What is the best approach to manage HIV mutations and drug resistance in patients with impaired viral suppression?

Managing HIV Mutations and Drug Resistance in Patients with Impaired Viral Suppression

Resistance testing should be performed while the patient is taking the failing antiretroviral regimen, and the entire regimen must be switched to at least 2-3 fully active agents based on resistance testing results—never add a single drug to a failing regimen. 1

Immediate Assessment When Viral Suppression Fails

Confirm Virological Failure

• Virological failure is defined as HIV RNA >200 copies/mL and must be confirmed with repeat testing 1
• Obtain resistance testing while the patient remains on the failing regimen (or within 4 weeks of stopping) 1
• Measure viral load on two separate occasions to confirm the failure is not due to intercurrent infection, vaccination, or assay variability 1
• A minimal significant change in viral load is a threefold or 0.5-log10 increase 1

Critical Factors to Evaluate Before Changing Therapy

• Adherence assessment is the most critical first step—involve case managers or social workers, as inadequate adherence is a primary cause of treatment failure 1
• Screen for mental health disorders and substance use disorders, as these jeopardize adherence and must be addressed 1
• Obtain detailed history of all current and past antiretroviral medications 1
• Review CD4+ T cell count trends (>30% decrease in absolute count or >3% decrease in percentage indicates significant decline) 1
• Distinguish drug failure from drug toxicity—if toxicity is the issue, substitute with alternative drugs from the same class 1

Resistance Testing Strategy

When to Perform Resistance Testing

• At initiation of care for all patients to detect transmitted resistance (strong recommendation) 1
• During confirmed virological failure while on the failing regimen 1
• In acute HIV infection if treatment is initiated 1
• Not recommended routinely before starting therapy in chronic infection unless there is documented exposure to resistant virus 1

Type of Resistance Testing

• Genotyping assays are preferred initially—results available in 1-2 weeks, detect specific resistance mutations in reverse transcriptase and protease genes 1
• Phenotyping assays measure viral growth at different drug concentrations but are more costly and take 2-3 weeks 1
• For integrase strand transfer inhibitor (INSTI) failure, genotypic testing for INSTI resistance is required 1
• For complex treatment histories, both genotyping and phenotyping may provide complementary information 1
• Tropism testing is mandatory if considering a CCR5 antagonist 1

Switching Antiretroviral Therapy for Virological Failure

Core Principles for Regimen Changes

• The goal is maximal viral suppression to <50 copies/mL to prevent further resistance development 1
• Complete replacement of the regimen with different drugs is ideal—use at least 2-3 fully active agents based on resistance testing 1
• Never add a single active agent to a failing regimen 1
• Consultation with an HIV specialist is strongly recommended when changing therapy for virological failure 1

Specific Switching Strategies Based on Failing Regimen

For NNRTI-based regimen failure:

• Switch to dolutegravir plus 2 NRTIs with ≥1 active drug determined by genotypic testing 1

For INSTI-based regimen failure:

• Switch to a boosted protease inhibitor (PI) plus 2 NRTIs with ≥1 fully active NRTI 1
• If raltegravir or elvitegravir resistance is present, use dolutegravir dosed twice daily plus at least 1 fully active agent 1

For PI-based regimen failure:

• Virological failure with resistance mutations is rare with PIs 1
• Focus on adherence support or switch to an alternative regimen that improves adherence and tolerability 1
• If PI resistance is documented, consider two new PIs with new NRTIs due to cross-resistance within the PI class 1

Special Considerations for Switching

Hepatitis B co-infection:

• Continue tenofovir alafenamide or tenofovir disoproxil fumarate unless contraindicated 1
• Switching to lamivudine or emtricitabine alone without tenofovir will not maintain HBV suppression 1

Patients with NRTI resistance mutations:

• Do not switch from a boosted PI to a drug with low genetic barrier (NNRTI or raltegravir) 1

Limited treatment options:

• For clinically stable patients with detectable viremia but no optimal change available, delaying therapy changes may be prudent to await newer agents 1
• Partial viral suppression is superior to no suppression 1
• Consider clinical trial enrollment when no approved drug options remain 1

Monitoring After Regimen Change

• Assess viral load 1 month after switching regimens 1
• Expect <0.5-0.75 log10 reduction in viral load by 4 weeks or <1 log10 reduction by 8 weeks 1
• Therapy should suppress viral load to undetectable levels (<50 copies/mL) within 4-6 months 1
• Monitor CD4+ cell count trends as a complementary marker 1
• Do not measure viral load during or within 4 weeks after treatment of intercurrent infections or immunizations 1

Common Pitfalls to Avoid

• Never continue a failing regimen long-term—while some data suggest partial suppression provides benefit, accumulation of >6 resistance mutations leads to progressively increasing viral loads and clinical deterioration 2
• Avoid monotherapy with boosted PIs or dolutegravir 1
• Do not rely solely on CD4 count—viral load is the key parameter for evaluating treatment response 1
• Resistance assays only detect dominant viral species; minority resistant variants may not be detected but can emerge under drug pressure 1
• Switching from 3-drug to 2-drug regimens is only appropriate when viral suppression is maintained and both agents are fully active 1