Chloroquine and hydroxychloroquine in coronavirus disease 2019 (COVID-19). Facts, fiction and the hype: a critical appraisal

Abstract

The coronavirus infection (COVID-19) has turned into a global catastrophe and there is an intense search for effective drug therapy. Of all the potential therapies, chloroquine and hydroxychloroquine have been the focus of tremendous public attention. Both drugs have been used in the treatment and prophylaxis of malaria. Long-term use of hydroxychloroquine is the cornerstone in the treatment of several auto-immune disorders. There is convincing evidence that hydroxychloroquine has strong in vitro antiviral activity against SARS-CoV-2. A few small uncontrolled trials and several anecdotal reports have shown conflicting results of such drug therapy in COVID-19. However, the results of preliminary large-scale randomized controlled trials have failed to show any survival benefit of such drug therapy in COVID-19. Despite the lack of such evidence, hydroxychloroquine has been used as a desperate attempt for prophylaxis and treatment of COVID-19. The drug has wide-ranging drug interactions and potential cardiotoxicity. Indiscriminate unsupervised use can expose the public to serious adverse drug effects.

Keywords: COVID-19; Chloroquine; Coronavirus; Hydroxychloroquine; Pandemic; SARS-CoV-2.

Figure 1

Mode of action of chloroquine in malaria and the mechanism of chloroquine drug resistance. Chloroquine (CQ) accumulates in the food vacuole of the parasite. The drug inhibits the formation of hemozoin (non-toxic) from the heme (toxic) released by the digestion of hemoglobin (Hb). The accumulated heme lyses membranes and leads to parasite death. Chloroquine résistance is due to a decreased accumulation of chloroquine in the food vacuole. The drug resistance is primarily mediated by mutant forms of the chloroquine resistance transporter (PfCRT) that causes efflux of chloroquine from the digestive vacuole.

Figure 2

Basis of hydroxychloroquine (HCQ) use in rheumatic diseases. The drug in antigen processing cells (APC) – namely plasmacytoid dendritic cells, monocytes, macrophages, and B cells – interferes with toll-like receptor (TLR)-mediated activation, signaling and cytokine production. In APC such as plasmacytoid dendritic cells and B cells, the drug inhibits antigen processing and subsequent major histocompatibility complex (MHC) class II-mediated antigen presentation to T cells. This prevents T cell activation, production of proinflammatory molecules and reduces the production of cytokines. Abbreviations: IL-1, interleukin 1; IL-6, interleukin-6; IFNγ, interferons; TNF, tumor necrosis factor; BAFF, B-cell activating factor.

Figure 3

Proposed sites of action of hydroxychloroquine in SARS-CoV-2 infection. The flow diagram shows stages of SARS-CoV-2 infection in the human host and subsequent mechanism of effects leading to target organ damage. The possible sites where HCQ may act are shown by the red arrows. Abbreviations: HCQ, hydroxychloroquine; ARDS, acute respiratory distress syndrome; ACE2 Angiotensin-converting enzyme 2; pp1a & pp1ab polyprotein 1a & polyprotein 1ab; nsp non-structural protein; RAS Renin-angiotensin system.