Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety: Systematic review of (hydroxy)chloroquine efficacy and safety

Abstract

Background: The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the repurposing of existing drugs. Several drugs are now being repurposed with the aim of identifying if these drugs provide some level of disease resolution. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ), first developed as an antimalarial therapy. There is increasing concern with regards to the efficacy and safety of these agents. The aims of this review are to systematically identify and collate studies describing the use of CQ and HCQ in human clinical trials and provide a detailed synthesis of evidence of its efficacy and safety. Methods and Findings: Searches for (COVID AND chloroquine [title/abstract] AND outcomes[full text]) and two (COVID AND hydroxychloroquine[title/abstract] AND outcomes[full text]) yielded 272 unique articles. Unique articles were manually checked for inclusion and exclusion criteria and also subjected to a quality appraisal assessment. A total of 19 articles were included in the systematic review. Seventy-five percent of observational studies employing an endpoint specific to efficacy recorded no significant difference in the attainment of outcomes, between COVID-19 patients given a range of CQ and/or HCQ doses, and the control groups. All clinical trials and 82% of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Seventy-five percent of the total papers focusing on cardiac side-effects found a greater incidence among patients administered a wide range of CQ and/or HCQ doses, with QTc prolongation the most common finding, in addition to its consequences of VT and cardiac arrest. Of the total studies using mortality rate as an end-point, 60% reported no significant change in the risk of death, while 30% showed an elevation, and 10% a depression, in treated relative to control patients. Conclusion: The strongest available evidence suggests that, relative to standard in-hospital management of symptoms, the use of CQ and HCQ to treat hospitalised COVID-19 patients has likely been unsafe. At the very least, the poor quality of data failing to find any significant changes in the risk of VT should preclude definitive judgment on drug safety until the completion of high-quality randomised clinical trials.

Efficacy of chloroquine and hydroxychloroquine in treating COVID-19 infection: a meta-review of systematic reviews and an updated meta-analysis

“…Of the reviews without meta-analysis, 4 concluded that there was evidence for higher risk of mortality in the HCQ group (40,43,51,52) and one review (53) reported evidence of lower mortality in the HCQ group. Two reviews reported evidence of higher mortality in the chloroquine group (40,46) (Supplementary Table S6).…”

“…The remaining 6 reviews (37,40,43,50,51,53) which did a narrative synthesis did not find a difference in the risk of transfer to the ICU, intubation or need for mechanical ventilation ( Supplementary Table S6).…”

“…Several systematic reviews and meta-analyses investigating the efficacy and the safety of CQ and HCQ have been published or are in the process of being published (8,13,16,28,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). Similar to the primary studies, systematic reviews and meta-analyses have presented contradictory findings.…”

Current evidence on chloroquine and hydroxychloroquine and their role in the treatment and prevention of COVID-19

“…Additionally, recent literature has suggested that chloroquine may be associated with significant adverse effects when used in high dosages in the management of hospitalised COVID-19 patients (Takla, preprint, 2020) 33 , as the dosages required to reach therapeutic concentrations may increase the risk of adverse outcomes in this patient population 30 . Until results on the safety of chloroquine for the treatment of COVID-19 from high-quality randomised clinical trials (RCT) have been appraised, no specific recommendations on the safety of chloroquine in the management of patients with SARS COV-2 can be made, but it is advised that clinicians should avoid its use in patients with risk factors for QT prolongation.…”

“…Although numerous countries have incorporated the off-label use of these drugs in their treatment policies, data guiding the rational dosing of these drugs in COVID-19 are lacking. A systematic review found that at least 4 different treatment regimens have been used thus far in studies assessing the use of chloroquine in COVID-19, with total dosages ranging from 3 000 mg to 20 000 mg over the course of treatment (Takla, preprint, 2020) 33 . Pre-clinical evidence suggests that relatively high dosages may be required in order to reach therapeutic tissue concentrations quickly 53 .…”