What are the recommended antiviral therapies for COVID-19 treatment?

COVID-19 Antiviral Therapies

Primary Recommendation

For non-severe COVID-19 patients at high risk of hospitalization, nirmatrelvir/ritonavir (Paxlovid) is the first-line antiviral treatment, demonstrating a 39% reduction in hospitalization risk and 61% reduction in mortality. 1, 2

Risk Stratification for Treatment Selection

High-Risk Patients (Strong Indication for Antivirals)

• Age ≥65 years - this group shows the greatest absolute risk reduction from treatment 2
• Immunocompromised status including hematological malignancies 3
• Multiple comorbidities (diabetes, cardiovascular disease, chronic lung disease) 1, 3
• Unvaccinated individuals - though vaccinated patients also benefit 2

Moderate-Risk Patients (Conditional Indication)

• Younger adults with 1-2 risk factors may consider nirmatrelvir/ritonavir, though benefit is smaller 1

Low-Risk Patients

• Do not treat with nirmatrelvir/ritonavir - benefits are trivial and do not justify drug interaction risks 1

Antiviral Treatment Options (In Order of Preference)

First-Line: Nirmatrelvir/Ritonavir (Paxlovid)

• Dosing: 300 mg nirmatrelvir/100 mg ritonavir orally twice daily for 5 days 4
• Timing: Must initiate within 5 days of symptom onset 1, 4, 5
• Renal adjustment required:
  • eGFR 30-59 mL/min: reduce to 150 mg/100 mg twice daily 4
  • eGFR <30 mL/min: 300 mg/100 mg once on day 1, then 150 mg/100 mg once daily days 2-5 4
• Efficacy: Reduces hospitalization by 26-39% and mortality by 61-73% in real-world studies 2, 6
• Additional benefits: Reduces symptom duration (median 13 vs 15 days) and COVID-19-related medical visits 5

Second-Line: Remdesivir

• Indication: When nirmatrelvir/ritonavir contraindicated due to drug interactions or renal impairment 3
• Route: Intravenous administration (major feasibility limitation for outpatients) 1
• Efficacy: Demonstrates faster recovery rates, particularly in patients with low-flow oxygen requirements and <10 days of symptoms 3

Third-Line: Molnupiravir

• Indication: When both nirmatrelvir/ritonavir and remdesivir are unavailable or contraindicated 3
• Efficacy: Lower hospitalization/death rate (6.8% vs 9.7% placebo), but inferior to nirmatrelvir/ritonavir in indirect comparisons 1, 3
• Safety concerns: Potential mutagenic effects limit its preferential use 1

Specialized Populations: Convalescent Plasma

• Indication: Elderly patients with mild COVID-19 when antivirals unavailable, or immunocompromised patients with hematological malignancies 1, 3
• Requirement: Must be high-titer convalescent plasma 1

Critical Drug Interaction Management

Before Prescribing Nirmatrelvir/Ritonavir

Ritonavir is a potent CYP3A4 inhibitor causing potentially life-threatening drug interactions 4, 7

Absolute Contraindications (Do Not Co-Prescribe):

• Drugs highly dependent on CYP3A4 clearance where elevated levels cause serious harm 4
• Potent CYP3A inducers that reduce nirmatrelvir/ritonavir efficacy 4
• HIV protease inhibitor-containing DAA regimens for hepatitis C 1

Management Strategies:

• Review ALL medications using Liverpool COVID-19 drug interaction tool before prescribing 1, 7
• Pause comedications for the 5-day treatment course when safe to do so 7
• Adjust doses of certain medications (e.g., reduce immunosuppressants, anticoagulants) 7
• Monitor symptoms for drug toxicity during and several days after treatment 1, 7

Specific High-Risk Interactions

• Tenofovir with lopinavir/ritonavir: Relatively contraindicated; switch to entecavir temporarily 1
• Statins, immunosuppressants, anticoagulants: Require dose adjustment or temporary discontinuation 7

Treatments to AVOID

Strong Recommendations Against Use

• Hydroxychloroquine: No benefit on clinical progression, may increase mortality and invasive mechanical ventilation risk, causes diarrhea/nausea 1
• Lopinavir/ritonavir alone: Does not reduce severe conversion rate, increases diarrhea and nausea 1
• Ribavirin alone: Toxicity at required doses outweighs benefits 1
• Corticosteroids in non-severe COVID-19: No effect on clinical deterioration, may prolong viral clearance 1

Do Not Combine Antivirals

• No evidence supports combining antiviral therapies - use monotherapy only 1

Special Populations

Pregnant and Breastfeeding Patients

• Nirmatrelvir/ritonavir may be considered despite limited data - no serious adverse reactions reported in WHO Vigibase 1
• Represents an option to reduce disease progression risk 1

Hepatitis B Patients

• Do not stop nucleoside antivirals during COVID-19 treatment to avoid HBV reactivation 1
• Screen for HBsAg if systemic corticosteroids or tocilizumab used ≥7 days 1
• Initiate HBV antiviral therapy according to existing guidelines if newly diagnosed 1

Patients with Liver Disease

• Monitor liver function twice weekly in patients on potentially hepatotoxic medications 1
• Withhold off-label COVID-19 treatments if moderate-to-severe liver injury develops 1
• Nirmatrelvir/ritonavir not recommended in severe hepatic impairment (Child-Pugh Class C) 4

Common Pitfalls to Avoid

• Missing the 5-day treatment window - emphasize early testing and rapid treatment initiation 1, 4
• Failing to screen for drug interactions before prescribing nirmatrelvir/ritonavir 4, 7
• Treating low-risk patients - wastes resources and exposes to unnecessary drug interaction risks 1
• Using hydroxychloroquine or lopinavir/ritonavir based on outdated protocols 1
• Delaying treatment for additional testing - clinical diagnosis sufficient to initiate therapy 1