Viral clearance: A potential predictor of COVID-19 treatment efficacy

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Jun 22 2023

Scientists worldwide are continually working to develop effective treatments and preventive measures against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Two effective COVID-19 treatments include monoclonal antibodies and small-molecule antivirals; however, these treatments are most effective when administered during the early infection phase.

Study: Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: A systematic review and meta-analysis. Image Credit: Pand P Studio / Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The emergence of SARS-CoV-2 variants that escape immune protection also exhibits reduced efficacy against monoclonal antibody treatment, thus warranting more effective antivirals. Although placebo-controlled clinical trials are considered the gold standard to evaluate the effectiveness of a treatment, other approaches could be developed to accelerate the assessment process to determine effective COVID-19 therapies and ultimately reduce mortality rates. 

During phase II clinical trials of COVID-19 antiviral agents, the difference in the viral burden between the placebo and treated group at different times post-therapy is measured to determine treatment effectiveness in reducing viral loads. 

To assess the efficacy of novel COVID-19 therapeutics, the virological effect, defined as the extent of viral load reduction in the treated group compared to controls, was analyzed. However, whether the virological effect indicates a preventive effect against progression to severe infection remains unclear.

About the study

A new systematic review and meta-analysis were recently posted to the medRxiv* preprint server. Herein, researchers determine the virological effects of COVID-19 treatment and its clinical efficacy in the same trial.

The current study explored the relationship between the virological effect of treatment and clinical efficacy in accordance with disease progression in unvaccinated outpatients treated for mild to moderate SARS-CoV-2 infection. Relevant data on randomized controlled trials (RCTs) related to COVID-19 treatments in outpatients were obtained from Scopus, PubMed, and medRxiv, from inception to September 27, 2022. Here, studies that reported both virological and clinical outcomes were included.

Clinical outcomes were assessed based on disease progression, which was evaluated by analyzing the need for hospitalization or death within 28 days after treatment commencement. Virological outcomes were also assessed by measuring the viral load, which reflects the viral ribonucleic acid (RNA) copies in upper respiratory tract swabs within seven days of the treatment.

Studies that failed to present the outcomes of the RCTs were excluded. The RoB 2.0 tool was used to limit the risk of bias assessment.

Study findings

A total of 1,372 unique studies were identified, of which fourteen fulfilled the study criteria. Six RCTs investigated small molecule antiviral therapies; eight were linked to monoclonal antibodies-based treatment. Although most studies enrolled adult participants, two included adolescents with risk factors for severe disease.

Out of the fourteen studies, six excluded individuals with a history of chronic infection, and two excluded individuals were hospitalized due to severe SARS-CoV-2 infection. A risk of bias assessment was performed on all studies, which mostly revealed a low risk of bias.

The current study analyzed the effectiveness of treatment administered to unvaccinated COVID-19 outpatients in reducing the viral RNA levels in upper respiratory tract swabs. This reduction in SARS-CoV-2 RNA levels indicates the clinical efficacy of the treatment in preventing hospitalization and death.

A strong association between the virological treatment effect at days three and five and clinical outcomes was observed. If a novel antiviral agent leads to an extra 2.3-fold drop in viral load by day three, it could indicate 50% clinical protection from hospitalization.

However, virological outcomes on day five could be a marginally better predictor of clinical outcomes as compared to those on day three. Thus, virological clearance could be used as an effective surrogate to determine clinical efficacy, particularly for early-stage of clinical trials. 

No evidence was found regarding a relationship between virological outcomes at day seven and clinical outcomes. This could be because not many studies have considered this time point, whereas other studies reported insignificant viral load between control and treated groups at this time point.

There is a possibility that some treatments may influence clinical outcomes without affecting virological outcomes in the upper respiratory tract. Thus, a lack of virological efficacy may not always suggest poor clinical outcomes.

Conclusions

The association between virological outcomes and clinical outcomes may act as a tool to predict treatment efficacy. Future phase I and II clinical trials are needed to evaluate virological outcomes on at least days one, three, and five to understand whether a virological treatment effect is present at the observed time points.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.