What is the recommended treatment for an adult patient with a positive COVID-19 diagnosis, particularly those at high risk for progression to severe disease?

Treatment of Adult Patients with Positive COVID-19

For adults with confirmed COVID-19 at high risk for severe disease, prescribe nirmatrelvir-ritonavir (Paxlovid) 300 mg/100 mg orally twice daily for 5 days, initiated within 5 days of symptom onset. 1, 2, 3

Risk Stratification for Treatment

High-risk features that warrant antiviral treatment include:

• Age ≥65 years 2
• Unvaccinated status 2
• Immunosuppression 2
• Multiple comorbidities (≥3) 2
• Hematological disease 2
• Radiographic evidence of pneumonia 2

If the patient lacks these high-risk features, provide symptomatic treatment only (antipyretics, hydration, rest) without antivirals. 2

First-Line Treatment: Nirmatrelvir-Ritonavir (Paxlovid)

Dosing and Administration

Standard dose: Nirmatrelvir 300 mg (two 150 mg tablets) with ritonavir 100 mg (one tablet), all three tablets taken together orally twice daily for 5 days. 1, 3

Renal dosing adjustments: 3

• Mild renal impairment (eGFR ≥60 to <90 mL/min): No adjustment needed
• Moderate renal impairment (eGFR ≥30 to <60 mL/min): 150 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days
• Severe renal impairment (eGFR <30 mL/min, including hemodialysis): 300 mg/100 mg once on Day 1, then 150 mg/100 mg once daily on Days 2-5; take after hemodialysis on dialysis days

Critical Pre-Prescribing Requirements

Before prescribing nirmatrelvir-ritonavir, you must perform a comprehensive medication review using a drug interaction checker because ritonavir is a potent CYP3A4 inhibitor that can cause severe, life-threatening, or fatal drug interactions. 3, 4

Absolute contraindications (do not prescribe if patient is taking): 3

• Alfuzosin, silodosin
• Amiodarone, dronedarone, flecainide, propafenone, quinidine
• Carbamazepine, phenobarbital, phenytoin, primidone
• Colchicine (in renal/hepatic impairment)
• Ergot derivatives (dihydroergotamine, ergotamine, methylergonovine)
• Lovastatin, simvastatin
• Lumacaftor/ivacaftor
• Lurasidone, pimozide
• Midazolam (oral), triazolam
• Ranolazine
• Rifampin, rifapentine
• Sildenafil (for pulmonary arterial hypertension)
• St. John's Wort

Evidence of Benefit

Nirmatrelvir-ritonavir reduces:

• All-cause mortality by 73% 5
• COVID-19-specific mortality 1
• Hospitalization risk by 26-39% 1, 5
• Long COVID incidence by 25% 2

The treatment window is critical: initiate within 5 days of symptom onset for effectiveness. 1, 2, 3

Second-Line Treatment: Molnupiravir

Use molnupiravir only when nirmatrelvir-ritonavir is contraindicated or unavailable. 1, 2

Molnupiravir reduces all-cause mortality and time to recovery but is less effective than nirmatrelvir-ritonavir. 1, 2 The same 5-day symptom onset window applies. 2

Treatments to AVOID

Do not prescribe the following for outpatient COVID-19 treatment: 1, 2

• Ivermectin (no benefit demonstrated)
• Sotrovimab (not effective against current variants)
• Hydroxychloroquine (no benefit, potential harm)
• Azithromycin (unless bacterial superinfection documented)
• Systemic corticosteroids (for outpatients without hypoxia)
• Lopinavir-ritonavir (insufficient evidence)
• Vitamin D supplementation (no benefit)

The early 2020 guidelines recommending various combinations of lopinavir/ritonavir, hydroxychloroquine, ribavirin, and interferons 1 have been superseded by current evidence showing these agents are ineffective or harmful. 2

Monitoring During Treatment

• Complete the full 5-day course even if symptoms improve 3
• Continue isolation per public health recommendations 3
• Monitor for hypersensitivity reactions 2
• If baseline liver abnormalities present, monitor hepatic function 2
• Symptoms commonly persist into the fourth week (only 28.9% report complete resolution by week 4) 2

Common Pitfalls to Avoid

Failing to screen for drug interactions before prescribing nirmatrelvir-ritonavir can result in life-threatening events. 3, 4 Ritonavir's potent CYP3A4 inhibition causes rapid and significant increases in levels of co-administered medications. 4

Prescribing antivirals to low-risk patients without high-risk features exposes them to unnecessary drug interaction risks without meaningful benefit. 2

Delaying treatment beyond 5 days of symptom onset significantly decreases effectiveness for both nirmatrelvir-ritonavir and molnupiravir. 1, 2, 6

For hospitalized patients with severe COVID-19, nirmatrelvir-ritonavir shows no mortality benefit and should not be initiated after hospitalization for severe disease. 7 However, if a patient started nirmatrelvir-ritonavir as an outpatient and subsequently requires hospitalization, complete the 5-day course. 3