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.
In this randomized, double-blind, placebo-controlled trial, we investigated the efficacy of hydroxychloroquine as Covid-19 postexposure prophylaxis. In this trial, high doses of hydroxychloroquine did not prevent illness compatible with Covid-19 when initiated within 4 days after a high-risk or moderate-risk exposure.
We used a pragmatic approach to recruitment and follow-up of participants through Internet-based self-referral and online follow-up surveys, and we couriered the trial interventions directly to participants’ homes. This approach allowed for recruitment across North America, minimized the risk of SARS-CoV-2 infection to researchers, lowered the burden of research participation, and provided a timely answer to this question of whether postexposure prophylaxis was effective. Moreover, this approach allowed broad geographic participation regardless of anyone’s physical distance from academic centers, increasing the generalizability of the findings. One result of our approach was that enrolled participants were generally younger and healthier than those at risk for severe Covid-19. Although the risk of severe Covid-19 is related to age and coexisting conditions,the risk of acquiring symptomatic infection is generally still present among adults, regardless of age. Although PCR or serologic testing for asymptomatic infection would have added to the scientific strength of this trial, this was not possible, and we cannot assess an effect on mild or asymptomatic infections. Although a marginal possible benefit from prophylaxis in a more at-risk group cannot be ruled out, the potential risks that are associated with hydroxychloroquine may also be increased in more at-risk populations, and this may essentially negate any benefits that were not shown in this large trial involving younger, healthier participants.
We acknowledge that this trial has limitations. Because of the lack of availability of diagnostic testing in the United States, the vast majority of the participants, including health care workers, were unable to access testing. Thus, an a priori symptomatic case definition was used — the U.S. clinical case definition of probable Covid-19.This trial represents real-world implementation after exposure. In the context of a randomized trial design, any non–SARS-CoV-2 viral infection (e.g., influenza, adenovirus, or rhinovirus) should be equally distributed in the trial groups. Owing to the Internet-based approach used to rapidly recruit participants in the context of a pandemic, data were obtained by means of participant report. The types and frequency of symptoms that were observed are similar to those in previous studies involving U.S. health care providers.The U.S. case definition is how probable Covid-19 cases are nationally reportable.However, the predictive power of this case definition is unknown, particularly in the younger populations that we studied; given the small number of PCR tests, it remains theoretically possible that hydroxychloroquine therapy limits proven infection. Reproduction of our results in other, ongoing trials would confirm our findings.
This randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for Covid-19. Whether preexposure prophylaxis would be effective in high-risk populations is a separate question, with trials ongoing. In order to end the pandemic, a reduction in community transmission is needed.
Reference & Source information: https://www.nejm.org/
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