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

Background: Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated in nasopharyngeal or oropharyngeal swab eluates. We conducted 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.

Methods: Serial 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 1 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 was defined as maximising the expected Z score when comparing effective antivirals with no treatment. PLATCOV is registered at ClinicalTrials.gov, NCT05041907.

Findings: Between Sept 29, 2021, and Oct 20, 2023, 1262 patients were randomly assigned in the PLATCOV trial. Unblinded data were available from 800 patients (who provided 16 818 oropharyngeal viral quantitative PCR [qPCR] measurements), of whom 504 (63%) were female. 783 (98%) patients had received at least one vaccine dose and 703 (88%) 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 2-year period studied, median viral clearance half-lives estimated over 7 days shortened from 16·6 h (IQR 15·3 to 18·2) in September, 2021, to 9·2 h (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 reduction in viral clearance half-lives over time was observed in patients receiving antiviral drugs. For example, in the 158 patients assigned to ritonavir-boosted nirmatrelvir (3380 qPCR measurements), the median viral clearance half-life reduced from 6·4 h (IQR 5·7 to 7·3) in June, 2022, to 4·8 h (4·2 to 5·5) in October, 2023, a relative reduction of 26% (95% CrI -4 to 42).

Interpretation: SARS-CoV-2 viral clearance kinetics in symptomatic, vaccinated individuals accelerated substantially over 2 years of the pandemic, necessitating a change to how new SARS-CoV-2 antivirals are compared (ie, shortening the period of pharmacodynamic assessment). As of writing (October, 2023), antiviral efficacy in COVID-19 can be efficiently assessed in vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration.

Funding: Wellcome Trust.

Figure 1. PLATCOV trial profile and selection of patients for this analysis

This analysis included patients enrolled between Sept 30, 2021, and Oct 20, 2023, who met the modified intention-to-treat criteria and whose viral clearance data have been unblinded and published. Patients were excluded from the modified intention-to-treat population if protocol deviations occured on days 0–2.

Figure 2. Changes in symptoms duration at enrolment and baseline oropharyngeal eluate viral densities over a 2-year period (2021–23)

(A) The association between reported interval since symptom onset and baseline viral density. (B) Temporal changes in the reported interval since symptom onset. The vertical dashed line indicates the first omicron BA.1 infection enrolled in the study. (C) Temporal changes in the baseline viral density stratified by reported interval since symptom onset. Red lines represent mean estimated values and shaded areas the 95% CIs under a generalised additive model.

Figure 3. Individual patient data meta-analysis showing change over time in estimated rates of viral clearance between days 0 and 7 (α₀₋₇)

(A) Ivermectin. (B) Favipiravir. (C) Casirivimab–imdevimab. (D) Remdesivir. (E) Molnupiravir. (F) Ritonavir-boosted nirmatrelvir. Average clearance rates for each intervention (coloured lines) and the no study drug arm (grey line) were estimated from a spline fit. Treatment effects were parameterised as a proportional change in rate. The grey circles and grey lines for the no study drug arm are identical in each panel. Vertical lines show 95% credible intervals under the linear model. A negative sign of the clearance rate indicates a decreasing directional change in viral density. α₀₋₇=the rate of viral genome clearance estimated under a linear model fitted to the serial log viral densities (measured by qPCR in daily duplicate oropharyngeal viral swab eluates) between days 0 and 7.

Figure 4. Z scores for the six comparisons of treatment effect as a function of the follow-up duration

(A) Remdesivir versus no study drug. (B) Molnupiravir versus no study drug. (C) Casirivimab–imdevimab versus no study drug. (D) Nirmatrelvir versus molnupiravir. (E) Nirmatrelvir versus no study drug (before February, 2023). (F) Nirmatrelvir versus no study drug (after February, 2023). Boxplots show the median IQR of the Z scores for 50 bootstrap iterations. Each bootstrap dataset contained 50 patients per group. Vertical dashed lines indicate the follow-up durations with maximal Z scores. All comparisons use concurrent controls only.

Figure 5. Individual patient data meta-analysis of the treatment effect of the six randomised interventions relative to no study drug

The models were adjusted for temporal changes in viral clearance in the no study drug arm using penalised B-splines. Points represent the median posterior estimate and thick and thin lines the 80% and 95% credible intervals, respectively.