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

The ongoing Coronavirus disease 2019 (COVID- 19) pandemic has affected most of the countries in the world with unimagined infectious disease morbidity and mortality. Since its first detection in China in late December 2019, COVID-19 has now spread to over 210 countries/territories, with reports of local transmission happening across the world. As per WHO (as of 15th April, 2020), there has been a total of 1,914,916 confirmed cases and 123,010 deaths due to COVID-19 worldwide. 1 However, no specific drug has been approved for the treatment of COVID-19. As most of the affected countries are fighting everyday to flatten the curve by rigorous public health measures and political resolutions, world is eagerly looking for the vaccine or a specific treatment. Recent updates indicate the vaccine quest is at least a year away. Building on experience from past Ebola and MERS pandemics, various human trials on novel pharmacotherapeutics are in progress. 2 Drugs such as remdesivir and favipiravir are in exploratory phases of clinical trials, and need more time to complete phase 3 clinical trials. 3 In these unprecedented times, there is a pursuit for repurposing of existing drugs for treatment of the SARS-coronavirus 2 (SARS-Cov-2) infection on urgent basis. More than 20 drugs such as chloroquine, hydroxychloroquine, lopinavir, ritonavir, human immunoglobulin, arbidol, oseltamivir, methylprednisolone, bevacizumab, interferons and traditional Chinese medicines are aimed to be repositioned for COVID-19 treatment. 4 Forerunners among these are antimalarial drugs chloroquine and hydroxychloroquine which are used extensively in treatment of malaria and elsewhere since many decades. 5,6 These drugs are 4-aminoquinoline derivatives exhibiting wide range of in-vitro activity against viruses. Wide clinical usage experiences, affordability, feasibility of bulk production are the additional advantages. Their antiviral efficacy has been attributed to many different mechanisms. 7 Studies have demonstrated that chloroquine confers its considerable broad-spectrum antiviral effects by interfering with the fusion process of viruses by increasing the local pH. 8 Other mechanisms may include raise in endosomal pH in host cells thereby inhibiting auto-lysosome fusion and disrupting the enzymes needed for the viral replication. 9, 10 Hydroxychloroquine (HCQ) is synthesized by N-hydroxyethyl side chain substitution of chloroquine. This modification renders HCQ more soluble than chloroquine which may confer advantage of relative lesser toxicity. Similar to chloroquine, HCQ increases the pH and confers antiviral activity. Although the antimalarial activity of HCQ is equivalent to that of chloroquine, HCQ is preferred over chloroquine owing to its lower ocular toxicity. 11 It is also used in the treatment of rheumatoid arthritis, chronic discoid lupus erythematosus, and systemic lupus erythematosus. In addition to endosomal pH increase mentioned above, HCQ is also said to inhibit terminal glycosylation of ACE2 receptor, which is considered to be the target of SARS-CoV and SARS-CoV-2 cell entry. 12 The non-glycosylated ACE2 receptor might interact inefficiently with the SARS-CoV-2 spike protein, thus inhibiting the viral entry. 13 These myriad mechanisms of HCQ and its relative lesser toxicity profile as compared to chloroquine make it an attractive candidate in the pursuit of drug repositioning. In this highly demanding scenario of huge unmet need and steeply increasing mo