In this randomized clinical trial, although limited by early termination, there was no clinical benefit of hydroxychloroquine administered daily for 8 weeks as pre-exposure prophylaxis in hospital-based HCWs exposed to patients with COVID-19.

Despite promising early reports and strong in vitro performance, Hydroxychloroquine (HCQ) has become the major therapeutic disappointment of the COVID pandemic.

Research published online today by Journal of the American Medical Association (JAMA) Internal medicine looked at the drug as means to protect health care workers against COVID19. HCQ use by doctors and nurses was widespread in the early weeks of the pandemic, and the drug became standard of care in places like Singapore.

Did a regimen of hydroxychloroquine, 600 mg, per day, reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a pre-exposure prophylaxis strategy when taken by hospital-based health care workers?  In this double-blind, placebo-controlled randomized clinical trial that included 132 participants and was terminated early, there was not a significant difference in reverse-transcriptase polymerase chain reaction–confirmed SARS-CoV-2 incidence between hydroxychloroquine and placebo cohorts.

Among hospital-based health care workers, daily hydroxychloroquine did not prevent SARS-CoV-2 infection, although the trial was terminated early and may have been underpowered to detect a clinically important difference.

Health care workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) are at risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, to our knowledge, there is no effective pharmacologic prophylaxis for individuals at risk.

The randomized, double-blind, placebo-controlled clinical trial (the Prevention and Treatment of COVID-19 With Hydroxychloroquine Study) was conducted at 2 tertiary urban hospitals, with enrollment from April 9, 2020, to July 14, 2020; follow-up ended August 4, 2020. The trial randomized 132 full-time, hospital-based HCWs (physicians, nurses, certified nursing assistants, emergency technicians, and respiratory therapists), of whom 125 were initially asymptomatic and had negative results for SARS-CoV-2 by nasopharyngeal swab. The trial was terminated early for futility before reaching a planned enrollment of 200 participants.

The primary outcome was the incidence of SARS-CoV-2 infection as determined by a nasopharyngeal swab during the 8 weeks of treatment. Secondary outcomes included adverse effects, treatment discontinuation, presence of SARS-CoV-2 antibodies, frequency of QTc prolongation, and clinical outcomes for SARS-CoV-2–positive participants. Of the 132 randomized participants (median age, 33 years [range, 20-66 years]; 91 women [69%]), 125 (94.7%) were evaluable for the primary outcome. There was no significant difference in infection rates in participants randomized to receive hydroxychloroquine compared with placebo (4 of 64 [6.3%] vs 4 of 61 [6.6%]; P > .99). Mild adverse events were more common in participants taking hydroxychloroquine compared with placebo (45% vs 26%; P = .04); rates of treatment discontinuation were similar in both arms (19% vs 16%; P = .81). The median change in QTc (baseline to 4-week evaluation) did not differ between arms (hydroxychloroquine: 4 milliseconds; 95% CI, −9 to 17; vs placebo: 3 milliseconds; 95% CI, −5 to 11; P = .98). Of the 8 participants with positive results for SARS-CoV-2 (6.4%), 6 developed viral symptoms; none required hospitalization, and all clinically recovered.

The pandemic triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 6.8 million people in the US, with more than 200 000 deaths to date. The illness caused by the SARS-CoV-2 virus, coronavirus disease 2019 (COVID-19), has spread broadly with significant effects on elderly and minority individuals, those with significant comorbidities, and members of the health care workforce. Public health measures to prevent COVID-19 disease have largely depended on physical distancing, use of facial covers and personal protective equipment (PPE), and hand hygiene. Health care workers (HCWs) assigned to treating patients with COVID-19 have frequent potential exposures, raising the question of whether pharmacologic prophylaxis is warranted.

Medication-based prevention and treatment of COVID-19 have proven challenging. To our knowledge, to date, only 2 medications, dexamethasone and remdesivir, have been shown to improve outcomes in severe COVID-19 disease, and no treatment has proven effective in mild to moderate disease. Furthermore, no pharmacologic prophylaxis for COVID-19 has been established. Given the many HCWs with substantial COVID-19 exposure worldwide, there is great interest in finding an effective medication to prevent viral transmission.

Similar to other studies of hydroxychloroquine for either viral prophylaxis or COVID-19 treatment, we found that the medication was generally well tolerated, with the exception that patients treated with hydroxychloroquine, 600 mg, for 8 weeks experienced significantly higher rates of grade 1 to 2 diarrhea than patients treated with placebo. In addition, we found no significant differences in cardiac adverse events between the hydroxychloroquine and placebo groups. Myocardial inflammation associated with SARS-CoV-2 infection may increase susceptibility to potential cardiac effects of hydroxychloroquine. Therefore, the lack of QTc prolongation or arrythmias in our study’s cohort cannot be used to infer cardiac safety of hydroxychloroquine for active COVID-19 treatment. Furthermore, some studies have involved the combined use of azithromycin, a known QTc-prolonging compound, and hydroxychloroquine; azithromycin use was an exclusion criterion in our investigation.

Prophylaxis studies of infectious diseases are highly sensitive to disease frequency. In Pennsylvania, daily COVID-19 incidence fell during the course of enrollment  starting at 14.8 cases per 100 000 population per day on April 9, 2020, and ending at 7.1 cases per 100 000 population per day on July 14, 2020. The overall SARS-CoV-2 infection rate in the study cohort was 6.4%; it is possible that a study of similar design conducted in a community with higher disease prevalence might yield a higher HCW infection rate and possibly more power to detect a prophylactic benefit from hydroxychloroquine. Alternatively, it is possible that uniform use of PPE and hand hygiene was sufficiently effective to reduce HCW infection to low levels, as seen in our study population.

The randomized clinical trial did not detect a reduction in SARS-CoV-2 transmission with prophylactic administration of hydroxychloroquine, and all participants who did contract SARS-CoV-2 were either asymptomatic or had mild disease courses with full recoveries. As such, we cannot recommend the routine use of hydroxychloroquine among HCWs to prevent COVID-19.