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

Abstract

Tenofovir\xa0has shown promising evidence of improving COVID-19 clinical\noutcomes in observational studies, still to be confirmed in clinical\ntrials. Disease severity might be reduced under\xa0prophylaxis with the\nprodrug tenofovir disoproxil fumarate (TDF), while the protection seems\nto decrease, or even to lack, when using the alternative prodrug\ntenofovir alafenamide fumarate (TAF).\xa0\xa0Aiming to understand why\nTDF-prophylaxis might reduce COVID-19 severity upon infection we\ndeveloped a multi-scale analysis framework combining\xa0in\nvitro\xa0susceptibility data, molecular docking, and within-host dynamics\nmodeling, and using remdesivir–the only antiviral approved to date\nagainst COVID-19– as a point of reference.First, our docking model\npredicted that intracellularly active tenofovir diphosphate binds into\nthe SARS-CoV-2 RNA polymerase in the same site as the antiviral\nremdesivir triphosphate, but presents lower binding energy, likely\nreducing the overall inhibition of viral replication and making the\nantiviral efficacy more susceptible to the drug intracellular\nconcentration. Second, using data from\xa0in\nvitro\xa0viral\xa0cultures with plausible TDF therapeutic\nconcentrations, we estimated that the drug can inhibit SARS-COV-2\nreplication at an efficacy ranging between 54-99%\xa0\xa0conditional to the\nviral cycle length. Third, assuming values approximating this range of\ninhibition for\xa0in vivo\xa0viral replication during human SARS-COV-2\ninfection, we found that prophylaxis with TDF with high penetration into\nviral target cells is capable of delaying viral replication, mitigating\ndirect cell damage and allowing time for the host to mount the adaptive\nimmunity. Last, we found that the potential antiviral effect can be\nsubstantially reduced when TDF is given after infection begins.\xa0Our work\nprovides a potential mechanistic explanation of the observed clinical\neffect of TDF against SARS-CoV-2 infection. The proposed inference\nframework can help to optimize the evaluation of antiviral therapies for\nCOVID-19, in particular those targeting the RNA dependent RNA\npolymerase.