Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo controlled randomized trial in healthcare workers (preprint)

Objective: To assess the effect of hydroxychloroquine (HCQ), Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC), 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 plus HCQ 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. 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. Adverse events were generally mild. Conclusion: 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. These findings support launching randomized trials of TDF/FTC for the early treatment of COVID-19.

Evaluating SARS-CoV-2 infection under tenofovir-based antiviral prophylaxis: a multi-scale modeling analysis upon experimental data (preprint)

Tenofovir has shown promising evidence of improving COVID-19 clinical outcomes in observational studies, still to be confirmed in clinical trials. Disease severity might be reduced under prophylaxis with the prodrug tenofovir disoproxil fumarate (TDF), while the protection seems to decrease, or even to lack, when using the alternative prodrug tenofovir alafenamide fumarate (TAF).  Aiming to understand why TDF-prophylaxis might reduce COVID-19 severity upon infection we developed a multi-scale analysis framework combining  in vitro  susceptibility data, molecular docking, and within-host dynamics modeling, and using remdesivir–the only antiviral approved to date against COVID-19– as a point of reference.First, our docking model predicted that intracellularly active tenofovir diphosphate binds into the SARS-CoV-2 RNA polymerase in the same site as the antiviral remdesivir triphosphate, but presents lower binding energy, likely reducing the overall inhibition of viral replication and making the antiviral efficacy more susceptible to the drug intracellular concentration. Second, using data from  in vitro  viral   cultures with plausible TDF therapeutic concentrations, we estimated that the drug can inhibit SARS-COV-2 replication at an efficacy ranging between 54-99%  conditional to the viral cycle length. Third, assuming values approximating this range of inhibition for  in vivo  viral replication during human SARS-COV-2 infection, we found that prophylaxis with TDF with high penetration into viral target cells is capable of delaying viral replication, mitigating direct cell damage and allowing time for the host to mount the adaptive immunity. Last, we found that the potential antiviral effect can be substantially reduced when TDF is given after infection begins. Our work provides a potential mechanistic explanation of the observed clinical effect of TDF against SARS-CoV-2 infection. The proposed inference framework can help to optimize the evaluation of antiviral therapies for COVID-19, in particular those targeting the RNA dependent RNA polymerase.

Brief communication: A meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19 (preprint)

Background: There is disagreement about whether hydroxychloroquine (HCQ) is effective as prophylaxis for COVID-19. We conducted a meta-analysis of randomized trials that study the effectiveness of HCQ to prevent COVID-19. Methods and Findings: A search of PubMed, Embase, medRxiv, and clinicaltrials.gov found three completed randomized trials: one pre-exposure prophylaxis trial and two post-exposure prophylaxis trials. We obtained or calculated the risk ratio of COVID-19 diagnosis for assignment to HCQ versus no HCQ (either placebo or usual care) for each trial, and then pooled the risk ratio estimates. The risk ratio estimated for each of the individual trials were 0.74 (95% CI 0.50-1.10), 0.83 (95% CI: 0.58-1.18), and 0.69 (95% CI: 0.35-1.37). The pooled risk ratio estimate was 0.78 (95% CI: 0.61-0.99). All three trials found a similar rate of adverse effects in the HCQ and no HCQ groups. Discussion: The available evidence indicates that HCQ reduces the risk of COVID-19 by about 20%. Yet the findings from the randomized trials were widely interpreted as evidence of lack of effectiveness of HCQ, simply because they were not statistically significant when taking them individually. Completion of the ongoing prophylaxis trials is needed to generate more precise estimates of the effectiveness of HCQ to prevent COVID-19.