Tenofovir Disoproxil Fumarate and severity of COVID-19 in people with HIV infection (preprint)

Background Effective, safe, and affordable antivirals are needed for COVID-19. Tenofovir has not been studied in randomized trials despite evidence consistent with its effectiveness against COVID-19. Methods We studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/ FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting. Results Of 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals [≥]50 years and 1.15 (0.59, 1.93) in younger individuals. Conclusion Our findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.

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.