Are Paxlovid and Lagevrio Equals?

Both nirmatrelvir-ritonavir (Paxlovid) and molnupiravir (Lagevrio) were associated with a reduction in death during the COVID-19 Omicron era, a large retrospective study of electronic health records from the Cleveland Clinic showed.

Compared with not receiving any treatment, nonhospitalized COVID patients who received nirmatrelvir-ritonavir saw an 84% reduction in mortality (adjusted hazard ratio 0.16, 95% CI 0.11-0.23) and those who took molnupiravir saw a 77% reduction in death (adjusted HR 0.23, 95% CI 0.16-0.34), according to Danyu Lin, PhD, of the University of North Carolina in Chapel Hill, and colleagues.

Treated patients, all of whom were at high risk of progressing to severe COVID-19, also saw a reduction in the combined endpoint of hospitalization or death whether they were on nirmatrelvir-ritonavir (adjusted HR 0.63, 95% CI 0.59-0.68) or molnupiravir (adjusted HR 0.59, 95% CI 0.53-0.66), they reported in JAMA Network Open.

“We show that these two drugs work very similarly,” Lin told MedPage Today. “The fact that molnupiravir works as well as Paxlovid is an interesting finding, and I would say this finding is not inconsistent with existing literature.”

Indeed, earlier this week, the American College of Physicians (ACP) issued an updated version of its practice guidelines for outpatient management of COVID in the Omicron era and continued to recommend both antivirals equally. While molnupiravir was mentioned first in the guideline, Amir Qaseem, MD, PhD, MHA, chief science officer of ACP, told MedPage Today “there is no preferential order” for the two drugs.

“Both medications … are recommended to treat patients with confirmed mild-to-moderate COVID-19 in the outpatient setting who are at a high risk of progressing to severe COVID and within 5 days of onset of symptom onset,” Qaseem said.

Clinical guidelines from the National Institutes of Health, on the other hand, still recommend nirmatrelvir-ritonavir as the preferred therapy, while molnupiravir is an alternative therapy.

Lin suspects the reason why nirmatrelvir-ritonavir has become the “preferred” therapy in many clinicians’ minds is because of the data that came out of the original clinical trials for these drugs. Nirmatrelvir-ritonavir showed an 89% reduction in risk of progression to severe disease, compared with 48% for molnupiravir.

However, Lin noted, mortality data in those trials were limited, with just one death in the molnupiravir group versus nine in the placebo group, and no deaths in the nirmatrelvir-ritonavir groups versus seven in the placebo group.

Lin also pointed to the open-label PANORAMIC trial in the U.K that showed molnupiravir had no effect on mortality. While this trial may have affected perceptions about molnupiravir, Lin said the population was not actually one at high risk of progression to severe illness.

The ACP guidance took the PANORAMIC trial into account in its evidence review, noting that while it didn’t show a mortality benefit, it did show a higher recovery rate and a reduced time to recovery compared with usual care. And the authors noted that after their review was completed, a study in U.S. veterans — a more at-risk population — did show a mortality benefit for molnupiravir.

On the other hand, all five retrospective studies evaluated for nirmatrelvir-ritonavir consistently showed a reduction in hospitalization and mortality, according to ACP’s review.

In addition, a recently published study in eClinicalMedicine, part of the Lancet network of journals, examined electronic records from more than 75,000 patients in Hong Kong and used propensity score matching to compare the two antivirals head-to-head.

It found a lower risk of all-cause mortality (absolute risk reduction 0.61%, 95% CI 0.50-0.72) and hospital admission (ARR 3.73%, 95% CI 3.31-4.14) at 28 days for non-hospitalized patients taking nirmatrelvir-ritonavir compared with those taking molnupiravir, though there was no difference in risk of ICU admission or ventilatory support.

Overall, ACP concluded in their evidence review that nirmatrelvir-ritonavir “probably” reduces all-cause mortality and risk of hospitalization, and molnupiravir “probably” improves recovery and reduces time to recovery but “probably has no effect on all-cause mortality.”

Molnupiravir also has carried concerns about mutation burden inherent in the way it works. The compound boosts the viral mutation rate to the point that the virus can no longer replicate, and some early work suggested it could also induce mutations in host cells. There were also concerns about how the drug could impact the evolution of the virus overall.

While their study didn’t assess safety, Lin and colleagues wanted to update the data on these antivirals, as their trials were conducted during the Delta era in unvaccinated patients and they were authorized in late December 2021.

Lin and colleagues included 68,867 patients diagnosed with COVID at the Cleveland Clinic from April 1, 2022, to February 20, 2023 who were at high risk of progressing to severe disease and who were followed through 90 days after their diagnosis. Nearly 43% of study participants were 65 and older; 39% were men, and 75% were white.

During this time period, Omicron evolved from BA.2, to BA.4/5, then to BQ.1/1.1, and then to XBB/XBB.1.5.

About 22,600 people received nirmatrelvir-ritonavir, about 5,300 received molnupiravir, and about 41,000 had no treatment. There were 30 deaths among those on nirmatrelvir-ritonavir, 27 deaths among those on molnupiravir, and 588 deaths in the no-treatment group.

At 90 days after COVID diagnosis, the cumulative incidence of death was 0.15% for patients treated with nirmatrelvir-ritonavir and 1.05% for untreated patients. Cumulative incidence of death at 90 days was 0.60% for molnupiravir-treated patients and 1.57% for those untreated.

Lin said the associations of both drugs for both outcomes were seen across subgroups defined by age, race and ethnicity, date of COVID diagnosis, vaccination status, previous infection status, and co-existing conditions.

While they acknowledged that their study was limited by unmeasured confounders, Lin and his team concluded that both drugs were associated with reductions in mortality and hospitalization in patients infected with Omicron who were at risk for progression to severe disease. They noted that the findings were important because of nirmatrelvir’s contraindications.

“Drug-drug interactions are significant for Paxlovid,” Lin said. “Molnupiravir has been under-studied and under-used. Maybe we should study it a bit more. It seems to be more effective than we thought.”

William Schaffner, MD, of Vanderbilt University Medical Center in Nashville, who was not involved in the study or the ACP guidance, told MedPage Today that at his institution, nirmatrelvir-ritonavir has been the drug of choice to treat outpatients at risk of progression to severe disease.

“I would think it would take something substantial — a substantial benefit, or Paxlovid suddenly doesn’t work against new strains — before people changed en masse,” Schaffner said. “But having two drugs that are available, that are reasonably comparable, to treat the same condition, is always better than having one.”

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