What is the recommended antiviral treatment for a patient with confirmed COVID-19 (Coronavirus Disease 2019) who is at high risk for severe illness and has no contraindications to the medication?

COVID-19 Antiviral Treatment

Nirmatrelvir/ritonavir (Paxlovid) is the first-line antiviral treatment for high-risk COVID-19 patients, demonstrating a 39% reduction in hospitalization and 61% reduction in mortality when initiated within 5 days of symptom onset. 1

Patient Selection Criteria

High-risk patients who should receive treatment include: 1, 2

• Unvaccinated individuals 2
• Age ≥65 years 2
• Immunocompromised status (including hematological malignancies) 1
• Multiple comorbidities (diabetes, cardiovascular disease, chronic lung disease) 1
• Radiographic evidence of pneumonia 2

Do NOT treat low-risk patients without risk factors for severe disease, as potential risks from drug interactions and adverse effects outweigh trivial benefits in this population. 2

First-Line Treatment: Nirmatrelvir/Ritonavir (Paxlovid)

Dosing Regimen

Standard dosing: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) orally twice daily for 5 days. 1, 3

Timing is critical: Initiate treatment as soon as possible after diagnosis and within 5 days of symptom onset. 1, 3 Delaying beyond this window significantly reduces effectiveness. 2

Administration: Take with or without food at approximately the same time each day. 3

Dose Adjustments for Renal Impairment

Moderate renal impairment (eGFR 30-59 mL/min): 150 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days. 3

Severe renal impairment (eGFR <30 mL/min) including hemodialysis: 3

• 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 3

Severe hepatic impairment (Child-Pugh Class C): Paxlovid is not recommended. 3

Critical Drug Interaction Management

MANDATORY pre-prescription screening: Review ALL medications using the Liverpool COVID-19 drug interaction tool before prescribing, as ritonavir is a potent CYP3A4 inhibitor that can cause serious, life-threatening, or fatal drug interactions. 1, 3, 4

Contraindicated medications: 3

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

Special hepatitis B consideration: Do NOT stop nucleoside antivirals during COVID-19 treatment to avoid HBV reactivation. 1

Second-Line Treatment: Remdesivir

Remdesivir is the preferred alternative for patients with problematic drug interactions with ritonavir, pregnant patients, or when Paxlovid is contraindicated. 2

• Route: Intravenous administration (3-day course) 2
• Efficacy: Demonstrates faster recovery rates, particularly in patients with low-flow oxygen requirements and <10 days of symptoms 1

Third-Line Treatment: Molnupiravir

Molnupiravir is an oral option when Paxlovid is unavailable or contraindicated, but it is inferior to nirmatrelvir/ritonavir in indirect comparisons. 1, 2

Special Populations

Pregnant and breastfeeding patients: Consider nirmatrelvir/ritonavir despite limited data, using shared decision-making about potential risks versus benefits. 1, 2

Immunocompromised patients with hematological malignancies: Consider convalescent plasma when antivirals are unavailable. 1

Treatments to AVOID

Do NOT use the following, as they lack benefit or increase risk of adverse effects: 1

• Hydroxychloroquine
• Lopinavir/ritonavir alone
• Ribavirin alone

Common Pitfalls to Avoid

Missing the 5-day treatment window: Emphasize early testing and rapid treatment initiation. 1 The efficacy of nirmatrelvir/ritonavir drops significantly after 5 days of symptom onset. 2

Failing to screen for drug interactions: This is the most critical safety concern with Paxlovid due to ritonavir's potent CYP3A4 inhibition. 1, 4

Treating low-risk patients: Avoid unnecessary treatment in patients without risk factors for severe disease, as the absolute benefits are trivial and do not justify the risks. 2

Safety Monitoring

Monitor for: 3

• Hypersensitivity reactions (anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Hepatic transaminase elevations if baseline abnormalities present
• Dysgeusia (5.8% of patients) and diarrhea (2.1% of patients) as most common adverse events

HIV-1 consideration: Paxlovid use may lead to HIV-1 developing resistance to protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection. 3