Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV)

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 genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We carried out an individual patient data meta-analysis of unblinded arms in the PLATCOV platform trial to characterise changes in viral clearance kinetics and infer optimal design and interpretation of antiviral pharmacometric evaluations. PLATCOV is registered at ClinicalTrials.gov,NCT05041907.MethodsSerial viral density data were analysed from symptomatic, previously healthy, adult patients (within 4 days of symptom onset) 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 under a hierarchical Bayesian linear model with B-splines used to characterise temporal changes in enrolment viral densities and clearance rates. Bootstrap 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 when comparing effective antivirals with no treatment.ResultsBetween 29 September 2021 and 20 October 2023, 1262 patients were randomised. Unblinded data were available from 800 patients (16,818 oropharyngeal viral qPCR measurements) of whom 63% (504/800) were female. 98% (783/800) had received at least one vaccine dose and over 88% (703/800) were fully vaccinated. 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 16.6 hours (interquartile range [IQR]: 15.3 to 18.2) in September 2021 to 9.2 hours (IQR: 8.0 to 10.6) in October 2023 in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% [95% credible interval (CrI): 19 to 64%]. A parallel trend was observed in treated patients. In the 158 patients randomised to ritonavir-boosted nirmatrelvir (3,380 qPCR measurements), the median viral clearance half-life declined from 6.4 hours (IQR: 5.7 to 7.3) in June 2022 to 4.8 hours (IQR: 4.2 to 5.5) 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.