Discussion
febrile, molnupiravir-treated SARS-CoV-2 viruses, fever
DISEASE PROGRESSION, DISEASE, EVENT
To our knowledge, this is the first comparative pharmacodynamic assessment of COVID-19 antiviral treatments in patients. The study shows that both molnupiravir and ritonavir-boosted nirmatrelvir accelerate viral clearance in early COVID-19. This supports the results of previous clinical trials and studies with sparse viral sampling. The antiviral effect of ritonavir-boosted nirmatrelvir was substantially greater than that of molnupiravir. This corresponds approximately with the differences in clinical benefits reported in earlier randomised and observational studies.The main indication for oral antiviral treatment in patients with COVID-19 is prevention of disease progression.A mutational signature associated with molnupiravir-treated SARS-CoV-2 viruses has been identified previously in the AGILE CST-2 clinical trial,Despite characterising comparative antiviral efficacy satisfactorily with small patient numbers, this study has several limitations. It is a single-centre study. Population differences in immune status and pharmacokinetics might affect therapeutic responses. We intentionally evaluated the interventions in adults at low risk with high viral burdens in order to optimise the comparative assessment of the different drugs, and not in patients at high risk or older patients who are at greatest risk of disease progression. Protection against severe disease could not be assessed in this study as no-one was hospitalised. Although the rates of symptom resolution and viral clearance were correlated, only a third of patients were febrile initially, so correlates of fever clearance were not established reliably. Viral rebound was noted although the study was not designed to characterise this fully. The analysis population was described as a modified intention-to-treat population, which excluded randomly assigned patients who provided insufficient data for analysis of viral clearance (only two were excluded). This could in theory introduce bias by selecting on a post-randomisation event; however, the primary endpoint was virological (and masked to the investigators), so this is highly unlikely.The considerable intra-individual variability in nasopharyngeal (or oropharyngeal) viral loads results in a low signal-to-noise ratio. Frequent sampling over 5–7 days is therefore required to measure clearance rates. Oropharyngeal sampling is well tolerated, whereas frequent nasopharyngeal sampling is not. This simple approach allows pharmacometric characterisation and comparison of antivirals with patient numbers usually of between 30 and 100 per group.For the For the MORU Tropical Health Network site see 