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Journal Article Multicenter Study Randomized Controlled Trial Adaptive Clinical Trial Ppublish 14 citations

PubMed: 38677300 DOI: 10.1016/S1473-3099(24)00183-X

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).

Lancet Infect Dis 24(9):953-963

Authors: Phrutsamon Wongnak, William H K Schilling, Podjanee Jittamala, Simon Boyd, Viravarn Luvira, Tanaya Siripoon, Thundon Ngamprasertchai, Elizabeth M Batty, Shivani Singh, Jindarat Kouhathong, Watcharee Pagornrat, Patpannee Khanthagan, Borimas Hanboonkunupakarn, Kittiyod Poovorawan, Mayfong Mayxay, Kesinee Chotivanich, Mallika Imwong, Sasithon Pukrittayakamee, Elizabeth A Ashley, Arjen M Dondorp, Nicholas P J Day, Mauro M Teixeira, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, Nicholas J White, James A Watson

Affiliations

  • Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
  • Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
  • Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Department of Tropical Hygiene, Mahidol University, Bangkok, Thailand.
  • Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Department of Tropical Hygiene, Mahidol University, Bangkok, Thailand.
  • Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Laos; Institute for Research and Education Development, University of Health Sciences, Vientiane, Laos.
  • Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand.
  • Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Laos.
  • Clinical Research Unit, Center for Advanced and Innovative Therapies, Universidade Federal de Minas Gerais, Brazil.
  • Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
  • Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

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.

MeSH

Research Design, Sars-Cov-2, Vaccines, Pharmaceutical Preparations, Severe Acute Respiratory Syndrome-Related Coronavirus, Communicable Diseases, Antiviral Agents

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