Viral clearance: a potential predictor of treatment efficacy with COVID-19

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

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

*Important news: medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.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 shows reduced efficacy against monoclonal antibody treatment, justifying more effective antivirals. Although placebo-controlled clinical trials are considered the gold standard for evaluating the efficacy of a treatment, other approaches could be developed to speed up the evaluation process to determine effective therapies against COVID-19 and ultimately reduce mortality rates.

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

to evaluate the effectiveness of new COVID-19 therapies, the virological effect, defined as the degree of viral load reduction in the treated group compared to controls, was analysed. However, it is not yet clear whether the virological effect indicates a preventive effect against progression to severe infection.

About the study

A new systematic review and meta-analysis were recently published in the medRxiv* preprint server. In this paper, the investigators determine the virologic 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 according to 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, we included studies that reported both virological and clinical.

Clinical outcomes were assessed based on disease progression, which was assessed by looking at the need for hospitalization or death within 28 days of starting treatment. Virologic outcomes were also assessed by measuring viral load, which reflects viral ribonucleic acid (RNA) copies in upper respiratory tract smears within seven days of treatment.

Studies that could not present the results of RCTs were excluded. The RoB 2.0 tool was used to limit the risk of bias assessment.

Study findings

A total of 1372 unique studies were identified, of which fourteen met the study criteria. Six RCTs investigated small molecule antiviral therapies; eight were linked to monoclonal antibody-based treatment. Although most studies included adult participants, two included adolescents with risk factors for severe disease.

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

The current study looked at the effectiveness of treatment given to unvaccinated COVID-19 outpatients in reducing 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 was observed between the effect of virologic treatment on days three and five and clinical outcomes. If a new antiviral agent leads to an additional 2.3-fold drop in viral load by day 3, it could indicate 50% clinical protection against hospitalization.

However, virologic results on day five might be a marginally better predictor of clinical outcomes compared to day three. Therefore, virological clearance could be used as an effective surrogate to determine clinical efficacy, particularly for early stages of clinical trials.

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

The possibility exists that some treatments may influence clinical outcomes without affecting virologic outcomes in the upper respiratory tract. Therefore, the lack of virological efficacy may not always suggest poor clinical outcomes.

conclusions

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

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