A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Abstract

Background: Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.

Methods: We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.

Results: We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.

Conclusions: After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).

Figure 1. Screening and Randomization.

Of the 821 participants who underwent randomization, 96 did not complete the day 14 follow-up survey, of whom 8 formally withdrew from the trial (4 in each group). Investigators confirmed the vital status and lack of infection in 19 participants (10 in the hydroxychloroquine group and 9 in the control group); 17 completed some follow-up surveys without symptoms before being lost to follow-up (13 in the hydroxychloroquine group and 4 in the control group). A total of 52 participants never completed any surveys after enrollment and did not respond to investigators e-mails, text messages, or telephone calls (23 in the hydroxychloroquine group and 29 in the control group). SARS-CoV-2 denotes severe acute respiratory syndrome coronavirus 2.

Figure 2. Cumulative Incidence of Illness Compatible with Coronavirus Disease (Covid-19).

The cumulative incidence of illness compatible with Covid-19 was 11.8% in the hydroxychloroquine group (49 of 414 participants) and 14.3% in the placebo group (58 of 407) (P=0.35). The difference equates to a number needed to treat to prevent one infection of 42 persons (lower boundary of the 95% confidence interval for the number needed to treat to prevent one infection, 14 persons; upper boundary of the 95% confidence interval for the number needed to treat to harm 1 person, 50 persons). When we excluded participants who were lost to follow-up, who withdrew, or who were not fully adherent to the trial intervention, the results were similar. When we excluded 13 persons with possible Covid-19 cases who had only one symptom compatible with Covid-19 and no laboratory confirmation, the incidence of new Covid-19 still did not differ significantly between the two groups: 10.4% in the hydroxychloroquine group (43 of 414 participants) and 12.5% in the placebo group (51 of 407) (P=0.38). The vertical bars represent 95% confidence intervals. (Details on symptoms and the adjudication of cases are provided in the Supplementary Appendix.)