Should the patient be prescribed Paxlovid (nirmatrelvir/ritonavir) for COVID-19 treatment?

Should the Patient Be Prescribed Paxlovid?

Paxlovid should be prescribed for patients with mild-to-moderate COVID-19 who are at high risk for progression to severe disease, provided treatment can be initiated within 5 days of symptom onset and there are no contraindicated drug interactions or severe hepatic impairment. 1, 2

Risk Stratification Determines Treatment Decision

The World Health Organization strongly recommends Paxlovid for high-risk patients with non-severe COVID-19, based on high-certainty evidence showing important reduction in hospitalization and moderate certainty of survival benefit. 1 For moderate-risk patients, the WHO conditionally recommends Paxlovid, acknowledging smaller but still important benefits. 1 However, the WHO conditionally recommends against Paxlovid use in low-risk patients, as benefits are trivial. 1

High-Risk Criteria Include:

• Age ≥65 years 3
• Immunocompromised status (including hematological malignancies, transplant recipients) 3
• Unvaccinated or vaccine non-responders 3
• Multiple comorbidities 4, 5

Critical Pre-Prescribing Requirements

1. Timing Window

Treatment must be initiated within 5 days of symptom onset for optimal effectiveness. 1, 6, 2 This necessitates rapid diagnostic testing and prescription fulfillment. 1

2. Drug Interaction Assessment (MANDATORY)

Before prescribing, you must consult the Liverpool COVID-19 Drug Interaction Tool to identify contraindicated medications and those requiring dose adjustment or temporary discontinuation. 1, 6 Ritonavir is a potent CYP3A4 inhibitor causing numerous clinically significant drug-drug interactions that can result in potentially severe, life-threatening, or fatal events. 2 This is the primary safety concern with Paxlovid. 6

Contraindicated co-medications include: 2

• Drugs highly dependent on CYP3A for clearance where elevated concentrations cause serious/life-threatening reactions
• Potent CYP3A inducers that may cause loss of virologic response

3. Renal Function Assessment

Dose adjustment is required for renal impairment: 6, 2

• Normal renal function (eGFR ≥60): 300 mg nirmatrelvir + 100 mg ritonavir twice daily for 5 days 2
• Moderate impairment (eGFR 30-59): 150 mg nirmatrelvir + 100 mg ritonavir twice daily for 5 days 6, 2
• Severe impairment (eGFR <30) including hemodialysis: 300 mg nirmatrelvir + 100 mg ritonavir once on Day 1, then 150 mg nirmatrelvir + 100 mg ritonavir once daily Days 2-5 (after dialysis on dialysis days) 2

Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury. 6

4. Hepatic Function Assessment

Paxlovid is not recommended in severe hepatic impairment (Child-Pugh Class C). 2 Use with caution in patients with severe liver impairment, as trials excluded this population. 6

Real-World Effectiveness Data

Paxlovid demonstrates substantial real-world effectiveness:

• 39% reduction in hospitalization risk (absolute risk reduction 0.9 percentage points) 5
• 61% reduction in death risk (absolute risk reduction 0.2 percentage points) 5
• 51% reduction in hospitalization rate across all age groups and vaccination statuses 7

These benefits persist in the Omicron era and among vaccinated patients, with particularly pronounced effects in patients aged ≥65 years. 5, 8

Special Populations

Immunocompromised Patients

For patients with hematological malignancies or transplant recipients with mild COVID-19, nirmatrelvir/ritonavir is recommended as a treatment option (graded CIIt). 3 Among immunocompromised patients, remdesivir was independently associated with lower mortality risk, suggesting antivirals are particularly important in this population. 9

Pregnant Patients

Paxlovid may be an option for pregnant people to reduce disease progression, though uncertainty exists regarding potential serious adverse reactions. 6 No reports of serious adverse reactions in parent or child have been documented in WHO Vigibase to date. 6

Common Pitfalls to Avoid

1. Missing the 5-day treatment window: Effectiveness diminishes significantly after 5 days of symptom onset 1, 2

2. Failing to check drug interactions: This is the most common cause of serious adverse events and is entirely preventable with proper screening 6, 2

3. Not adjusting dose for renal impairment: Failure to reduce dose can lead to drug accumulation and increased adverse effects 6, 2

4. Prescribing to low-risk patients: Benefits are trivial in this population and do not justify potential drug interactions 1

Monitoring During Treatment

Monitor patients for:

• Common adverse effects: Dysgeusia (altered taste) and diarrhea occur more frequently with Paxlovid but rarely lead to discontinuation 6, 10
• Signs of drug accumulation in patients with renal impairment 6
• Clinical deterioration requiring renal function reassessment 6

When Paxlovid Cannot Be Used

If Paxlovid is contraindicated or unavailable, remdesivir is the first-line alternative, particularly for patients with CYP3A4 drug interactions, pregnant patients, and children. 9 Molnupiravir is the second-line alternative, only for high-risk patients, and is contraindicated in pregnancy, breastfeeding, and men not using contraception. 9