Rethinking the role of hydroxychloroquine in the treatment of COVID-19

Abstract

There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Keywords: COV-SARS-2; SARS; coronavirus; immune; immunology.

Figure 1

COVID‐19 clinical course of illness. The first phase of COVID‐19 infection involves an incubation period of variable duration, with a median of 5.1 days. The second is an acute mild phase that most commonly includes flu‐like symptoms like cough, fevers, and myalgias, but can also include gastrointestinal symptoms. Some patients progress to an ARDS hyperinflammatory phase that is often marked by dyspnea, tachypnea, and hypoxemia. The respiratory viral load rises before the onset of symptoms and peaks around the onset of symptoms. It declines over the first week. Severe cases have higher viral loads compared with mild cases. Prolonged viral shedding in severe and mild cases is reported

Figure 2

Schematic—proposed mechanisms of action of HCQ in SARS‐CoV‐2 infection. HCQ can limit coronavirus infection and reduce inflammatory and immune cell function. Treatment with HCQ alters the n‐terminal glycosylation of ACE‐2, which can reduce the affinity of ACE2‐S1 (Spike) interactions, though the impact on the interaction of other relevant surface proteins is unclear. HCQ can also inhibit viral infection by disrupting endosomal acidification to interfere with viral fusion. Induction of cytokine expression resulting from innate immune signaling is also impacted by HCQ mediated reduction in DNA/RNA binding and activation of cGAS/STING signaling and altered endosomal pH also disrupts binding to TLR7/9. Elevated endosomal pH can also alter (cross‐)presentation of antigen by MHC Class I and II, modifying the development and activation of antigen‐specific T cell and B cell populations