(55) Daily Tenofovir Disoproxil Fumarate/Emtricitabine and Hydroxychloroquine for Pre-Exposure Prophylaxis of COVID-19: A Double-Blind Placebo Controlled Randomized Trial in Healthcare Workers. A Randomized Clinical Trial

Publication Number: 729

Background: TDF/FCT and HCQ are generic drugs, widely prescribed and with a proven safety record. Both drugs have been found to be ineffective in hospitalized patients with COVID-19, but the repurposing of tenofovir (TDF)/emtricitabine (FTC) and hydroxychloroquine (HCQ) for the prevention of COVID-19 is supported by several lines of evidence. We studied TDF/FTC, HCQ and their combination as pre-exposure prophylaxis on the risk of symptomatic COVID-19

Objectives: To assess the effect of TDF/FCT, HCQ, and their combination as pre-exposure prophylaxis on the risk of symptomatic COVID-19.

Methods: EPICOS is a double-blind, placebo-controlled randomized trial conducted in 51 hospitals in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to: daily TDF/FTC (245mg of TDF and 200 mg of FTC once daily) plus HCQ (200 mg once daily) for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo and TDF/FTC placebo plus HCQ placebo. The primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19 infection. The target sample size was 4000 participants. We compared group-specific 14-week risks via differences and ratios with 95% confidence intervals (CI).

Results: Of 1002 individuals screened, 926 (92.4%) were eligible; 64.2% recruited in Spain, 22.3% in Bolivia, and 13.6% in Venezuela. Median age was 38 years (range 18 - 68), 62.5% were female, 62.3% worked at inpatient care, and comorbidities were rare. Compared with the placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00, 1.98) for TDF+HCQ, 0.34 (0.00, 2.06) for TDF, and 0.49 (0.00, 2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21, 1.00) for TDF+HCQ, 0.81 (0.44, 1.49) for TDF, and 0.73 (0.41, 1.38) for HCQ. The proportion of individuals with adverse events ranged between 21.1% in the placebo group and 31.3% in the TDF/FTC group. Most were mild and of gastrointestinal nature

Conclusions: A beneficial effect of TDF/FTC and HCQ, alone or in combination, as pre-exposure prophylaxis for COVID-19 cannot be ruled out but effect estimates are imprecise because the target sample size was not met. Our trial estimates for TDF/FTC are consistent with estimates from a experimental study in France and several large observational cohorts of persons with HIV or hepatitis B virus in Spain and South-Africa. Randomized trials of TDF/FTC for the early treatment of COVID-19 are needed