Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence

Umesh Devappa Suranagi; Harmeet Singh Rehan; Nitesh Goyal

After three months of its detection in China in late December 2019, novel SARS Cov-2 infection has spread to almost all countries in the world and by far threatening to be the biggest pandemic of modern times. With nearly two million infections and more than 123,000 deaths growing up in alarming rate, specific treatment is the most important requirement of the world. Hydroxycholoroquine with the relatively better safety profile than choloroquine 45 and possible better antiviral efficacy 21 offers to be a compelling hope of choice in times of desperation, in the midst of pandemic. We systematically searched various databases and Clinical trial registries to evaluate the evidence. During the previous outbreak of SARS, an in-vitro study demonstrated the anti-corona viral effect of HCQ and choloroquine. 20 More recently Chinese researchers conducted in-vitro studies in cell lines and demonstrated the potential antiviral activity of HCQ against SARS-CoV2 as compared to chloroquine. 21, 22 It is relevant to note that these studies were the basis of initial opinions and general consensus statements given by various panels across the world during the early stages of the current pandemic. We found out that there is scarcity of well conducted and adequately reported human studies of HCQ use in COVID-19. This is in agreement with the other authors with similar findings of lack of literature in this regard. 28, 29, 30, 46 The earliest nonempirical evidence came from China in form of report letter in which more than 100 patients with COVID pneumonia showed clinical improvement and changes in image findings on chloroquine administration. 43 It is pertinent to note that this letter was the brief report of ongoing many trials in various locations in China, neither it mentioned any specific data regarding interventions, study design, study population and outcome measures, nor any adverse events were discussed. We encountered and translated another Chinese RCT of HCQ compared to standard care in 30 COVID-19 patients. The investigators did not find any significant difference between treatment and control group in both nasopharyngeal swab negativity and duration of illness. 25 This study was an open label trial with small sample size and had high risk of confounding and selection bias, the authors agreed that primary end point was weak and more robust end points with larger sample size is required to establish the effects. Gautret et al, 23 in a non randomized clinical trial in 36 COVID-19 patients, reported viral load reduction by HCQ and its reinforcement by azithromycin. This study had major limitations in the form of small sample size, absence of randomization and masking, lack of intention to treat analysis and long term follow up, there was no clinical endpoint as outcome measure. Among pre-print, non-peer reviewed studies, an RCT by Chen Z et al. exploring HCQ and azithromycin in 62 patients reported significant improvement in time to clinical recovery and radiological findings. However, sample size in this study is small and risk of selection bias (omission of severely ill patients, and patients with organ dysfunctions) and confounding bias is high. Authors did not involve patients with prolonged QT intervals and comments on safety profile of the treatment were brief. Endpoints did not include viral RNA clearance and lab investigations; follow-up is not reported in the study. 26 A non-comparative observational French follow-up study in 80 COVID-19