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

Managing HIV Mutations and Drug Resistance

When viral suppression fails (HIV RNA >200 copies/mL confirmed on repeat testing), immediately obtain resistance testing while the patient remains on the failing regimen, then completely replace the entire regimen with at least 2-3 fully active agents based on resistance results—never add a single drug to a failing regimen. 1, 2

Confirm True Virological Failure

• Virological failure is defined as HIV RNA >200 copies/mL and must be confirmed with repeat testing on two separate occasions 1, 2
• A minimal significant change in viral load is a threefold or 0.5-log10 increase 1, 2
• Measure viral load twice to exclude transient elevations from intercurrent infection, recent vaccination, or assay variability 1, 2

Assess Adherence Before Changing Therapy

Adherence assessment is the most critical first step—inadequate adherence is the primary cause of treatment failure and must be addressed before attributing failure to resistance. 2

• Involve case managers or social workers to evaluate adherence barriers 2
• Screen for mental health disorders (depression, anxiety) and substance use disorders, as these directly jeopardize adherence 2
• Obtain detailed history of all current and past antiretroviral medications to identify previous exposures that may have selected for archived resistance 2

Obtain Resistance Testing While on Failing Regimen

• Perform resistance testing while the patient remains on the failing regimen, or within 4 weeks of stopping if already discontinued 1, 2
• Genotyping is preferred over phenotyping due to faster turnaround time (1-2 weeks vs 2-3 weeks) and lower cost 1
• For integrase strand transfer inhibitor (INSTI) failure, genotypic testing for INSTI resistance is required 2
• If considering a CCR5 antagonist, tropism testing is mandatory 2

Important caveat: Resistance assays only detect dominant viral species (>20% of the viral population); minority resistant variants may not be detected but can emerge rapidly under drug pressure. 2

Switching Strategy Based on Resistance Results

The goal is maximal viral suppression to <50 copies/mL to prevent further resistance development—complete replacement of the regimen with different drugs is ideal. 1, 2

• Use at least 2-3 fully active agents based on resistance testing results 1, 2
• Never add a single active agent to a failing regimen 1, 2
• Consultation with an HIV specialist is strongly recommended when changing therapy for virological failure 2

Class-Specific Switching Algorithms:

For NNRTI-based regimen failure:

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

For INSTI-based regimen failure:

• Switch to a boosted protease inhibitor (PI) plus 2 NRTIs with ≥1 fully active NRTI 2
• High baseline viral load (≥100,000 copies/mL) and low CD4 counts (<200 cells/mm³) are the strongest predictors of INSTI failure 3

For PI-based regimen failure:

• Focus on adherence support first, or switch to an alternative regimen that improves adherence and tolerability 2
• If PI resistance is documented, consider two new PIs with new NRTIs due to cross-resistance within the PI class 2
• Cross-resistance within drug classes (especially PIs and NNRTIs) is common—viral strains resistant to one drug often have reduced susceptibility to most or all drugs in that class 1

Critical Contraindications

• Do not switch from 3-drug to 2-drug regimens unless viral suppression is maintained and both agents are fully active 2
• In patients with NRTI resistance mutations who are virologically suppressed on a boosted PI, do not switch to regimens containing drugs with low genetic barriers to resistance (e.g., NNRTIs or raltegravir) 1
• Avoid monotherapy with boosted PIs or dolutegravir 2

Monitoring After Regimen Change

• Assess viral load 1 month after switching regimens 1, 2
• Expect <0.5-0.75 log10 reduction in viral load by 4 weeks or <1 log10 reduction by 8 weeks 1, 2
• Therapy should suppress viral load to undetectable levels (<50 copies/mL) within 4-6 months 1, 2
• Monitor CD4+ cell count trends as a complementary marker—a >30% decrease in absolute count or >3% decrease in percentage indicates significant decline 2
• Do not rely solely on CD4 count—viral load is the key parameter for evaluating treatment response 2

Distinguish Drug Failure from Drug Toxicity

• If toxicity is the issue rather than virological failure, substitute with alternative drugs from the same class rather than switching the entire regimen 2
• Review CD4+ T cell count trends to assess immunological impact 2