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 continuing coronavirus disease 2019 (COVID-19) pandemic. Two effective COVID-19 treatments include monoclonal antibodies and small-molecule antivirals; nonetheless, these treatments are only when administered through the early infection phase.
Study: Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: A scientific review and meta-analysis. Image Credit: Pand P Studio / Shutterstock.com
*Vital notice: medRxiv publishes preliminary scientific reports that should not peer-reviewed and, subsequently, shouldn’t be thought to be conclusive, guide clinical practice/health-related behavior, or treated as established information.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 practical antivirals. Although placebo-controlled clinical trials are considered the gold standard to judge the effectiveness of a treatment, other approaches may very well be developed to speed up the assessment process to find out effective COVID-19 therapies and ultimately reduce mortality rates.
During phase II clinical trials of COVID-19 antiviral agents, the difference within the viral burden between the placebo and treated group at different times post-therapy is measured to find out treatment effectiveness in reducing viral loads.
To evaluate the efficacy of novel COVID-19 therapeutics, the virological effect, defined because the extent of viral load reduction within the treated group in comparison with controls, was analyzed. Nevertheless, whether the virological effect indicates a preventive effect against progression to severe infection stays unclear.
Concerning the study
A latest 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 identical trial.
The present study explored the connection 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 each virological and clinical outcomes were included.
Clinical outcomes were assessed based on disease progression, which was evaluated by analyzing the necessity for hospitalization or death inside 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 inside seven days of the treatment.
Studies that didn’t present the outcomes of the RCTs were excluded. The RoB 2.0 tool was used to limit the chance of bias assessment.
Study findings
A complete 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 aspects for severe disease.
Out of the fourteen studies, six excluded individuals with a history of chronic infection, and two excluded individuals were hospitalized attributable 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 present 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 stopping hospitalization and death.
A robust association between the virological treatment effect at days three and five and clinical outcomes was observed. If a novel antiviral agent results in an additional 2.3-fold drop in viral load by day three, it could indicate 50% clinical protection from hospitalization.
Nevertheless, virological outcomes on day five may very well be a slightly higher predictor of clinical outcomes as in comparison with those on day three. Thus, virological clearance may very well be used as an efficient surrogate to find out 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 may very well be because not many studies have considered this time point, whereas other studies reported insignificant viral load between control and treated groups presently point.
There may be a possibility that some treatments may influence clinical outcomes without affecting virological outcomes within the upper respiratory tract. Thus, a scarcity of virological efficacy may not all the time 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 judge virological outcomes on at the very least days one, three, and five to know whether a virological treatment effect is present on the observed time points.
*Vital notice: medRxiv publishes preliminary scientific reports that should not peer-reviewed and, subsequently, shouldn’t be thought to be conclusive, guide clinical practice/health-related behavior, or treated as established information.
Journal reference:
- Preliminary scientific report.
Elias, M. K., Khan, S. R., Stadler, E., et al. (2023) Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: A scientific review and meta-analysis. medRxiv. doi:10.1101/2023.06.18.23291566