What are the next steps for treating COVID-19 in patients who are not responding to Paxlovid (nirmatrelvir/ritonavir)?

Treatment of COVID-19 in Patients Not Responding to Paxlovid

For hospitalized COVID-19 patients who are not responding to Paxlovid or in whom Paxlovid is not appropriate, the cornerstone of therapy is dexamethasone 6 mg daily for up to 10 days combined with prophylactic-dose anticoagulation, with the addition of IL-6 receptor antagonists (tocilizumab or sarilumab) for patients with increasing oxygen requirements and evidence of systemic inflammation (CRP ≥75 mg/L). 1, 2

Initial Assessment and Stratification

When a patient is not responding to Paxlovid, immediately assess:

• Oxygen requirements: Document current oxygen saturation, supplemental oxygen needs, and trajectory over the past 24-48 hours 1
• Inflammatory markers: Obtain CRP level (threshold ≥75 mg/L is critical for treatment decisions) 1, 2
• Disease severity: Classify as moderate (requiring oxygen support, saturation >90%), severe (saturation 90-94%, respiratory rate >30/min), or critical (ARDS, mechanical ventilation, septic shock) 3, 2
• Vaccination and serostatus: Determine if patient is seronegative, as this affects monoclonal antibody eligibility 3, 2

Treatment Algorithm Based on Disease Severity

For Moderate COVID-19 (Oxygen Support Required, Saturation >90%)

Primary therapy:

• Dexamethasone 6 mg daily for 10 days - this is the single most important mortality-reducing intervention 1, 2
• Prophylactic-dose anticoagulation with LMWH or unfractionated heparin 1
• Remdesivir may be considered 3, 2

If patient is seronegative:

• Consider casirivimab/imdevimab or high-titer convalescent plasma 3, 2

If worsening despite dexamethasone AND systemic inflammation present:

• Add IL-6 receptor antagonist (tocilizumab or sarilumab) 3, 1, 2
• Alternative: JAK inhibitors (baricitinib/tofacitinib) or anti-IL-1 (anakinra) 3

For Severe/Critical COVID-19 (Saturation <90%, Mechanical Ventilation, ARDS)

Primary therapy:

• Dexamethasone 6 mg daily - strongly recommended 3, 1, 2
• Therapeutic or prophylactic-dose anticoagulation based on clinical judgment 3, 1
• Remdesivir may be considered, though evidence is mixed for invasive mechanical ventilation 3, 2

If seronegative and on non-invasive ventilation:

• Casirivimab/imdevimab may be considered (no data for invasive mechanical ventilation) 3

If COVID-19-related inflammation present:

• Add second immunosuppressant: anti-IL-6 agents (tocilizumab or sarilumab) preferred 3, 1, 2
• The IL-6 receptor antagonist reduces the combined endpoint of mechanical ventilation or death (OR 0.74,95% CI 0.72-0.88) 1

Respiratory Support Optimization

• High-flow nasal cannula (HFNC) or noninvasive CPAP should be used for hypoxemic acute respiratory failure without immediate indication for invasive mechanical ventilation 3, 1, 2
• These interventions are aerosol-generating and require appropriate PPE 3
• Do not delay mechanical ventilation in patients not responding to HFNC or CPAP 3
• Prone positioning may improve oxygenation in non-intubated patients and is widely used for mechanically ventilated patients 3

Critical Pitfalls to Avoid

Corticosteroid misuse:

• Never use corticosteroids in patients not requiring supplemental oxygen - there is no mortality benefit and potential harm 3, 1, 2
• Corticosteroids should NOT be used in mild COVID-19 3, 2

Anticoagulation errors:

• Do not change anticoagulant regimen based solely on D-dimer levels 1
• Monitor renal function and platelet counts for anticoagulation decisions 1
• LMWH is preferred over unfractionated heparin due to lack of routine monitoring requirements 1

Ineffective therapies to avoid:

• Hydroxychloroquine - strongly recommended against 1, 2
• Lopinavir-ritonavir - strongly recommended against 3, 1, 2
• Azithromycin - should not be used in absence of bacterial infection 1, 2
• Remdesivir for invasive mechanical ventilation - suggested against by European Respiratory Society 1, 2

Timing Considerations

IL-6 receptor antagonists are most beneficial when:

• Added to corticosteroids within 24 hours of requiring noninvasive or invasive ventilatory support 1
• CRP ≥75 mg/L or other markers of systemic inflammation are present 1, 2

Special Populations

For immunocompromised patients (hematological malignancies, transplant recipients):

• Higher risk of severe COVID-19, particularly with AML, age >60 years, and active disease 2
• Consider anti-SARS-CoV-2 monoclonal antibodies if seronegative 3, 2
• Same treatment algorithm applies but with heightened vigilance 3

For patients with pre-existing anticoagulation needs:

• Switch to therapeutic-dose LMWH or unfractionated heparin if oral anticoagulation needs discontinuation during hospitalization 1
• Continue antiplatelet therapy and add prophylactic-dose LMWH for stroke patients on antiplatelet therapy 1

Monitoring Parameters

• Oxygen saturation: Continuous monitoring, with significant improvement expected within 24-48 hours of appropriate therapy 4
• Inflammatory markers: Repeat CRP to guide escalation decisions 1
• Renal function and platelet counts: For anticoagulation safety 1
• Clinical trajectory: Assess for worsening requiring escalation to mechanical ventilation 3