Hydroxychloroquine comes up short in post-exposure prophylaxis trial for COVID-19
Results of a randomized trial testing hydroxychloroquine as a prophylactic following high- or moderate-risk exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) indicate the drug does not significantly prevent illness compatible with coronavirus disease 2019 (COVID-19) or confirmed infection when taken within 4 days after exposure. Using what they describe as a "pragmatic" approach to recruitment and follow-up, through Internet-based self-referral and online follow-up surveys, the authors, led by David R. Boulware, MD, University of Minnesota, Minneapolis, reported in The New England Journal of Medicine that the study allowed broad geographic participation and helped provide a timely answer to the question of whether post-exposure prophylaxis with hydroxychloroquine was effective.
The study recruited 821 asymptomatic adults across the US and parts of Canada (Quebec, Manitoba and Alberta) who had household or occupational exposure to someone with confirmed COVID-19. People with symptoms of COVID-19 or PCR-proven SARS-CoV-2 infection were excluded. High-risk exposure was defined as being less than 6 ft from a COVID-19 patient for more than 10 minutes, wearing neither a mask nor an eye shield, while moderate risk meant wearing a mask, but no eye shield. The study population had a median age of 40 years, was roughly evenly split between men and women, and participants were generally considered to be healthy, although 27.4% (225/821) reported chronic health conditions, with hypertension (99/821 [12.1%]) being the most common, followed by asthma (62/821 [7.6%]).
Overall, 87.6% of the participants (719/821) reported a high-risk exposure to a confirmed COVID-19 contact. Healthcare workers accounted for 66.4% of participants (545/821), the majority being physicians or physician assistants (342/545 [62.8%]) and nurses or nursing assistants (128/545 [23.5%]). Among the 29.8% of participants (245/821) who enrolled as a household contact, most were exposed to an infected spouse, partner or parent.
Enrollment began on March 17, 2020, with recruitment performed primarily via the use of social media outreach as well as traditional media platforms. Within 4 days after exposure, participants were randomised to receive either hydroxychloroquine or placebo (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The authors said this dosing regimen was chosen "on the basis of pharmacokinetic simulations to achieve plasma concentrations above the SARS-CoV-2 in vitro half maximal effective concentration for 14 days."
Follow-up email surveys were sent on days 1, 5, 10 and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness or hospitalizations. The primary outcome was the incidence of either laboratory-confirmed COVID-19 or illness compatible with COVID-19 within 14 days. Some secondary outcomes included the incidence of hospitalization for COVID-19 or death, the incidence of PCR-confirmed SARS-CoV-2 infection, the incidence of COVID-19 symptoms and the severity of symptoms, if any.
Results showed that new cases of either PCR-confirmed or symptomatically compatible COVID-19 developed in 13.0% (107/821) of participants during the 14 days of follow-up. The incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49/414 [11.8%]) and those receiving placebo (58/407 [14.3%]) (P=0.35). Two hospitalizations were reported, one in each group. No arrhythmias or deaths occurred.
Of 113 participants in whom symptomatic illness developed, 16 had PCR-confirmed disease, 74 had illness that was compatible with probable COVID-19 per the US case definition, 13 had possible COVID-19 with compatible symptoms and epidemiologic linkage, and 10 were adjudicated as not having COVID-19 on the basis of the symptom complex. Four additional participants had positive PCR tests and were asymptomatic during the 14-day trial period, although symptoms eventually developed in 3 of these.
The authors said one result of the approach they used was that enrolled participants were generally younger and healthier than those at risk for severe COVID-19. Further, while PCR or serologic testing for asymptomatic infection would have added to the scientific strength of the trial, "this was not possible, and we cannot assess an effect on mild or asymptomatic infections." However, they noted that while "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."
Researchers also highlighted the lack of availability of diagnostic testing in the US during the course of the study, noting that the "vast majority" of participants, including healthcare workers, were unable to access testing. In an accompanying editorial, Myron S. Cohen, MD, University of North Carolina, Chapel Hill, North Carolina, remarked that "indeed, the specificity of participant-reported COVID-19 symptoms is low, so it is hard to be certain how many participants in the trial actually had COVID-19." He also pointed to participants reporting "less-than-perfect adherence [to the interventions], more notably in the group receiving hydroxychloroquine," as another potential limitation of the trial.
Meanwhile, looking ahead, the authors said "whether pre-exposure prophylaxis would be effective in high-risk populations is a separate question, with trials ongoing."