When is it best to give Paxlovid (nirmatrelvir/ritonavir) for COVID-19 in high-risk patients?

When to Give Paxlovid for COVID-19

Paxlovid should be initiated as soon as possible after COVID-19 diagnosis in high-risk patients, ideally within 5 days of symptom onset, as this timing window is critical for maximizing effectiveness in preventing hospitalization and death. 1, 2

Patient Selection: Risk Stratification is Essential

High-Risk Patients: Strong Recommendation for Treatment

For patients with non-severe COVID-19 at high risk of hospitalization, Paxlovid is strongly recommended. 1, 3 High-risk criteria include:

• Age ≥65 years 4
• Immunocompromised status (including hematological malignancies, transplant recipients) 4
• Unvaccinated or vaccine non-responders 4
• Multiple chronic medical conditions 3

The WHO guideline provides high-certainty evidence showing important reduction in hospitalization and moderate certainty of survival benefit in this population. 4

Moderate-Risk Patients: Conditional Recommendation

For patients at moderate risk of hospitalization, Paxlovid may be used, but this is a conditional recommendation due to smaller absolute benefits compared to high-risk patients. 1 The decision should weigh the high-certainty evidence of reduced hospitalization against individual patient factors and drug interaction risks. 1

Low-Risk Patients: Not Recommended

For patients at low risk of hospitalization, Paxlovid should not be used, as benefits are trivial with high certainty for both mortality and hospitalization. 1

Critical Timing Considerations

The 5-Day Window

Treatment must be initiated within 5 days of symptom onset for optimal effectiveness. 1, 2 Real-world effectiveness data demonstrates:

• Treatment dispensed 0-5 days after symptom onset: 79.6% effectiveness in preventing hospitalization or death 5
• Treatment dispensed on the day of testing (within 0-5 days of symptoms): 89.6% effectiveness 5
• Treatment dispensed 6+ days after symptom onset: effectiveness declined to 43.8% 5

However, emerging evidence suggests Paxlovid may still provide benefit when initiated beyond 5 days in patients with high viral loads, particularly in reducing viral burden and shortening disease course. 6 This represents an important nuance when patients present late but have documented high viral loads.

Real-World Effectiveness Across Populations

Paxlovid demonstrates substantial effectiveness even in highly vaccinated populations, with 39% relative risk reduction for hospitalization and 61% relative risk reduction for death. 7 Absolute risk reduction for hospitalization is particularly pronounced in patients aged 65+ years compared to younger patients. 7

Mandatory Pre-Treatment Assessment

Drug-Drug Interaction Screening is Non-Negotiable

Before prescribing Paxlovid, you must systematically review all patient medications using the Liverpool COVID-19 Drug Interaction Tool, as ritonavir is a strong CYP3A4 inhibitor causing potentially life-threatening drug interactions. 4, 3, 2, 8

Contraindicated medications include:

• Certain antiarrhythmics highly dependent on CYP3A for clearance 3, 2
• Specific anticoagulants 3
• Certain statins 3
• Potent CYP3A inducers that may reduce Paxlovid effectiveness 2

The FDA boxed warning emphasizes that ritonavir may lead to greater exposure of concomitant medications, resulting in potentially severe, life-threatening, or fatal events. 2

Renal Function Assessment Required

Check renal function before prescribing, as dose adjustments are mandatory for renal impairment. 4, 2

• Moderate renal impairment (eGFR 30-59 mL/min): Reduce to 150 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days 4, 2
• 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 2
• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury 4

Hepatic Impairment Considerations

Paxlovid is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). 2 Use with caution in patients with severe liver impairment, as clinical trials excluded this population. 4

Dosing and Administration

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. 2 Administer at approximately the same time each day, with or without food. 2

Common Pitfalls to Avoid

1. Missing the treatment window: Delaying treatment beyond 5 days significantly reduces effectiveness 5
2. Failing to screen for drug interactions: This is the primary safety concern and can result in life-threatening events 2, 8
3. Incorrect dosing in renal impairment: Failure to adjust dose can lead to drug accumulation and toxicity 4, 2
4. Treating low-risk patients: This wastes limited resources and exposes patients to unnecessary drug interaction risks 1
5. Not prioritizing high-risk patients when supply is limited: Where availability is constrained, Paxlovid should be reserved for those at highest risk 1

Special Population Considerations

Pregnant patients: Paxlovid may be an option to reduce disease progression, though uncertainty exists regarding potential serious adverse reactions. 4 No reports of serious adverse reactions in parent or child have been documented in WHO Vigibase to date. 4

Vaccinated patients: Paxlovid remains effective in vaccinated populations, with similar absolute risk reduction for hospitalization compared to unvaccinated patients. 7

Monitoring During Treatment

Monitor for common adverse effects including dysgeusia and diarrhea, which occur more frequently than placebo but rarely lead to discontinuation. 4, 3 Watch for signs of hepatotoxicity, as hepatic transaminase elevations have been reported with ritonavir. 2