Authors’ response

We thank the authors of the letter for their critical reading of our case-control investigation1. During this investigation, we matched the cases and controls by time and location using the date of testing and laboratory where they were tested following the development of symptoms of respiratory tract infection, to limit the variability between cases and controls. The overall purpose of our investigation was to identify factors associated with SARS-CoV-2 infection (protective or risk posing). However, we realize that examining the safety and efficacy of pre-exposure prophylaxis, based on hydroxychloroquine (HCQ), would require clinical trials as indicated in the discussion section of our article1.

Chloroquine (CQ) and HCQ are known to have extensive tissue spread, resulting in a large volume of distribution in the human body. Single-dose kinetics studies in the context of malaria chemoprophylaxis show that adequate plasma levels of chloroquine may be achieved only after four weeks. During this period, the individual taking CQ prophylaxis may not achieve the desired plasma concentration of the drug needed for protection2. These findings prompted the recommendation that CQ prophylaxis in malaria-naïve travellers be initiated at least two weeks prior to entry into malaria-endemic areas. Interestingly, our study also provided a similar hint of protection against SARS-CoV-2 infection obtained through HCQ chemoprophylaxis, where a dose-response relationship appeared unfolding after the intake of four or more maintenance doses following the initial loading dose.

Importantly, although CQ and HCQ are efficiently concentrated in lung tissue over time, reaching at least 11.8 times the concentration in plasma, in vivo concentrations needed to counter SARS-CoV-2 infection, may be achieved in a dose-dependent manner34. For a drug like HCQ where lysosomal sequestration is known and can lead to variable concentrations in various body tissues compared to plasma levels5, information regarding HCQ levels, specifically in lung tissues, is important as far as the activity against SARS-CoV-2 and other respiratory viruses is concerned. With the current evidence, it is unclear if parameters such as area under the curve (AUC) can be reliably used to predict levels in respiratory tissues and drug efficacy6.

As our study was specifically conducted to identify the associations between various exposure variables and SARS-CoV-2 infection in symptomatic healthcare workers (HCWs), it would be inappropriate to extrapolate the findings to home-based contacts of confirmed cases of COVID-19. Notwithstanding the findings of our study, we would still like to underscore the necessity of pondering over protective behavioural factors and appropriate use of personal protective equipment along with plausible chemoprophylaxis-based biologic intervention while examining the occurrence of SARS-CoV-2 infection in HCWs.