What antiviral treatment is recommended for high-risk patients with COVID-19, such as older adults, immunocompromised individuals, and those with underlying health conditions like diabetes, heart disease, or chronic lung disease?

Antiviral Treatment for COVID-19

For high-risk patients with COVID-19, nirmatrelvir/ritonavir (Paxlovid) is the first-line antiviral treatment and should be initiated within 5 days of symptom onset. 1, 2, 3

Patient Selection for Antiviral Treatment

High-risk patients who require treatment include: 1, 3

• Age ≥65 years (with risk increasing substantially at age ≥90 years) 4, 5
• Unvaccinated individuals 1, 3
• Immunocompromised patients, including those with:
  • Active hematologic malignancies on chemotherapy 1, 6
  • Solid organ transplantation 7
  • B-cell depleting therapies 6
  • HIV/AIDS or other immunosuppressive conditions 3
• Chronic medical conditions, specifically:
  • Diabetes mellitus (especially insulin-dependent or with microvascular/macrovascular complications) 4, 3
  • Cardiovascular disease 4, 3
  • Chronic lung disease including COPD and asthma 4, 3
  • Chronic kidney disease 4, 3
  • Obesity (BMI >25) 4, 3
  • Hypertension 4, 3
  • Active cancer 4, 3

Low-risk patients without these conditions should NOT receive antiviral treatment, as the risks of drug interactions and adverse effects outweigh trivial benefits. 1

First-Line Treatment: Nirmatrelvir/Ritonavir (Paxlovid)

Dosing and administration: 1, 3

• 300 mg nirmatrelvir with 100 mg ritonavir orally twice daily for 5 days 3
• Must be initiated within 5 days of symptom onset (efficacy decreases significantly after this window) 1, 2, 3
• Can be taken with or without food 1

Efficacy data: 3

• 86% relative risk reduction in hospitalization or death in the EPIC-HR trial 3
• 39% relative risk reduction in hospitalization and 61% reduction in death in real-world effectiveness studies 1
• Zero deaths in the Paxlovid arm versus 12 deaths (1.2%) in placebo arm through Day 28 3
• Remains effective against Omicron subvariants 1

Critical safety considerations before prescribing: 1

• Mandatory comprehensive medication review to identify potential drug interactions with ritonavir (a strong CYP3A inhibitor) 1
• Monitor for hypersensitivity reactions 1
• Assess hepatic function if baseline abnormalities present 1

Alternative Antiviral Options

Remdesivir is the preferred alternative when Paxlovid is contraindicated: 1, 2, 8

• Indicated for: patients with problematic drug interactions with ritonavir, pregnant patients, children, and hospitalized patients not on mechanical ventilation 1, 2
• 3-day IV course for outpatients or hospitalized patients 1
• Improves survival, reduces disease progression, decreases time to clinical recovery, and reduces readmission rates 8
• Should NOT be used in mechanically ventilated patients (no survival benefit) 2

Molnupiravir is a less effective oral alternative: 1, 2

• Only when Paxlovid is unavailable or contraindicated 1, 2
• Paxlovid demonstrates superior reduction in hospitalization compared to molnupiravir based on indirect comparisons 1

Special Populations

Severely immunocompromised patients with treatment failure: 6

• Approximately 50% of severely immunocompromised patients fail initial monotherapy 6
• Antiviral combination therapy (sequential or concurrent use of ≥2 agents) achieves 91.7% success rate versus 50% for repeat monotherapy 6
• Consider combination therapy for persistent or recurrent COVID-19 in patients with hematologic malignancies or those receiving B-cell depleting therapy 6

Pregnant and breastfeeding patients: 1

• May consider Paxlovid use through shared decision-making about potential risks versus benefits 1
• Remdesivir is preferred alternative for pregnant patients 1

Patients with cardiovascular disease: 4

• Those with poorly controlled hypertension, advanced heart failure (physiological stages C or D), pulmonary hypertension, or adult congenital heart disease with poor physiological stage are at highest risk 4
• Should prioritize prompt vaccination and antiviral treatment 4

Critical Pitfalls to Avoid

Timing errors: 1, 2, 7

• Do not delay treatment beyond 5 days of symptom onset - efficacy decreases significantly 1, 2
• Among patients not offered treatment, 22.7% were excluded due to symptom duration >5 days, representing missed opportunities 7

Undertreating the oldest adults: 5

• Only 35.2% of patients ≥90 years receive treatment versus 48.4% of those aged 65-74 years 5
• Patients aged ≥90 years have 1.54 times the odds of being untreated compared to those aged 65-74 years, despite having the highest risk for severe outcomes 5

Inappropriate exclusions: 7

• Do not withhold treatment solely because symptoms are mild - 48.9% of high-risk patients were not offered treatment for this reason alone 7
• Among untreated patients with severe outcomes, 78.9% never received outpatient antivirals 5

Drug interaction oversights: 1, 7

• Concern about drug interactions led to treatment withholding in only 5.7% of cases, but requires thorough medication review before prescribing 1, 7

Patient education failures: 7

• 20% of high-risk patients declined treatment when offered 7
• Advance planning and patient education about antiviral benefits before positive test results can improve uptake 7

Prophylaxis Considerations

Pre-exposure prophylaxis with long-acting monoclonal antibodies: 9

• Recommended for high-risk immunocompromised patients who are unvaccinated, vaccine non-responders, or not expected to mount adequate immune response 9
• Target population includes patients with active hematological malignancy on treatment, recent HSCT (<6 months), severe immunosuppression, and documented vaccine non-response 9

Post-exposure prophylaxis: 9

• Strongly recommended for high-risk patients with documented COVID-19 exposure who are unvaccinated, vaccine non-responders, or immunocompromised 9
• Should be administered within 72 hours of exposure 9