A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19

Abstract

Background Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. Methods We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)–confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. Results The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. Conclusions Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053 .)

The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials

“…The remaining three trials required contact with a COVID-19 patient (i.e. post-exposure prophylaxis) [ 15 , 16 , 18 ]. Thirty four percent of participants had inappropriate PPE donned during their exposures.…”

“…Four trials enrolling 4921 patients (was reduced to 3094 in the analysis to account for cluster-effect) reported on developing COVID-19 (defined by either symptoms or PCR confirmation) [ 15 – 18 ]. Prophylactic hydroxychloroquine did not reduce the risk of developing COVID-19 (RR 0.82, 95% CI 0.65 to 1.04; I 2 = 0%, P = 0.90; moderate certainty) ( Fig 2 ) ( Table 2 and S8 Table ).…”

“…All four trials (n = 3094 participants) reported on hospitalization [ 15 – 18 ]. The use of hydroxychloroquine compared to placebo did not reduce the risk of hospitalizations (RR 0.72, 95% CI 0.34 to 1.50; I 2 = 0%, P = 0.80; moderate certainty) ( Fig 3 ).…”

Filling the Gap Until Full Vaccine Deployment in the War on Coronavirus Disease-19

“…In terms of pharmaceutical interventions, most trials have been planned to test the effectiveness of therapeutic candidates in advanced COVID-19, when patients are already hospitalized, while very few studies have addressed early interventions for the prevention of hospitalization [ 33 ]. Following the negative results obtained in trials testing the efficacy of hydroxychloroquine as post-exposure prophylaxis [ 34 , 35 ], only the very recent clearance of two monoclonal antibody-based therapeutic candidates for emergency use in the United States (bamlanivimab and the combination casirivimab and imdevimab) and the release of interim authorization for bamlanivimab in Canada have given an option to keep people infected with SARS-CoV-2 out of hospital. Bamlanivimab (LY-CoV555) is a recombinant, neutralizing human monoclonal antibody directed against the spike protein of SARS-CoV-2, and capable of blocking viral attachment and entry into human cells.…”

Effective post-exposure prophylaxis of Covid-19 is associated with use of hydroxychloroquine: Prospective re-analysis of a public dataset incorporating novel data

“…11,38 Self-selection bias inherent in this type of study may have been compounded by FDA cautions regarding HCQ. 6 Unlike similar studies, 34,35 the original PEP study was not cluster-randomized. 38 Several limitations relate to the estimation of the interval between exposure and treatment with 24-hour windows of uncertainty on either side.…”