What is the recommended treatment for a high-risk patient diagnosed with COVID-19, specifically considering the use of Paxlovid (nirmatrelvir/ritonavir)?

Paxlovid for High-Risk COVID-19 Patients

For high-risk patients with mild-to-moderate COVID-19, initiate nirmatrelvir/ritonavir (Paxlovid) as soon as possible after diagnosis and within 5 days of symptom onset, as it reduces hospitalization by 39% and death by 61%. 1, 2, 3

Who Should Receive Paxlovid

High-risk patients with mild-to-moderate COVID-19 are the target population, defined as those at increased risk for progression to severe disease, hospitalization, or death. 1, 4

• Timing is critical: Treatment must begin within 5 days of symptom onset to be effective. 1, 2, 4
• Both vaccinated and unvaccinated patients benefit, with similar absolute risk reductions for hospitalization regardless of vaccination status. 3, 5
• Older patients (≥65 years) derive the greatest benefit, with substantially higher absolute risk reduction compared to younger patients. 3
• Immunocompromised patients show enhanced effectiveness, particularly those with underlying neurological or cardiovascular disease. 5

Dosing Regimen

Standard dosing: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), all three tablets taken together twice daily for 5 days. 4

Dose adjustments for renal impairment are mandatory: 4

• Moderate renal impairment (eGFR 30-59 mL/min): 150 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days
• Severe renal impairment (eGFR <30 mL/min) including hemodialysis:
  • Day 1: 300 mg nirmatrelvir with 100 mg ritonavir once
  • Days 2-5: 150 mg nirmatrelvir with 100 mg ritonavir once daily
  • Administer after hemodialysis on dialysis days

Administer with or without food at approximately the same time each day. 4

Critical Drug Interactions

Ritonavir is a potent CYP3A4 inhibitor that causes potentially life-threatening drug interactions. 4, 6

Absolute contraindications (do not prescribe Paxlovid if patient is taking): 4

• Drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions
• Potent CYP3A inducers that would reduce nirmatrelvir/ritonavir effectiveness

Before prescribing, review ALL patient medications to assess for drug-drug interactions and determine if comedications require dose adjustment, temporary interruption, or additional monitoring. 4, 6

Pragmatic management options for drug interactions include: 6

• Preemptive pausing of the comedication during the 5-day treatment course
• Symptom-driven pausing if interactions develop
• Patient counseling about additional risks

Absolute Contraindications

Do not prescribe Paxlovid if: 4

• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir
• Concurrent use of drugs highly dependent on CYP3A with serious toxicity risk
• Concurrent use of potent CYP3A inducers
• Severe hepatic impairment (Child-Pugh Class C)

Serious Adverse Events to Monitor

Hypersensitivity reactions including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported. 4

• Immediately discontinue Paxlovid if signs of clinically significant hypersensitivity or anaphylaxis occur and initiate appropriate supportive care. 4

Hepatotoxicity with transaminase elevations, clinical hepatitis, and jaundice can occur due to the ritonavir component. 4

Evidence Quality and Strength

The recommendation is supported by high certainty evidence from the EPIC-HR trial showing important reduction in hospitalization risk and moderate certainty evidence for survival benefit without increased adverse events. 1

Real-world effectiveness data confirms trial results: 3, 5

• 39% relative risk reduction for hospitalization (0.9 percentage point absolute reduction) 3
• 61% relative risk reduction for death (0.2 percentage point absolute reduction) 3
• Effectiveness maintained in the Omicron era 5

Indirect comparisons show nirmatrelvir/ritonavir may reduce hospitalization more than molnupiravir (moderate certainty), with little or no difference compared to remdesivir (low certainty). 1

Common Pitfalls to Avoid

Do not delay treatment while awaiting specialist consultation - the 5-day window from symptom onset is narrow and effectiveness diminishes with delay. 1, 4

Do not prescribe without thoroughly reviewing drug interactions - the ritonavir component causes serious interactions that can be life-threatening. 4, 6

Do not use as pre-exposure or post-exposure prophylaxis - Paxlovid is not approved for prevention of COVID-19. 4

Do not assume vaccination eliminates the need for treatment - vaccinated high-risk patients still benefit from Paxlovid. 3, 5

Be aware of COVID-19 rebound - some patients experience symptom recurrence after completing treatment, though this does not negate the overall benefit. 7

Special Populations

Pregnant and breastfeeding patients may consider use based on individual risk-benefit assessment. 1

Immunocompromised patients derive particular benefit and should be prioritized for treatment. 5

Patients with hematologic malignancies or active cancer represent a high-risk group that benefits from treatment. 8, 9