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.
Lancet Infect Dis. 2024 Sep;24(9):953-963. doi: 10.1016/S1473-3099(24)00183-X. Epub 2024 Apr 24.
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.
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.
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).
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.
Wellcome Trust.
有效的抗病毒药物可预防 COVID-19 导致的住院和死亡。通过测量从鼻咽或口咽拭子洗脱液中定量估计的 SARS-CoV-2 清除率，可在体内有效地评估抗病毒功效。我们对 PLATCOV 平台试验的未设盲臂进行了个体患者数据荟萃分析，以描述病毒清除动力学的变化，并推断抗病毒药代动力学评估的最佳设计和解释。
对来自大型多中心、随机、适应性、药效动力学、平台试验（PLATCOV）的无症状、既往健康的成年患者（症状出现后 4 天内）的连续病毒密度数据进行了分析，该试验比较了 SARS-CoV-2 的抗病毒干预措施。在分层贝叶斯线性模型下估计了 1 周内的病毒清除率，其中 B 样条用于描述登记病毒密度和清除率的时间变化。使用自举重采样来评估药代动力学评估的最佳随访时间，其中最佳定义为当比较有效抗病毒药物与无治疗时，预期 Z 分数最大化。PLATCOV 在 ClinicalTrials.gov 注册，NCT05041907。
2021 年 9 月 29 日至 2023 年 10 月 20 日，PLATCOV 试验中随机分配了 1262 名患者。800 名患者（提供了 16818 次鼻咽病毒定量 PCR [qPCR]测量）的未设盲数据可用，其中 504 名（63%）为女性。783 名（98%）患者至少接受过一剂疫苗接种，703 名（88%）患者已完全接种疫苗。SARS-CoV-2 病毒清除呈双相（双指数）。有效的干预措施加速了第一阶段（α）。对于研究的所有有效干预措施，当评估登记后第 5 天之前的连续数据时，获得了最大的判别能力（最大预期 Z 分数）。在研究的 2 年期间，未接受抗病毒药物治疗的患者中，7 天内估计的病毒清除半衰期从 2021 年 9 月的 16.6 小时（IQR 15.3-18.2）缩短至 2023 年 10 月的 9.2 小时（8.0-10.6），相当于相对减少 44%（95%可信区间 [CrI] 19-64）。接受抗病毒药物治疗的患者的病毒清除半衰期也随时间呈平行减少。例如，在 158 名被分配到利托那韦增强奈玛特韦的患者（3380 次 qPCR 测量）中，病毒清除半衰期从 2022 年 6 月的 6.4 小时（IQR 5.7-7.3）缩短至 2023 年 10 月的 4.8 小时（4.2-5.5），相对减少 26%（95% CrI-4-42）。
在大流行的 2 年中，症状性、接种疫苗的个体中 SARS-CoV-2 病毒清除动力学明显加快，这需要改变如何比较新的 SARS-CoV-2 抗病毒药物（即缩短药代动力学评估的时间）。截至撰写本文（2023 年 10 月），可使用每日采集的 2 次口咽拭子洗脱液的连续 qPCR 高效评估 COVID-19 中的抗病毒功效。
惠康信托基金会。
