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

patients reported 97.5% of respiratory samples were negative for virus cultures at Day 5. This study too involved only mild illness patients and did not report adverse effect profile and being an uncontrolled observational study, the strength of evidence tends to be low. 27 In contrast, a similar study from France, which imitated the dosage regimen of the previous French non randomized open label study, 23 observed that there is no evidence of rapid viral reduction and clinical benefit from the combination therapy of HCQ and azithromycin. It is pertinent to note that this study was conducted only in 11 patients with severe COVID-19. 24 We also searched, identified and analyzed clinical trial databases to explore the ongoing active clinical trials (Supplementary table 1) and found out relevant 27 clinical trials. Many trials among these are in advanced phases and few trials are expecting completion in near future. Earlier registered Chinese clinical trials are expected to come out with definitive results in next few weeks and also robust designed RCTs elsewhere in the world are expected to produce their interim results shortly henceforth. (Supplementary table 1) It is appropriate to note that none of the published studies of HCQ in COVID-19 have emphasized on the adverse effects and toxicity profile of the drugs in treated patients. Chen Z et al 26 reported two adverse events, however due to very small sample size it is difficult to attribute these to HCQ. Even though HCQ has relatively better safety profile than chloroquine, owing to its prolonged pharmacokinetics (537 hours half life) and gradual elimination, it has potential to cause various adverse events ranging from commonly seen gastrointestinal upset, 47 and chronic retinal toxicity, 48 to serious adverse effects like fulminant hepatic failure, 49 severe cutaneous adverse reactions. 50 An important adverse effect of HCQ is cardiac conduction defects and ventricular arrhythmias. QT prolongation and arrhythmias can be precipitated by concomitant use of azithromycin. 44 Small but absolute risk of cardiovascular death is seen to be associated significantly with azithromycin as compared to fluoroquinolones. 51 It is important to note that overdose or poisoning of HCQ is difficult to treat. Caution is warranted in patients with hepatic and renal dysfunction, and regular ECG monitoring is advised in patients with cardiovascular diseases. Irrational use in general population without credible evidence may pose greater risk than benefit. To best of our knowledge, this systematic review is the most comprehensive exploration and analysis of existing literature in this topic till date. Our review has limitations in its rigor due to the scarce existing data and diverse study types available. The rapidly emerging knowledge base of COVID-19 poses the possibility that few studies (particularly unpublished/under peerreview) remain un-captured. However, we have tried our best to mitigate this by allowing broadest search terms and by including many databases and repositories. We have also tried to comprehensively analyze and assess the existing data under the critical lens of factual judgment. In this background, we believe that expert opinions and clinical consensus statements given by various international authorities for the use of HCQ either as prophylaxis to high risk individuals 15 and healthcare professionals 16 or as emergency treatment of COVID-19 patients. 17,18 lacks strong evidence base.