What is the preferred treatment between Paxlovid (nirmatrelvir and ritonavir) and Lagevrio (molnupiravir) for a patient with COVID-19 and impaired renal function?

Paxlovid vs Lagevrio (Molnupiravir) for COVID-19 Treatment

Paxlovid (nirmatrelvir/ritonavir) is the superior choice over Lagevrio (molnupiravir) for treating COVID-19 in high-risk patients, with greater reductions in hospitalization and mortality, and a better safety profile. 1, 2

Comparative Efficacy

Hospitalization Reduction

• Paxlovid demonstrates superior efficacy in preventing hospitalization compared to molnupiravir, with moderate certainty evidence showing greater absolute risk reduction. 1
• Real-world data shows Paxlovid reduces hospitalization risk by 26-39% and mortality by 61-73% in high-risk patients. 3, 4
• Molnupiravir reduces hospitalization/death from 9.7% to 6.8%, which is less impressive than Paxlovid's effect. 2
• Direct comparison evidence indicates remdesivir may result in larger reductions in hospitalization than molnupiravir, and Paxlovid likely performs similarly or better than remdesivir. 1

Mortality Benefit

• Both drugs show little or no difference in mortality when directly compared (high certainty), but Paxlovid's overall mortality reduction in real-world settings (61-73%) is more robust. 1, 3, 4
• Molnupiravir probably reduces mortality with moderate certainty evidence, but the WHO emphasizes Paxlovid's superior profile. 1

Safety Profile: Critical Differences

Molnupiravir's Significant Safety Concerns

• Molnupiravir carries serious genotoxicity concerns based on preclinical data showing potential for malignancy, mutagenesis, and reproductive harm. 1
• Absolute contraindications for molnupiravir include: 1
  • Pregnancy (causes embryo-fetal lethality and teratogenicity in animal studies)
  • Breastfeeding
  • Children (impacts growth plate thickness and bone formation)
  • Men planning to conceive (must use contraception during treatment and for 3 months after)
  • Women of childbearing potential (must use contraception during treatment and for 4 days after)
• Younger adults should avoid molnupiravir due to unknown long-term genotoxicity risks. 1

Paxlovid's Safety Considerations

• The primary safety concern with Paxlovid is drug-drug interactions due to ritonavir's CYP3A4 inhibition, not genotoxicity. 5
• Common adverse effects include dysgeusia and diarrhea, which do not lead to increased discontinuation rates. 5
• Paxlovid may be used in pregnancy to reduce disease progression, with no serious adverse reactions reported to date in WHO Vigibase. 5

Clinical Decision Algorithm

When to Choose Paxlovid (First-Line)

• Use Paxlovid for all high-risk patients with non-severe COVID-19 unless contraindicated by severe renal impairment (eGFR <30) or problematic drug interactions. 2, 6, 5
• Check the Liverpool COVID-19 Drug Interaction Tool before prescribing. 5
• For moderate renal impairment (eGFR 30-60), reduce dose to 150 mg nirmatrelvir with 100 mg ritonavir twice daily. 5
• Initiate within 5 days of symptom onset, as early as possible. 6, 5

When to Choose Molnupiravir (Second-Line)

• Only use molnupiravir when both Paxlovid and remdesivir are unavailable or contraindicated, and only in high-risk patients. 2
• Never use molnupiravir in: 1
  • Pregnant or breastfeeding individuals
  • Children
  • Men planning to conceive (without 3-month contraception commitment)
  • Women of childbearing potential (without contraception)
  • Younger adults not at high risk

Remdesivir as Alternative

• Remdesivir is the preferred alternative to Paxlovid when drug interactions are problematic, not molnupiravir. 1, 2
• Remdesivir is particularly appropriate for pregnant patients, children, and those with CYP3A4 drug interactions. 1, 2

Risk Stratification for Treatment

High-Risk Criteria (Treatment Indicated)

• Age ≥65 years 5
• Immunocompromised status (hematological malignancies, transplant recipients) 5
• Unvaccinated or vaccine non-responders 5
• Chronic medical conditions (cardiovascular disease, diabetes, chronic lung disease, obesity) 6

Moderate and Low-Risk Patients

• The WHO conditionally recommends against Paxlovid for moderate-risk patients and suggests not using it for low-risk patients, as benefits do not outweigh harms and costs. 1, 6
• The same applies to molnupiravir—avoid in non-high-risk populations. 1

Common Pitfalls to Avoid

• Do not use molnupiravir as a first-line alternative to Paxlovid—remdesivir is superior. 1, 2
• Do not prescribe molnupiravir without thoroughly screening for pregnancy, reproductive plans, and age considerations. 1
• Do not delay treatment—both drugs must be started within 5 days of symptom onset, ideally as early as possible. 6, 5
• Do not skip drug interaction screening for Paxlovid—use the Liverpool tool systematically. 5
• Do not assume vaccination eliminates the need for treatment—Paxlovid remains effective in vaccinated high-risk patients. 4