Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure.

Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations.

Results: We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08).

Conclusions: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.

Figure 1.

CONSORT Diagram

Figure 2:. Kaplan Meier Estimates of Time to Covid-19 Compatible illness.

The probability of SARS CoV-2 infection over time is shown for the three study groups. The hazard ratio for twice weekly hydroxychloroquine prophylaxis was 0.72 (95%CI 0.44 to 1.16; p = 0.18) and for once weekly hydroxychloroquine was 0.74 (95%CI 0.46 to 1.19; p=0.22) as compared with placebo. The inset graph shows more detail.

Figure 3:. Hydroxychloroquine drug concentrations.

Right-side axes indicate extrapolated plasma concentrations assuming blood to plasma ratio of 7.2 and hydroxychloroquine molecular weight of 336 g/mol.(16) Panel A shows trough drug concentrations in participants taking once weekly compared with twice weekly hydroxychloroquine. All participants had detectable hydroxychloroquine in whole blood samples. Panel B depicts drug concentrations in participants from both hydroxychloroquine arms with and without Covid-19 compatible illness. Participants with Covid-19 compatible illness had median concentrations of 154 ng/mL compared with 133 ng/mL among those without symptomatic Covid-19 compatible illness (P=0.08). Red dashed line indicates extrapolated EC50 target assuming blood to plasma ratio of 7.2, target EC50 of 0.7μm = 235 ng/mL plasma = 1690 ng/mL whole blood.(5)