Three antiviral therapies—molnupiravir, nirmatrelvir–ritonavir, and simnotrelvir–ritonavir—may improve or accelerate recovery time among adult outpatients with confirmed COVID-19 infections during the Omicron period, whereas ensitrelvir may not demonstrate meaningful recovery benefits and could increase adverse events..
In a living, rapid review, investigators synthesized randomized controlled trials and cohort studies evaluating oral antivirals in symptomatic adult outpatients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. They focused on recovery, time to recovery, hospitalization, mortality, and adverse events, identifying six randomized controlled trials (RCT) and one retrospective cohort study conducted between November 2021 and September 2025, encompassing trial populations ranging from 383 to 25,783 patients and a cohort of 147,099 patients.
Molnupiravir Improves Recovery and Reduces Long-Term Symptoms
Molnupiravir was found to probably improve recovery and reduce the time to recovery. In the PANORAMIC trial, early recovery at 14 days occurred in 32% of the patients receiving molnupiravir vs 23% receiving usual care, corresponding to 1.62 times the likelihood of recovery. Median time to recovery was 9 days with molnupiravir vs 15 days with usual care, reflecting a 1.36 likelihood of faster recovery.
Molnupiravir also reduced persistent symptoms at 3 to 6 months, reported in 8.5% of treated patients vs 11% of controls. Mortality rates were similar between groups, at 0.02% vs 0.04%, and hospitalization rates didn't differ significantly. Serious adverse events occurred in less than 1% of the patients in both groups, and overall adverse event rates were similar.
In a head-to-head comparison with favipiravir involving 977 patients, the recovery rates at 28 days were similar, at about 87% vs 86%, with no statistically significant differences in serious or overall adverse events.
Nirmatrelvir–Ritonavir Increases Recovery but Raises Adverse Events
Nirmatrelvir–ritonavir was associated with higher recovery rates compared with no antiviral therapy. In a randomized trial, 70.7% of the patients receiving nirmatrelvir–ritonavir recovered vs 53.6% of untreated patients, and symptom resolution occurred faster in treated patients.
However, adverse events were more common. In a cohort study of 123,432 patients, adverse events occurred in 1.3% of the patients receiving nirmatrelvir–ritonavir vs 1.0% of untreated patients. No serious adverse events were reported in the RCT, although the trial size was limited.
Direct comparison between nirmatrelvir–ritonavir and molnupiravir showed no statistically significant difference in recovery, with rates of 70.7% vs 68.8%, although the evidence was limited by small sample size.
Simnotrelvir–Ritonavir Shortens Recovery but Increases Adverse Events
Simnotrelvir–ritonavir reduced median recovery time by 36 hours compared with placebo in a randomized trial involving 1,007 patients. However, adverse events were reported in 29% of the treated patients vs 22% of those receiving placebo. No mortality or hospitalization benefit was demonstrated.
Ensitrelvir Does Not Improve Recovery and Increases Adverse Events
Ensitrelvir didn't significantly improve recovery outcomes. In two RCTs involving 3,914 patients, the time to recovery was not meaningfully reduced compared with placebo. Adverse events were substantially higher, affecting 44% of patients receiving 125 mg of ensitrelvir vs 25% of those receiving placebo. Higher-dose ensitrelvir produced similar findings, with adverse events reported in 53.6% vs 24.8% of placebo recipients.
The serious adverse events and mortality rates were similar between the groups, but the lack of recovery benefit combined with increased adverse events raised questions about its outpatient utility.
Study Design and Limitations
The review included trials conducted in multiple countries, including the United Kingdom, China, Thailand, and multinational settings, with mean patient ages ranging from mid-30s to early 60s. Female participation ranged from 41% to 62%. The vaccination rates were high, with up to 94% of patients receiving three or more vaccine doses.
The risk of bias was present across studies, primarily as a result of their open-label designs and subjective recovery assessments. The cohort study also had a moderate bias risk because of limitations in data anonymization and prespecified analysis plans. Evidence certainty varied across outcomes, and the investigators noted limited evidence for several clinical endpoints, particularly mortality and hospitalization.
“Three COVID-19 antivirals improved or accelerated recovery, with varying adverse event profiles,” concluded lead study author Isolde Sommer, MSc, MPH, PhD, of the Department for Evidence-based Medicine and Evaluation at the University for Continuing Education Krems in Austria, and colleagues, adding that “[m]olnupiravir probably offers long-term benefits.”
Disclosures: The review was funded by American College of Physicians (ACP), which assisted in the development of the KQs, study inclusion criteria, and selection of the outcomes of interest but was not involved in the data collection, analysis, or manuscript preparation.
Living, Rapid Practice Points From the ACP (Version 3)
The ACP reaffirmed its guidance recommending nirmatrelvir–ritonavir or molnupiravir for symptomatic adult patients with confirmed mild to moderate COVID-19 infections in the outpatient setting who are at high risk for progression to severe disease and can initiate treatment within 5 days of symptom onset, according to updated living, rapid practice points. The update found no evidence warranting changes to prior recommendations and formally retired the topic from living status.
The version 3 update was developed by the ACP Population Health and Medical Science Committee based on a focused update of a living, rapid review conducted by the ACP Center for Evidence Reviews at Cochrane Austria. The review addressed the SARS-CoV-2 Omicron variant and included six RCTs and one retrospective cohort study evaluating outpatient antiviral therapies in vaccinated and unvaccinated adult patients.
According to the researchers, updated evidence suggests that nirmatrelvir–ritonavir combination therapy may improve recovery at 20 days and reduce the time to recovery compared with no nirmatrelvir–ritonavir combination therapy (low-certainty evidence). Prior cohort data, not reassessed in this update, had shown reductions in all-cause mortality and COVID-19 infection–related hospital admissions. Evidence on harms was mixed: one randomized trial yielded insufficient evidence on adverse events, while one cohort study suggested an increased risk of adverse events during 28 days of follow-up.
For molnupiravir, moderate-certainty evidence from randomized trials showed improved recovery through 28 days and reduced time to recovery compared with usual care, along with fewer persistent symptoms. New evidence also indicated no difference in COVID-19 infection–related hospital admissions at 28 days or at 3 to 6 months as well as no difference in serious adverse events compared with usual care.
Direct comparisons between the two antivirals were limited. Low-certainty evidence suggested no difference in recovery at 20 days between nirmatrelvir–ritonavir and molnupiravir, with insufficient data to compare other outcomes of interest between the two treatments.
The Population Health and Medical Science Committee reaffirmed recommendations against the use of ivermectin and sotrovimab in this setting and issued no advice for ensitrelvir, favipiravir, or simnotrelvir–ritonavir because of insufficient or negative evidence. Lopinavir–ritonavir had no eligible evidence for the Omicron variant. Nirmatrelvir–ritonavir combination therapy received full US Food and Drug Administration (FDA) approval for the treatment of COVID-19 infections. Molnupiravir is authorized for the treatment of COVID-19 infections in certain adult patients under FDA emergency use authorization
The researchers noted that future research, particularly RCTs, is needed to clarify the efficacy and comparative effectiveness of antiviral treatments on mortality and hospital admission in adult patients with COVID-19 infections in the outpatient setting. Evidence certainty for these outcomes was lower than for recovery and harms. In addition, the role of antiviral treatment in frail, older adult patients and those living in congregate situations needs further study, as these populations were underrepresented in the included studies.
In addition, further research is also needed to determine whether treatment effects differ by patient age, gender, or comorbid conditions; immunity status; symptom duration; and disease severity. Data were limited on prior SARS-CoV-2 infections, time since previous SARS-CoV-2 infections, and time since last vaccination.
Because this update didn't result in important changes to conclusions, and it's unlikely that high-quality RCTs will emerge in the future for current supported treatments, the Population Health and Medical Science Committee is retiring this topic from living status.
Disclosures:
All researchers declared financial and intellectual conflicts of interest, which were reviewed and managed by the ACP. Disclosure forms are available with the article online.
Source: Review, Clinical Guidelines