Molnupiravir May Offer Modest 6-Month Benefits for High-Risk COVID Patients

People with acute COVID-19 who took the antiviral drug molnupiravir (Lagevrio) reported modest improvements in symptoms, less time off from work or study, and less healthcare utilization at 6 months post-infection, a follow-up analysis of the prospective, open-label PANORAMIC trial suggested.

Among patients who received molnupiravir 800 mg twice per day plus usual care for 5 days after diagnosis with COVID-19, 8.5% reported persistent symptoms at 6 months compared with 11% who received usual care only (adjusted risk difference -2.5%), reported Christopher Butler, MBChB, MD, of the University of Oxford in England, and colleagues in Lancet Infectious Diseases.

At 3 months after treatment, use of healthcare or social services was also lower in the molnupiravir group at 14.1% versus 15.5% in the usual care group (adjusted risk difference -1.4%). There was a trend in the same direction at 6 months, but the adjusted risk difference was only -0.5%.

There were no differences in hospitalizations or deaths between the two groups at 3 and 6 months follow-up.

“This study was a secondary long-term analysis, and although we did not correct for multiplicity, the number of statistically superior outcomes make chance a very unlikely explanation of the results,” the researchers wrote. “The trial design was pragmatic and open-label; therefore, participants were not masked and recovery and well-being outcomes were ascertained by self-reporting.”

The study showed that the numbers needed to treat were high, noted co-author Victoria Harris, PhD, also of University of Oxford, in a press release. “For instance, only one person would have less severe symptoms from a total of 53 people who took molnupiravir, and only one person would have used fewer NHS [National Health Service] services from a total of 71 people who took molnupiravir,” she said.

Among participants who received molnupiravir, 17.9% reported having any time off from work or study at 3 months versus 22.4% in the usual care group, for an adjusted risk difference of -5.3%. At 6 months, 4.4% in the molnupiravir group reported having time off from work or study versus 5.4% in the usual treatment group (adjusted risk difference -1.1%), and about 91 patients would need to be treated to benefit one patient.

Molnupiravir is an expensive drug, Harris pointed out. In the U.S., a 5-day course costs about $1,000 without insurance coverage.

“Given the small additional number of participants who benefited from taking molnupiravir, compared to those who did not take the drug, long-term health benefits will need to be weighed up against costs and any unwanted effects,” she emphasized.

The trial did not address the efficacy of molnupiravir in preventing long COVID, but Ziyad Al-Aly, MD, of the VA St. Louis Health Care System in Missouri, said in an accompanying editorial that antivirals may one day play a role in long COVID treatment and prevention.

“The use of antivirals to reduce the risk of long COVID is grounded in the hypothesis that viral persistence and possible ongoing replication of SARS-CoV-2 are major mechanistic pathways responsible for long COVID,” he commented. “Evidence for this hypothesis is growing.” Studies have identified persistence of viral RNA or protein fragments and the presence of T-cell activation and double-stranded viral RNA months to years after infection with SARS-CoV-2, Al-Aly noted.

“The promising results from the PANORAMIC trial are consistent with results from well conducted observational analyses as they both converge on finding a modest effect of molnupiravir in reducing the risk of long COVID in high-risk individuals,” Al-Aly wrote.

“Concerns, however, have been raised about the mutagenicity of molnupiravir,” he pointed out. “Furthermore, effectiveness of molnupiravir or [other SARS-CoV-2 antivirals] in reducing risk of long COVID in low-risk populations, including younger individuals with no comorbid medical conditions, has not been evaluated,” he cautioned.

The CDC recommends molnupiravir as an alternative to nirmatrelvir-ritonavir (Paxlovid) for the treatment of acute mild-to-moderate COVID-19 in non-pregnant adults at risk for severe disease, to be started within 5 days of symptom onset.

The PANORAMIC trial took place from December 2021 to April 2022 and included 25,783 participants who were randomly assigned to molnupiravir twice a day for 5 days plus usual care (n=12,821) or usual care alone (n=12,962) generally within 5 days of a COVID-19 infection.

To enroll, patients had to be either 50 years and older or 18 and older with at least one comorbidity. Mean age of participants was 56.6 years, 58.6% were female, and 93% had received at least three vaccine doses. Comorbidities included lung disease in 24%, hypertension in 22%, obesity in 15%, diabetes in 12%, a weakened immune system in 9%, and heart disease in 8%.

In the initial analysis of the trial, molnupiravir failed to reduce the risk for hospitalization or death at 28 days from COVID-19 in high-risk, vaccinated outpatients, but did shorten recovery times from a median of 15 days to 9 days (HR 1.36).

Long-term follow-up data for the current analysis were available for about 89% of all participants — about 92% in the treatment group and 87% in the usual care group.

Researchers contacted participants at 3 and 6 months and asked them to complete online or telephone questionnaires. Patients were asked to rate how well they felt, whether they had taken time off from work or study, or if they had been hospitalized. Patients also rated symptoms on a 4-point scale. Symptoms included fever, cough, shortness of breath, fatigue, muscle aches, nausea, vomiting, diarrhea, loss of taste or smell, headache, dizziness, abdominal pain, or feeling unwell.

The authors acknowledged that the open-label study design may have influenced patient self-reports of recovery and well-being. They also emphasized that the study was not an efficacy trial.

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