Does molnupiravir improve outcomes in vaccinated COVID-19 patients?

The addition of molnupiravir to usual care does not reduce hospitalization or death in vaccinated, community-dwelling individuals at high risk of serious outcomes of COVID-19, results of the UK-based PANORAMIC trial showed. However, it may provide other benefits such as reducing time to recovery.

Participants in this multicentre, open-label trial were 25,783 community-dwelling high-risk individuals (age ≥50 years or ≥18 years with relevant comorbidities; mean age 56.6 years) with symptomatic (≤5 days) confirmed COVID-19 infection*. They were randomized 1:1 to receive usual care with or without oral molnupiravir (800 mg BID for 5 days)**. Ninety-four percent of participants had received ≥3 doses of a SARS-CoV-2 vaccine. Sixty-nine percent of participants had comorbidities.

At day 28 post-randomization, all-cause hospitalization or death did not differ between individuals in the molnupiravir + usual care and usual care-alone groups (1 percent each; adjusted odds ratio, 1.06, 95 percent Bayesian credible interval, 0.81–1.41; probability of superiority, 0.33). [Lancet 2022;doi:10.1016/S0140-6736(22)02597-1]

There was no apparent benefit in any of the subgroups analysed including presence or absence of comorbidities, heart or lung disease, obesity or diabetes, age, symptom duration, or use of inhaled corticosteroids.

However, molnupiravir + usual care appeared to improve time between randomization and first recovery compared with usual care alone (median 9 vs 15 days; estimated benefit 4.2 days; posterior probability of superiority >0.99), as well as estimated time to first recovery (median 10.4 vs 14.6 days; hazard ratio, 1.36).

Presentation at emergency department was comparable between groups (6 percent in each group), as was the number of new infections in participants’ households (36 percent [molnupiravir + usual care] vs 37 percent [usual care alone]). However, compared with those assigned to usual care alone, those assigned to molnupiravir + usual care were more likely to report early sustained recovery (32 percent vs 23 percent) and less contact with general practitioners (20 percent vs 24 percent), and shorter times to sustained recovery (21 vs 24 days), sustained alleviation of all symptoms (9 vs 12 days), and reduction of symptom severity (7 vs 9 days). They also had fewer moderate or severe symptoms at days 7, 14, and 28.

“[The] faster patient-reported recovery was consistent with a reduction in detectable virus and viral load in participants who received molnupiravir compared with those who received usual care only,” noted the authors.

Serious adverse event (AE) incidence was low and did not differ between the molnupiravir + usual care and usual care-alone groups (0.4 percent vs 0.3 percent). None of the serious AEs were deemed related to molnupiravir. There were no AEs of special interest. About 1 percent of molnupiravir + usual care recipients withdrew from the trial due to molnupiravir-related AEs.

Any role in the vaccinated population?

According to the authors, prior studies on the effectiveness of molnupiravir in reducing adverse outcomes in COVID-19 have primarily focused on unvaccinated individuals and were conducted before the omicron wave.

“[In this trial,] molnupiravir did not reduce hospitalizations or deaths in a community-based vaccinated adult population with COVID-19 who were at increased risk of an adverse outcome, either overall or in any patient subgroups,” they said.

“[However,] the trial suggests that this treatment could have other benefits when being used to treat COVID-19, such as a faster recovery time and reduced follow up with health services,” remarked lead author Professor Christopher Butler from the University of Oxford, Oxford, UK.

“This could help to ease the burden on UK health services through the treatment of selected patients at home, during times of high disease burden and pressure on key services.  We therefore hope this new evidence will be of use to policymakers when preparing strategies for managing COVID-19 infections over the winter,” he continued.

The results also highlight that in this high-risk population, vaccination provides the best protection against hospitalization and death, the authors added, noting that the findings may not apply to those at extremely high risk of severe outcomes.

“While it’s critical to ensure that patients who are likely to benefit from treatment with antiviral treatments, such as molnuvirapir, receive them, using antivirals to treat patients who are unlikely to benefit carries the risk of further driving antimicrobial resistance, wasting resources, and exposing people to unnecessary harm,” said study co-author Professor Ly-Mee Yu, also from the University of Oxford.

“Therefore, our study contributes to the valuable evidence base on who should not be treated with these precious, newly discovered agents, to empower clinicians to make decisions led by robust evidence when prescribing treatments for COVID-19 infections,” she said.  

*PCR- or ART-positive COVID-19 within the past 7 days.

**The patients received treatment between December 8, 2021 and April 27, 2022, which was considered the peak of the omicron wave in the UK.