Molnupiravir vs. Nirmatrelvir-Ritonavir for Early Symptomatic COVID-19

By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A randomized, controlled, multicenter Phase II clinical trial compared molnupiravir, ritonavir-boosted nirmatrelvir, or no drug for low-risk adult patients ages 18-50 years with symptomatic COVID-19. Viral clearance was 84% faster with ritonavir-boosted nirmatrelvir and 37% faster with molnupiravir compared to no treatment.

SOURCE: Schilling WHK, Jittamala P, Watson JA, et al. Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): An open-label, phase 2, randomised, controlled, adaptive trial. Lancet Infect Dis 2024;24:36-45.

The development and clinical implementation of the oral antiviral medications molnupiravir and nirmatrelvir-ritonavir (N-R; brand name: Paxlovid) for COVID-19 was a major advancement. However, both drugs have disadvantages. Molnupiravir causes a high frequency of SARS-CoV-2 mutations, while N-R has been associated with symptom and viral rebounds after treatment. Thus, there are questions about the risks and benefits of these drugs, especially for patients at low risk of COVID-19 complications. Schilling and colleagues aimed to provide guidance on this issue by evaluating the antiviral effect of molnupiravir and N-R compared to no treatment in low-risk adults with COVID-19.

The study is a multicenter, randomized, controlled, Phase II clinical trial that has enrolled patients from Brazil, Thailand, Laos, and Pakistan and is ongoing. The current analysis only included patients from Thailand. The patients were between 18 and 50 years of age, had COVID-19 symptoms for less than 96 hours, had a positive test for COVID-19 by lateral flow antigen or polymerase chain reaction (PCR), and had an oxygen saturation ≥ 96%. Exclusion criteria were taking any concurrent medications; chronic illness; laboratory abnormalities, including anemia, thrombocytopenia, abnormal liver function tests, and a reduced glomerular filtration rate; pregnancy; or pneumonia. Patients were randomly assigned to receive molnupiravir, N-R, or no study drug. All treatments were directly observed. Viral loads were quantified using a PCR assay on oropharyngeal swabs. Whole genome sequencing was used to detect viral mutations.

The primary outcome of the study was the rate of viral clearance between days 0 and 7. The secondary outcomes included all-cause hospital admission for clinical deterioration up to 28 days, time to resolution of fever, and time to resolution of symptoms.

There were 65 patients randomized to receive molnupiravir, 59 to N-R, and 85 to no drug. The median age for the N-R group was 29 years (range 26-35), 30 years (range 26-36) for molnupiravir, and 29 years (range 24-36) for the no drug group. Compared to no study drug, patients who received molnupiravir cleared the virus 37% faster, and those who received N-R cleared it 84% faster. Notably, a secondary analysis by the investigators found that remdesivir increased viral clearance by 33%. The median estimated viral clearance half-life was 8.5 hours with N-R, 11.6 hours with molnupiravir, and 15.5 hours with no study drug. The timing of fever resolution was not significantly different between the groups. Time to resolution of symptoms was faster in the two antiviral groups compared to the no drug group (P = 0.011). No patients developed serious illness or were hospitalized.

Viral rebound was more common in the N-R group (six of 58; 10%) compared to the molnupiravir group (one of 65; 2%) and the no drug group (one of 84; 1%). Viral mutations in patients with persistent infection were more common after receiving molnupiravir (three of nine) than N-R (zero of three) or no study drug (zero of 19). There was no evidence of transmission of these mutant strains. Moreover, predicted models indicated that the fitness effects of the mutations were overall deleterious. Finally, many of the patients who received N-R experienced dysgeusia, but there were no serious adverse events associated with any treatment.

COMMENTARY

This is the first randomized clinical trial to compare molnupiravir and N-R to placebo in low-risk adult patients. Although both antiviral medications improved viral clearance, N-R was superior. The investigators hypothesized this was because N-R inhibits the main SARS-CoV-2 protease, thus leading to the most potent inhibition of viral replication. Viral rebound with N-R is a concern, and clinicians need to carefully discuss the risks and benefits of it with patients. For example, low-risk patients who experience viral rebound may miss more days of work compared to having a bout of COVID-19 treated symptomatically. Another issue that needs further investigation is whether prescribing N-R to low-risk patients reduces the risk of long COVID.

Although the study was well designed, there are a few limitations worth mentioning. First, given that these were young and low-risk patients, the results should not be extrapolated to other patient populations. Second, only one-third of the patients were febrile, so it is not possible to determine whether molnupiravir or N-R affected fever clearance. Third, viral clearance ideally should be measured over five to seven days, but this level of nasopharyngeal sampling is not tolerated in the real world. Finally, pregnant women and those with symptoms more than four days were excluded, which reduces the generalizability of the results.

COVID-19 cases are on the rise and, given how effective N-R is at preventing serious illness, it is difficult to comprehend why so few Americans are taking it. Indeed, a preprint on medRxiv reported that only approximately 15% of patients who are eligible to receive N-R actually do so.¹ The hesitation seems to come from physician concerns about drug interactions and patients worrying about viral rebound or the metallic aftertaste of the drug. For most patients with COVID-19, the benefits of N-R outweigh the risks, and this point should be conveyed more forcefully by the medical community and public health authorities. It will be interesting to see how the results of the current trial will be interpreted by guideline panels.

Reference

1. Hansen K, Makkar SR, Sahner D, et al. Paxlovid (nirmatrelvir/ritonavir) effectiveness against hospitalization and death in N3C: A target trial emulation study. medRxiv 2024; doi: https://doi.org/10.1101/2023.05.26.23290602