Evidence growing for COVID antivirals to cut poor outcomes, long COVID, experts say

COVID-19
Taking an antiviral

Phira Phone Wiang Phing / iStock

A recently published systematic review and meta-analysis found no evidence that the antiviral drugs nirmatrelvir/ritonavir (Paxlovid) and molnupiravir (Lagevrio) help prevent COVID-19 hospitalization, death, or persistent symptoms, results that the authors say call for reassessment of the role that oral antivirals play in the context of currently circulating SARS-CoV-2 variants and population immunity from vaccination, infection, or both.

The study, published on September 7 in Open Forum Infectious Diseases, isn't the first to draw such conclusions, but some experts have cast doubt on its methodology and conclusions. 

On December 12, 2023, the researchers pooled and analyzed the results of 23 randomized trials (14 published, including a RECOVERY Trial preprint) on the efficacy of Paxlovid or molnupiravir against severe COVID-19 or long COVID. The team estimated the relative risks of reducing death and hospitalization after treatment with molnupiravir and Paxlovid, respectively, at 0.62 (95% confidence interval [CI], 0.15 to 2.53) and 0.33 (95% CI, 0.03 to 3.35) amid the Omicron, Delta/Omicron, Delta, or Alpha variant eras. 

"Many of the primary outcomes were based on viral clearance, rather than patient-centered outcomes, such as hospitalization or death, and most positive trials were tested against unvaccinated populations and/or earlier strains of SARS-CoV-2," the authors wrote. "Against the backdrop of an evolving strain of virus and increasing population immunity, approval data for currently available treatments for COVID-19 need to be reevaluated, based on current strains and immunity."

Lack of risk stratification

But Ziyad Al-Aly, MD, chief of research and development at the VA St Louis Health Care System, said the key problem with the systematic review is that the authors lump together low- and high-risk patients, as well as outcomes (hospitalization and death), when antivirals are widely known to have little to no effect in low-risk patients (regulatory approval was for those with at least one risk factor for poor outcomes). He also noted the wide CIs, which suggest uncertainty.

"Their results show very high heterogeneity—a strong indicator that they are on the wrong track," he told the University of Minnesota's Center for Infectious Disease Research and Policy (CIDRAP) News via email. 

"They included studies that are measuring different effects; combining these studies in meta-analyses does not provide a reliable and useful summary effect," Al-Aly said. "Unfortunately, they don't do anything to investigate the source of heterogeneity or mitigate it in some way; they accept the result at face value." 

Unfortunately, they don't do anything to investigate the source of heterogeneity or mitigate it in some way; they accept the result at face value. 

Ziyad Al-Aly, MD

Angela Ulrich, PhD, MPH, CIDRAP researcher and assistant professor, agreed, saying she thought it interesting that the RECOVERY Trial preprint was included despite it being published beyond the systematic review's inclusion dates. The preprint, published on medRxiv on May 24, 2024, concluded that neither molnupiravir nor Paxlovid lowered death rates, shortened hospital stays, or lessened the risk of death or requiring invasive mechanical ventilation.

"I would like to see a sensitivity analysis, as I suspect these trial results heavily influence the meta-analysis estimates," she said. "It's also interesting that all of the trial outcome sources aren't cited. I was searching online to try to find each, but it's hard to tell which source they used, which would be helpful for determining whether they were appropriately included."

Study coauthor Vinay Prasad, MD, MPH, of the University of California San Francisco, didn't respond to a request for comment from CIDRAP News.

Substantial progress, much yet to learn

Last week Al-Aly published a commentary in The Lancet Infectious Diseases on the role of COVID-19 antivirals in reducing rates of long COVID in vaccinated patients. The commentary was based on a UK-researcher–led randomized controlled trial showing that molnupiravir reduced the risk of long COVID in high-risk COVID-19 patients (median effect size, 0.74 for persistent symptoms and 0.8 for severe symptoms at 6 months).

"In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months," the trial authors wrote. "However, the absolute differences in this open-label design are small with high numbers needed to treat."

In his commentary, Al-Aly said the evidence base is growing for the use of COVID-19 antivirals in long-COVID prevention. "The hypothesis that patients with established long COVID and evidence of viral persistence could also respond to antiviral therapy is plausible and should be thoroughly evaluated," he wrote. "We have made substantial progress during the past several years in characterising the epidemiology and mechanisms of long COVID, but much remains to be done in preventing and treating the condition."

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