门诊 COVID-19 治疗中病毒清除作为临床疗效替代指标的系统评价和荟萃分析。

Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: a systematic review and meta-analysis.

机构信息

Kirby Institute, University of New South Wales, Sydney, NSW, Australia.

Kirby Institute, University of New South Wales, Sydney, NSW, Australia; Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

出版信息

Lancet Microbe. 2024 May;5(5):e459-e467. doi: 10.1016/S2666-5247(23)00398-1. Epub 2024 Apr 4.

DOI:10.1016/S2666-5247(23)00398-1

PMID:38583464

Abstract

BACKGROUND

Surrogates of antiviral efficacy are needed for COVID-19. We aimed to investigate the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in outpatients treated for mild-to-moderate COVID-19.

METHODS

In this systematic review and meta-analysis, we searched PubMed, Scopus, and medRxiv from database inception to Aug 16, 2023, for randomised placebo-controlled trials that tested virus-directed treatments (ie, any monoclonal antibodies, convalescent plasma, or antivirals) in non-hospitalised individuals with COVID-19. We only included studies that reported both clinical outcomes (ie, rate of disease progression to hospitalisation or death) and virological outcomes (ie, viral load within the first 7 days of treatment). We extracted summary data from eligible reports, with discrepancies resolved through discussion. We used an established meta-regression model with random effects to assess the association between clinical efficacy and virological treatment effect, and calculated I to quantify residual study heterogeneity.

FINDINGS

We identified 1718 unique studies, of which 22 (with a total of 16 684 participants) met the inclusion criteria, and were in primarily unvaccinated individuals. Risk of bias was assessed as low in 19 of 22 studies for clinical outcomes, whereas for virological outcomes, a high risk of bias was assessed in 11 studies, some risk in ten studies, and a low risk in one study. The unadjusted relative risk of disease progression for each extra log copies per mL reduction in viral load in treated compared with placebo groups was 0·12 (95% CI 0·04-0·34; p<0·0001) on day 3, 0·20 (0·08-0·50; p=0·0006) on day 5, and 0·53 (0·30-0·94; p=0·030) on day 7. The residual heterogeneity in our meta-regression was estimated as low (I=0% [0-53] on day 3, 0% [0-71] on day 5, and 0% [0-43] on day 7).

INTERPRETATION

Despite the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes, this review provides evidence that treatment-induced acceleration of viral clearance within the first 5 days after treatment is a potential surrogate of clinical efficacy to prevent hospitalisation with COVID-19. This work supports the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy.

FUNDING

Australian Government Department of Health, Medical Research Future Fund, and Australian National Health and Medical Research Council.

摘要

背景

我们需要 COVID-19 的抗病毒疗效替代指标。本研究旨在探究门诊轻至中度 COVID-19 患者接受治疗后疾病向重症进展的临床疗效与病毒学治疗效果之间的关系。

方法

本系统评价和荟萃分析检索了从数据库建立到 2023 年 8 月 16 日的 PubMed、Scopus 和 medRxiv，纳入了评估非住院 COVID-19 患者使用病毒定向治疗（即任何单克隆抗体、恢复期血浆或抗病毒药物）的随机安慰剂对照试验。我们仅纳入了报告临床结局（即疾病进展至住院或死亡的发生率）和病毒学结局（即治疗后第 1 天内病毒载量）的研究。我们从合格报告中提取汇总数据，通过讨论解决差异。我们使用具有随机效应的既定荟萃回归模型来评估临床疗效与病毒学治疗效果之间的关联，并计算 I 来量化残留的研究异质性。

结果

我们确定了 1718 项独特的研究，其中 22 项（共 16684 名参与者）符合纳入标准，且主要纳入了未接种疫苗的个体。22 项研究中，19 项研究的临床结局的偏倚风险评估为低风险，而病毒学结局的偏倚风险评估为高风险的有 11 项研究，高风险的有 10 项研究，低风险的有 1 项研究。与安慰剂组相比，治疗组病毒载量每增加 1 对数拷贝/mL，第 3 天疾病进展的相对风险为 0.12（95%CI 0.04-0.34；p<0.0001），第 5 天为 0.20（0.08-0.50；p=0.0006），第 7 天为 0.53（0.30-0.94；p=0.030）。我们荟萃回归中的剩余异质性估计为低（第 3 天为 0%[0-53]，第 5 天为 0%[0-71]，第 7 天为 0%[0-43]）。