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

ABSTRACT

Background Surrogates of antiviral efficacy are needed for COVID-19. We investigated the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in unvaccinated outpatients treated for mild to moderate COVID-19. Methods We searched PubMed, Scopus and medRxiv from inception to 27th September 2022, for randomised controlled trials (RCTs) which tested potential treatments for COVID-19 in non-hospitalized patients. We included studies that reported both clinical and virological outcomes. Clinical outcomes were the rate of disease progression (generally hospitalization or death within 28 days of commencing treatment) and virological outcomes were viral load (viral RNA copies in upper respiratory tract swabs) within the first 7 days of treatment. Studies were excluded if they did not report on the outcome of a primary randomised controlled trial, or if results were reported in a more complete form in another publication. Risk of Bias assessment was performed using the RoB 2.0 tool. We used generalised linear models with random effects to assess the association between outcomes and account for study heterogeneity. Findings We identified 1372 unique studies of which 14 (with a total of 9257 participants) met inclusion criteria. Larger virological treatment effects at both day 3 and day 5 were associated with decreased odds of progression to hospitalisation or death in unvaccinated ambulatory subjects. The odds ratio (OR) for each extra two-fold reduction in viral load in treated compared to control subjects was 0.54 on both days 3 and 5 post treatment (day 3 95% CI 0.38 to 0.74, day 5 95%CI 0.41 to 0.72). There was no relationship between the odds of hospitalisation or death and virological treatment effect at day 7 (OR 0.91, 95%CI 0.74 to 1.13). 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 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 The authors were supported by the Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council and the University of New South Wales.