What are the oral antivirals for COVID-19 (Coronavirus disease 2019)?

Oral Antivirals for COVID-19

The two main FDA-approved oral antivirals for COVID-19 are nirmatrelvir/ritonavir (Paxlovid) and molnupiravir, with Paxlovid being significantly more effective at reducing hospitalization and death.

Primary Oral Antivirals

Nirmatrelvir/Ritonavir (Paxlovid)

• Mechanism: Nirmatrelvir is a SARS-CoV-2 main protease inhibitor, combined with ritonavir (a CYP3A inhibitor) to boost nirmatrelvir levels 1
• Dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together twice daily for 5 days 2
• Efficacy:
  • 86% reduction in hospitalization or death in high-risk patients 2
  • 84% reduction in all-cause mortality risk in critically ill patients 3
• Indication: Mild-to-moderate COVID-19 in adults and pediatric patients (≥12 years, ≥40 kg) at high risk for progression to severe disease 2
• Timing: Must be initiated within 5 days of symptom onset 2
• Renal Dose Adjustment:
  • Moderate impairment (eGFR 30-60 mL/min): 150 mg nirmatrelvir with 100 mg ritonavir twice daily
  • Severe impairment (eGFR <30 mL/min): 300 mg nirmatrelvir with 100 mg ritonavir once on Day 1, then 150 mg nirmatrelvir with 100 mg ritonavir once daily on Days 2-5 2

Molnupiravir

• Mechanism: Nucleoside analogue that induces viral RNA mutations 1
• Dosage: 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days 4
• Efficacy: 30% reduction in hospitalization or death compared to placebo 4
• Indication: Used when Paxlovid is contraindicated or unavailable 5
• Timing: Must be initiated within 5 days of symptom onset 5
• Key Limitation: Less effective than Paxlovid; concerns about embryo-fetal toxicity 4

Important Considerations

Drug Interactions with Paxlovid

• Critical Concern: Ritonavir is a strong CYP3A inhibitor that can cause significant drug interactions 2, 6
• Required Steps:
  1. Review all medications to assess potential drug-drug interactions
  2. Determine if concomitant medications require dose adjustment, temporary interruption, or additional monitoring
  3. Use the Liverpool COVID-19 Drug Interaction Tool for checking potential interactions 5
• Contraindications: Co-administration with drugs highly dependent on CYP3A for clearance where elevated concentrations may cause serious reactions 2

Patient Selection

• High Priority Patients for treatment:
  • Advanced age (≥65 years)
  • Uncontrolled chronic medical conditions
  • Immunocompromised status
  • Unvaccinated individuals
  • Pregnant patients 5

Alternative Treatment Options

• Remdesivir: May be considered when Paxlovid is contraindicated due to drug interactions
  • Requires intravenous administration over 3 days
  • Can be used in children aged ≥12 years with weight ≥40 kg 5

Common Pitfalls to Avoid

1. Delayed Initiation: Treatment must begin within 5 days of symptom onset for both antivirals
2. Failure to Screen for Drug Interactions: Critical for Paxlovid; can lead to serious adverse events
3. Improper Dosing in Renal Impairment: Dose adjustment is necessary based on renal function
4. Using Antibacterial Drugs Inappropriately: Avoid broad-spectrum antibiotics unless bacterial infection is suspected

Effectiveness Across Variants

• Both nirmatrelvir/ritonavir and molnupiravir remain effective against Omicron variants
• A large cohort study showed significant reductions in mortality and hospitalization regardless of virus strain, vaccination status, previous infection status, or comorbidities 7

The evidence strongly supports the use of oral antivirals, particularly Paxlovid, in high-risk patients with COVID-19 to reduce the risk of hospitalization and death when initiated early in the course of illness.