Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of phase 2 antiviral studies

Abstract

AbstractBackgroundEffective antiviral drugs prevent hospitalisation and death in COVID-19. Antiviral efficacy can be assessed efficiently in-vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral densities measured in nasopharyngeal or oropharyngeal swab eluates. The changing epidemiology of SARS-CoV-2 infection has substantially affected viral clearance kinetics and thus the optimal design and interpretation of antiviral pharmacometric evaluations.MethodsSerial viral density data were analysed from patients enrolled in a large multicentre randomised adaptive pharmacodynamic platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over one week were estimated and boot-strap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal is defined as maximising the expected z-score.ResultsBetween 29 September 2021 and 20 October 2023, 1264 patients were randomised. Unblinded data were available from 800 patients (16,818 oropharyngeal viral qPCR measurements). SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase (α) was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected z-score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the two year period studied, median viral clearance half-lives estimated over 7 days have shortened from 16.8 hours in September 2021 to 9.3 hours in October 2023 in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% [95% credible interval (CrI): 17 to 67%]. A parallel trend was observed in treated patients. In the ritonavir-boosted nirmatrelvir arm the median clearance half-life declined from 6.6 hours in June 2022 to 4.8 hours in October 2023, a relative reduction of 26% [95%CrI: -4 to 42%].ConclusionsSARS-CoV-2 viral clearance kinetics in symptomatic vaccinated individuals have accelerated substantially over the past two years. Antiviral efficacy in COVID-19 can now be assessed efficiently in-vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration.FundingWellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.