Is molnupiravir (Lagevrio) as effective as nirmatrelvir‑ritonavir (Paxlovid) in preventing hospitalization or death in high‑risk adults with mild‑to‑moderate COVID‑19?

No, Lagevrio (molnupiravir) is not as effective as Paxlovid (nirmatrelvir/ritonavir) for COVID-19

Paxlovid is superior to molnupiravir in preventing hospitalization and death in high-risk adults with mild-to-moderate COVID-19, and should be the preferred first-line oral antiviral when no contraindications exist. 1, 2, 3

Comparative Efficacy: Direct Evidence

Hospitalization Prevention

• Paxlovid demonstrates greater absolute risk reduction in hospitalization compared to molnupiravir (moderate certainty evidence), with the WHO explicitly stating that nirmatrelvir/ritonavir "probably reduces hospitalisation to a greater extent than molnupiravir." 1
• In clinical trials, Paxlovid reduced hospitalization/death by approximately 88% compared to molnupiravir's 30% reduction. 4
• Real-world data from the Omicron era showed Paxlovid reduced hospitalization risk by 84% (adjusted OR 0.16) while molnupiravir showed 100% efficacy in one cohort, though this was based on zero hospitalizations in a smaller sample. 5

Mortality Reduction

• Both drugs show similar effects on mortality when directly compared (high certainty evidence that molnupiravir "makes little or no difference to mortality" compared to Paxlovid). 1
• However, a 2023 cohort study found Paxlovid reduced mortality by 73% (HR 0.269) while molnupiravir reduced it by 77% (HR 0.23), suggesting comparable mortality benefits in real-world settings. 6, 7

WHO Guideline Hierarchy: Clear Preference for Paxlovid

The World Health Organization's living guideline establishes an explicit treatment hierarchy: 1, 2

1. First-line: Paxlovid - for high-risk patients with non-severe COVID-19
2. Second-line: Remdesivir - preferred over molnupiravir when Paxlovid unavailable
3. Third-line: Molnupiravir - only when both Paxlovid and remdesivir are unavailable or contraindicated

The WHO states that "nirmatrelvir/ritonavir and remdesivir represent superior choices to molnupiravir due to greater reductions in hospitalisation and due to safety concerns with molnupiravir." 1

Critical Safety Differences

Molnupiravir's Genotoxicity Concerns

• Molnupiravir carries serious safety concerns based on its mutagenic mechanism of action, including potential risks of malignancy (very low certainty), carcinogenesis in animal studies, and emergence of viral resistance. 1, 8
• The drug is contraindicated in pregnancy, breastfeeding, children (due to effects on bone growth plates), and requires reliable contraception in men for at least 3 months after treatment due to potential genotoxic effects on spermatogenesis. 1, 2
• These toxicity concerns led the WHO to make only a conditional (weak) recommendation for molnupiravir even in high-risk patients, with the guideline stating "concerns regarding toxicity will, for the majority of patients, outweigh the benefits" in moderate-risk patients. 1

Paxlovid's Drug Interaction Profile

• Paxlovid's primary safety concern is drug-drug interactions due to ritonavir's potent CYP3A4 inhibition, not genotoxicity. 2, 9
• These interactions are manageable through systematic screening using the Liverpool COVID-19 Drug Interaction Tool, temporary medication adjustments, or dose modifications. 2, 9
• Common adverse effects (dysgeusia, diarrhea) occur more frequently but rarely lead to discontinuation. 9

Risk-Stratified Recommendations

High-Risk Patients

• Paxlovid is strongly recommended (WHO strong recommendation) for patients ≥65 years, immunocompromised, unvaccinated, or with chronic conditions. 3
• Molnupiravir receives only a conditional recommendation even in this population, reserved for when Paxlovid and remdesivir are unavailable. 1, 2

Moderate-Risk Patients

• The WHO conditionally recommends AGAINST molnupiravir in moderate-risk patients, stating it "does not have an important impact on mortality and results in little or no reduction in hospital admission" (both high certainty). 1
• Paxlovid may be considered in moderate-risk patients based on individual circumstances. 3

Low-Risk Patients

• The WHO strongly recommends AGAINST molnupiravir in low-risk patients, with "high certainty of trivial benefit and serious concerns about possible long term harms." 1

Clinical Decision Algorithm

When treating high-risk COVID-19 patients within 5 days of symptom onset:

1. First choice: Paxlovid - Check for drug interactions using Liverpool tool; adjust or temporarily discontinue interacting medications when possible. 2, 9, 3

2. If Paxlovid contraindicated (severe drug interactions that cannot be managed, severe hepatic impairment): Use remdesivir as preferred alternative. 2

3. If both Paxlovid and remdesivir unavailable/contraindicated: Consider molnupiravir ONLY in high-risk patients, after counseling about genotoxicity concerns and confirming no pregnancy/breastfeeding and adequate contraception. 1, 2

4. Never use molnupiravir in: Pregnant or breastfeeding individuals, children, men not using contraception, or patients at moderate/low risk of hospitalization. 1, 2

Real-World Effectiveness Data

Recent observational studies during the Omicron era confirm Paxlovid's superior real-world performance: 6, 5, 7

• A 2023 N3C database study of over 1 million patients found Paxlovid reduced 28-day hospitalization by 26% and mortality by 73%. 7
• A 2023 Cleveland Clinic study showed both drugs reduced mortality (Paxlovid HR 0.16, molnupiravir HR 0.23) and hospitalization/death (Paxlovid HR 0.63, molnupiravir HR 0.59) across all Omicron subvariants. 6
• Both drugs accelerated viral clearance, though this is a secondary benefit compared to preventing severe outcomes. 5

Common Pitfalls to Avoid

• Do not prescribe molnupiravir as first-line therapy when Paxlovid is available and appropriate - this contradicts WHO guidelines prioritizing Paxlovid's superior efficacy and safety profile. 1, 2, 3
• Do not overlook molnupiravir's contraindications in reproductive-age individuals - the genotoxicity concerns require strict contraception counseling. 1, 2
• Do not dismiss Paxlovid too quickly due to drug interactions - many interactions can be managed through temporary medication holds or dose adjustments during the 5-day treatment course. 2, 9
• Do not delay treatment - both drugs must be initiated within 5 days of symptom onset, with earlier treatment yielding better outcomes. 9, 3, 5