Contraindications of COVID-19 Antiviral Therapies: A Comprehensive Analysis
(As of May 2025)

I. Key Contraindications of Major Antivirals

1. Paxlovid (Nirmatrelvir/Ritonavir)

• Absolute Contraindications:
  • Hypersensitivity to nirmatrelvir or ritonavir (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis).
  • Concurrent use of drugs metabolized primarily by CYP3A with narrow therapeutic indices (e.g., alfuzosin, triazolam, oral midazolam, pethidine, rivaroxaban).
  • Severe hepatic impairment (Child-Pugh Class C) or severe renal dysfunction (eGFR <30 mL/min).
• Relative Contraindications:
  • Moderate renal impairment (eGFR 30–60 mL/min): Dose adjustment to nirmatrelvir 150 mg + ritonavir 100 mg twice daily.
  • HIV patients (viral load >400 copies/mL): Risk of inducing HIV resistance.
• Special Populations:
  • Pregnancy: Contraindicated (potential teratogenicity).
  • Lactation: Use with caution due to potential secretion into breast milk.

2. Remdesivir

• Absolute Contraindications:
  • Severe hepatic impairment (ALT/AST >5x upper limit of normal) or severe renal dysfunction (eGFR <30 mL/min).
  • Hypersensitivity to remdesivir or excipients.
• Risk Warnings:
  • May cause acute kidney injury, hypotension, or hypersensitivity.
  • WHO recommends against use in non-severe cases (per 2020 guidelines).

3. Molnupiravir

• Absolute Contraindications:
  • Pregnancy (embryotoxicity observed in animal studies).
  • Hypersensitivity to active ingredients.
• Therapeutic Limitations:
  • Lower efficacy than Paxlovid; reserved as a secondary option.

II. Drug Interactions and Management Strategies

1. Paxlovid-Specific Interactions

• CYP3A Inhibitors/Inducers:
  • Contraindicated Combinations: Strong CYP3A inducers (e.g., carbamazepine, phenytoin) reduce Paxlovid concentrations, risking therapeutic failure.
  • Dose Monitoring Required: For CYP3A substrates (e.g., tacrolimus, cyclosporine), monitor plasma levels.
• High-Risk Drug Categories:
  

  Category	Representative Drugs	Risk Level
  α1-adrenergic antagonists	Alfuzosin	Contraindicated
  Anticoagulants	Rivaroxaban, Apixaban	Contraindicated
  Statins	Simvastatin, Lovastatin	Suspend during therapy
  Sedatives	Triazolam, oral midazolam	Contraindicated
  PDE5 inhibitors (PAH)	Sildenafil (Revatio®)	Contraindicated

2. Remdesivir and Molnupiravir Interactions

• Remdesivir may exacerbate cardiotoxicity when combined with chloroquine/hydroxychloroquine.
• Molnupiravir shows no significant interactions but should avoid combination with other antivirals.

III. Guidelines for Special Populations

1. Renal Impairment

• Paxlovid:
  • Moderate impairment (eGFR 30–60 mL/min): Reduce dose to nirmatrelvir 150 mg + ritonavir 100 mg twice daily.
  • Dialysis patients: Not recommended.
• Remdesivir: Contraindicated if eGFR <30 mL/min.

2. Hepatic Impairment

• Paxlovid: Contraindicated in Child-Pugh Class C; monitor closely in mild-to-moderate cases.
• Remdesivir: Use cautiously in severe impairment (Child-Pugh B/C).

3. Immunocompromised and Chronic Disease Patients

• HIV Patients: Paxlovid may induce resistance; combine with antiretroviral therapy.
• Cardiovascular Disease: Avoid high-risk drugs (e.g., amiodarone, ranolazine).

IV. Global Alternatives and Priority Strategies

1. Preferred Therapies

• Priority Order: Paxlovid > Remdesivir > Molnupiravir (based on efficacy/safety).
• Alternative Regimens:
  • For mild cases without Paxlovid access: Inhaled corticosteroids (e.g., budesonide).
  • Immunocompromised patients: Long-acting monoclonal antibodies (e.g., sotrovimab) + T-cell vaccines.

2. Timing and Duration

• Paxlovid: Initiate within 5 days of symptom onset; 5-day course.
• Remdesivir: Intravenous administration for severe cases (200 mg Day 1, then 100 mg daily for 5 days).

V. Safety Monitoring and Risk Assessment

1. Risk Assessment Tools:

• Use Liverpool COVID-19 Drug Interactions Checker or TGA/PI documents to evaluate interactions.
  2. Monitoring Parameters:
• Laboratory Tests: Baseline liver function (ALT/AST), renal function (eGFR), HIV viral load.
• Clinical Observation: Hypersensitivity, arrhythmias, bleeding tendencies.

Conclusion

Contraindications for COVID-19 antivirals center on metabolic interactions, organ function, and special population risks. Clinical decisions must prioritize:

1. Avoiding Absolute Contraindications: Strictly screen for drug interactions (e.g., alfuzosin) and hepatic/renal status.
2. Dynamic Dose Adjustments: Tailor Paxlovid doses by eGFR; opt for remdesivir or supportive care in severe organ impairment.
3. Protecting Vulnerable Groups: Prohibit oral antivirals in pregnancy; prioritize monoclonal antibodies.
4. Global Surveillance: Track zoonotic mutations via “One Health” frameworks to prevent cross-species resistance.

Future research focuses on non-CYP3A-dependent antivirals (e.g., CRISPR-Cas13) and mucosal delivery systems to overcome current limitations.

Data sourced from public references. For inquiries, contact: chuanchuan810@gmail.com.