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

COVID-19 Antiviral Therapy Recommendations

Primary Recommendation

For non-hospitalized patients with COVID-19 at high risk of hospitalization, nirmatrelvir/ritonavir (Paxlovid) is the first-line antiviral therapy and should be initiated within 5 days of symptom onset. 1, 2

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Risk Stratification for Treatment

High-Risk Patients (Strong Indication for Antivirals)

• Age ≥65 years 3
• Immunocompromised status (including hematological malignancies, transplant recipients) 1, 3
• Multiple comorbidities 3
• Unvaccinated or vaccine non-responders 1

Moderate-Risk Patients (Conditional Indication)

• Patients with some risk factors but lower baseline hospitalization risk 1
• Consider treatment on case-by-case basis weighing drug interactions 1

Low-Risk Patients (Not Recommended)

• Young, healthy individuals without risk factors 1
• Treatment provides trivial benefit and is not recommended 1

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First-Line Antiviral: Nirmatrelvir/Ritonavir (Paxlovid)

Efficacy Data

• Reduces hospitalization by 26-39% in real-world studies 4, 5
• Reduces mortality by 61-73% 4, 5
• Absolute risk reduction: 0.9% for hospitalization, 0.2% for death 4
• Effectiveness maintained in vaccinated patients and against Omicron variants 4

Dosing

• Standard dose: 300 mg nirmatrelvir (two 150 mg tablets) + 100 mg ritonavir (one tablet) twice daily for 5 days 2
• Moderate renal impairment (eGFR 30-59 mL/min): 150 mg nirmatrelvir + 100 mg ritonavir twice daily 2
• Severe renal impairment (eGFR <30 mL/min): 300 mg nirmatrelvir + 100 mg ritonavir once on Day 1, then 150 mg nirmatrelvir + 100 mg ritonavir once daily Days 2-5 2
• Initiate within 5 days of symptom onset 1, 2

Critical Drug Interactions

Ritonavir is a potent CYP3A inhibitor causing potentially life-threatening drug interactions. 2

Contraindicated medications include: 2

• Drugs highly dependent on CYP3A clearance where elevated levels cause serious reactions
• Potent CYP3A inducers that reduce nirmatrelvir/ritonavir levels

Use the Liverpool COVID-19 drug interaction tool before prescribing 1

Contraindications

• Severe hepatic impairment (Child-Pugh Class C) 2
• History of clinically significant hypersensitivity to nirmatrelvir or ritonavir 2
• Concomitant use of contraindicated medications 2

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Alternative Antiviral Options

Remdesivir (Second-Line)

• Indicated when nirmatrelvir/ritonavir contraindicated or unavailable 1, 3
• Demonstrates faster recovery rates, particularly in patients with low-flow oxygen requirements 3
• Major limitation: requires intravenous administration 1, 3
• Preferred over molnupiravir due to better efficacy and no safety concerns 1

Molnupiravir (Third-Line)

• Use only when nirmatrelvir/ritonavir and remdesivir are contraindicated or unavailable 1
• Reduced hospitalization/death by 6.8% vs 9.7% in trials 3
• Inferior to nirmatrelvir/ritonavir in indirect comparisons (moderate certainty) 1
• Safety concerns exist regarding potential mutagenicity 1

Special Populations: Hematological Malignancies

For immunocompromised patients with hematological malignancies: 1

• High-titer convalescent plasma may be considered
• Inhaled interferon beta-1a may be considered
• Prolonged viral replication may warrant extended antiviral therapy 1

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Combination Therapy

Do not combine antiviral therapies—there is no evidence of benefit. 1

For severe/critical COVID-19 requiring oxygen, combine antivirals with immunomodulatory therapy: 1

• Dexamethasone 6 mg daily for 10 days 1
• Consider adding tocilizumab or baricitinib to corticosteroids 1

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Common Pitfalls to Avoid

Timing Errors

• Must initiate within 5 days of symptom onset—efficacy diminishes after this window 1, 2
• Do not delay treatment waiting for test results if clinical suspicion is high

Drug Interaction Oversights

• Always check drug interactions before prescribing nirmatrelvir/ritonavir—ritonavir causes numerous serious interactions 1, 2
• Consider temporary discontinuation of interacting medications during 5-day treatment course 1

Inappropriate Use

• Do not use hydroxychloroquine—no benefit and may worsen outcomes 1
• Do not use lopinavir/ritonavir alone—ineffective and causes adverse effects 1
• Do not use corticosteroids in non-severe disease—may prolong viral clearance 1

Rebound Concerns

• SARS-CoV-2 rebound occurs with similar frequency in treated and untreated patients 6
• Rebound symptoms are mild with no reported hospitalizations or deaths 6
• Potential for rebound should NOT deter prescribing lifesaving antivirals 6

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Pregnant and Breastfeeding Patients

Pregnant and breastfeeding individuals with non-severe COVID-19 at high risk may consider nirmatrelvir/ritonavir. 1

• No serious adverse reactions reported in WHO Vigibase to date 1
• Uncertainty exists, but potential benefits outweigh theoretical risks in high-risk patients 1

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Hospitalized Patients

Non-Severe Disease (No Oxygen Requirement)

No evidence supports immunomodulatory therapy initiation 1

Requiring Supplemental Oxygen

Systemic corticosteroids (dexamethasone) are the cornerstone of therapy and decrease mortality 1

Add tocilizumab to corticosteroids—reduces disease progression and mortality 1

Consider adding baricitinib or tofacitinib to corticosteroids—may decrease progression and mortality 1