Why is pre-exposure prophylaxis with hydroxychloroquine a safe and rationale approach against SARS-CoV-2 infection?

The potentiality of Hydroxychloroquine (HCQ) for pre-exposure prophylaxis against SARS-CoV-2 has not been explored in randomized controlled trials. However, there is rationale behind this potentiality in terms of demonstrated in-vitro effect of HCQ against SARS-CoV-2, safety profile of HCQ in healthy individuals and a recent observational study demonstrating benefits of HCQ prophylaxis in terms of a significant reduction (>80%) in the odds of SARS-CoV-2 infection in the health-care workers (HCWs) with the intake of six or more doses of HCQ prophylaxis as per the guidelines of the National Task Force for COVID-19 in India. Hence, pre-exposure prophylaxis with HCQ in appears to be a reasonable strategy in the current scenario for prevention of SARS-CoV-2 infection in healthy HCWs.

Sir,

The potentiality of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19) was transiently affected by a multinational registry analysis [1] that reported adverse events with HCQ in COVID-19 patients. In lieu of serious scientific questions raised about this observational study, the Editors of The Lancet retracted the article. Very recently, Afra et al. highlighted the safety profile of HCQ, giving rest to concerns regarding the adverse effects of HCQ.

Various in vitro studies [2], [3], [4] have clearly demonstrated that HCQ inhibits the entry, replication and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, through varied mechanisms. Moreover, HCQ has a wide distribution in the lungs, where the HCQ concentration reaches a hundred times more than that in the blood, and this unique property might lead to a sufficiently high concentration necessary for inhibitory effects in the lung compartments [5]. Extrapolation of this notion paves way for rationality of HCQ as pre-exposure prophylaxis against SARS-CoV-2 infection.

A recent observational study [6] demonstrated the benefits of HCQ prophylaxis in terms of a significant reduction (>80%) in the odds of SARS-CoV-2 infection in healthcare workers (HCWs) with the administration of six or more doses of HCQ prophylaxis as per the guidelines of the National Task Force for COVID-19 in India [7]. This study also showed only fewer minor side effects with HCQ.

Data on HCQ suggest that it has a low risk of causing torsades de pointes based on its use in rheumatoid arthritis, systemic lupus erythematosus and antimalarial therapy [8]. However, there may be a greater QT-prolonging effect due to COVID-19 per se or in presence of electrolyte abnormalities, hypoxia, concomitant use of QT-prolonging medications and underlying cardiovascular disease, often seen in severe COVID-19 patients. HCQ has no QT-prolonging effect in healthy individuals.

Recently, Boulware et al. [9] reported the results of a randomised trial testing HCQ as post-exposure prophylaxis for COVID-19 and concluded that HCQ did not prevent SARS-CoV-2 infection when used as post-exposure prophylaxis within 4 days after exposure. However, there are many limitations to this study as acknowledged by the authors, the most important being that the long delay between perceived exposure to SARS-CoV-2 and initiation of HCQ (≥3 days in most participants) suggests that what was being assessed was prevention of symptoms or progression of COVID-19 rather than prevention of SARS-CoV-2 infection.

Hence, pre-exposure prophylaxis with HCQ appears to be a reasonable strategy in the current scenario for prevention of SARS-CoV-2 infection in healthy HCWs. However, large-scale randomised controlled studies are required to prove the beneficial role of HCQ as a prophylactic drug against SARS-CoV-2. One such large ongoing study, the Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ) trial, involving 15 000 HCWs (ClinicalTrials.gov ID NCT04334148) may throw more light on this issue.

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