 40 , 45 , 47 •, 60 , 61 ].…”

“…HCQ remains the cornerstone of therapy in patients with SLE, associated with decreased risk of flare, reduced longer-term morbidity and mortality, and improved pregnancy outcomes [57]. Supply issues of HCQ for SLE patient have since luckily resolved, following clinical trials in hospitalized COVID-19 patients, including a randomized controlled trial and three large observational studies, that failed to demonstrate benefit [58]. Furthermore, HCQ use in combination with azithromycin was associated with increased mortality due to cardiac arrhythmias in this population [58,59].…”