Tenofovir-Containing Antiretroviral Therapy and Clinical Outcomes of SARS-CoV-2 Infection in People Living with HIV.

Tenofovir has been hypothesized to be effective against COVID-19 and is available as two prodrugs, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), both part of antiretroviral therapy (ART) regimens. People living with human immunodeficiency virus (PLWH) might be at higher risk for COVID-19 progression; however, information about the impact of tenofovir on COVID-19 clinical outcomes remains controversial. The COVIDARE is a prospective observational multicentric study in Argentina. PLWH with COVID-19 were enrolled from September 2020 to mid-June 2022. Patients were stratified according to baseline ART into those with tenofovir (TDF or TAF) and those without. Univariate and multivariate analyses were performed to evaluate the impact of tenofovir vs. non-tenofovir-containing regimens on major clinical outcomes. Of the 1155 subjects evaluated, 927 (80%) received tenofovir-based ART (79% TDF, 21% TAF) whilst the remaining population was under non-tenofovir regimens. The non-tenofovir group had older age and a higher prevalence of heart and kidney disease. Regarding the prevalence of symptomatic COVID-19, tomographic findings, hospitalization, and mortality, no differences were observed. The oxygen therapy requirement was higher in the non-tenofovir group. In the multivariate analyses, a first model with adjustment for viral load, CD4 T-cell count, and overall comorbidities showed that oxygen requirement was associated with non-tenofovir ART. In a second model with adjustment by chronic kidney disease, tenofovir exposure was not statistically significant.

The Nucleoside/Nucleotide Analogs Tenofovir and Emtricitabine Are Inactive against SARS-CoV-2.

The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.

Computational drug re-purposing targeting the spike glycoprotein of SARS-CoV-2 as an effective strategy to neutralize COVID-19.

COVID-19 has intensified into a global pandemic with over a million deaths worldwide. Experimental research analyses have been implemented and executed with the sole rationale to counteract SARS-CoV-2, which has initiated potent therapeutic strategy development in coherence with computational biology validation focusing on the characterized viral drug targets signified by proteomic and genomic data. Spike glycoprotein is one of such potential drug target that promotes viral attachment to the host cellular membrane by binding to its receptor ACE-2 via its Receptor-Binding Domain (RBD). Multiple Sequence alignment and relative phylogenetic analysis revealed significant sequential disparities of SARS-CoV-2 as compared to previously encountered SARS-CoV and MERS-CoV strains. We implemented a drug re-purposing approach wherein the inhibitory efficacy of a cluster of thirty known drug candidates comprising of antivirals, antibiotics and phytochemicals (selection contingent on their present developmental status in underway clinical trials) was elucidated by subjecting them to molecular docking analyses against the spike protein RBD model (developed using homology modelling and validated using SAVES server 5.0) and the composite trimeric structures of spike glycoprotein of SARS-CoV-2. Our results indicated that Camostat, Favipiravir, Tenofovir, Raltegravir and Stavudine showed significant interactions with spike RBD of SARS-CoV-2. Proficient bioavailability coupled with no predicted in silico toxicity rendered them as prospective alternatives for designing and development of novel combinatorial therapy formulations for improving existing treatment regimes to combat COVID-19.