What are the alternatives to Paxlovid (nirmatrelvir/ritonavir) for treating COVID-19?

Alternatives to Paxlovid for COVID-19 Treatment

For patients who cannot take Paxlovid, remdesivir is the preferred alternative for high-risk patients with non-severe COVID-19, while molnupiravir should be reserved only for situations where both Paxlovid and remdesivir are unavailable or contraindicated. 1

Primary Alternative: Remdesivir

Remdesivir represents the superior alternative when Paxlovid is not an option, particularly for patients with problematic drug interactions with ritonavir or those in whom molnupiravir would be contraindicated (such as pregnant patients and children). 1

Efficacy Profile

• Remdesivir probably results in an important reduction in hospital admission risk (moderate certainty evidence) 1
• It demonstrates little or no impact on mortality, mechanical ventilation, or time to symptom resolution (moderate to low certainty) 1
• In high-risk patients, remdesivir reduced progression to severe COVID-19/hospitalization from 5.3% to 0.7% 1
• Among immunocompromised patients (hematologic malignancies/transplant recipients), remdesivir was independently associated with lower mortality risk 1

Administration Requirements

• Dosing regimen: 200 mg IV on day 1, followed by 100 mg IV on days 2 and 3 for a 3-day course in outpatients 1, 2
• For hospitalized patients requiring mechanical ventilation/ECMO: 10-day course; for others: 5-day course (extendable to 10 days if no clinical improvement) 2
• Must be initiated within 7 days of symptom onset (ideally within 5 days) 1, 2
• Requires intravenous infusion, which creates feasibility challenges compared to oral Paxlovid 1

Key Limitations

• The complex IV administration requirement makes remdesivir less practical than oral Paxlovid 1
• WHO conditionally recommends against remdesivir in moderate-risk patients, viewing it as inferior to Paxlovid due to administration burden 1
• Renal monitoring is needed: perform hepatic laboratory testing before and during treatment; kidney-related effects observed in animal studies at exposures lower than human doses 2

Secondary Alternative: Molnupiravir

Molnupiravir should only be used when both Paxlovid and remdesivir are unavailable or contraindicated, and only in high-risk patients. 1

Risk-Stratified Recommendations

• High-risk patients: WHO suggests molnupiravir may be used, but with significant concerns about toxicity that will outweigh benefits for many patients 1
• Moderate-risk patients: WHO suggests against molnupiravir—benefits are small and toxicity concerns predominate 1
• Low-risk patients: WHO strongly recommends against molnupiravir—benefits are trivial 1

Comparative Effectiveness

• Molnupiravir is inferior to Paxlovid: makes little or no difference to mortality (high certainty), probably has less benefit in reducing hospitalization (moderate certainty) 1
• Compared to remdesivir: little or no difference in mortality (high certainty), may have little or no difference in hospitalization reduction (low certainty) 1
• In clinical trials, molnupiravir reduced hospitalization/death from 9.7% to 6.8% 1

Critical Safety Concerns—Genotoxicity Risk

The major limitation of molnupiravir is its potential for mutagenesis, requiring specific precautions: 1

• Contraindicated in pregnancy and breastfeeding: Animal studies showed reproductive toxicity and effects on sperm production 1
• Men of reproductive age: Must use reliable contraception during treatment and for at least 3 months after the last dose 1
• Younger adults: The unknown long-term genotoxicity risk is higher in younger patients; avoid use in younger adults not at high risk 1
• Viral mutation concerns: Potential effects on SARS-CoV-2 mutation rates raise population-level safety questions 1, 3

Administration

• Dosing: 800 mg orally every 12 hours for 5 days 1
• Timing: Must be administered within 5 days of symptom onset, as early as possible 1
• Advantage: Oral administration with no significant drug interactions, unlike Paxlovid 4, 3

Monoclonal Antibodies (Variant-Dependent)

Anti-spike monoclonal antibodies may benefit immunocompromised patients who fail to develop humoral responses, but their use is highly dependent on circulating viral variants. 1

Key Considerations

• Previously available agents (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, regdanvimab) showed efficacy in reducing progression to severe COVID-19 or death 1
• Critical limitation: Activity is affected by specific viral mutations; most monoclonal antibodies have lost activity against current Omicron subvariants 1
• Choice must be based on local availability, national approval, and updated epidemiology of circulating variants 1
• Particularly relevant for hematologic malignancy/transplant patients who frequently fail to develop antibody responses 1

Agents NOT Recommended

The following have no evidence of benefit and should not be used: 1

• Hydroxychloroquine/chloroquine
• Lopinavir/ritonavir
• Azithromycin
• Ivermectin
• Arbidol
• Favipiravir

Clinical Decision Algorithm

When Paxlovid is contraindicated or unavailable:

1. First-line alternative: Remdesivir (3-day IV course for outpatients) 1

   • Preferred for patients with CYP3A4 drug interactions
   • Preferred for pregnant patients and children
   • Requires IV access and healthcare facility administration

2. Second-line alternative: Molnupiravir (only for high-risk patients) 1

   • Only when both Paxlovid and remdesivir unavailable
   • Contraindicated in pregnancy, breastfeeding, and men not using contraception
   • Avoid in younger adults without high-risk features

3. Special populations: Consider variant-specific monoclonal antibodies for immunocompromised patients 1

Common Pitfalls to Avoid

• Do not delay treatment while arranging alternatives—all antivirals must be started within 5-7 days of symptom onset 1, 2
• Do not use molnupiravir as first alternative to Paxlovid when remdesivir is available—remdesivir is superior due to molnupiravir's toxicity concerns 1
• Do not prescribe molnupiravir to pregnant patients, children, or young adults without discussing genotoxicity risks 1
• Do not assume monoclonal antibodies remain effective—verify activity against current circulating variants before use 1