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
• Genotyping is preferred over phenotyping due to faster turnaround time (1-2 weeks vs 2-3 weeks) and lower cost 1

Interpreting Resistance Results

• Genotyping detects specific mutations in reverse transcriptase and protease genes 1
• Phenotyping measures viral growth at different drug concentrations (fold-resistance) 1
• For patients with complex treatment histories, both genotypic and phenotypic testing may provide complementary information 1
• Consultation with an HIV resistance specialist is strongly encouraged for interpretation 1
• For integrase inhibitor regimens, specific INSTI resistance testing should be ordered 1

Switching Antiretroviral Therapy

Core Principles for Treatment Changes

• The goal is maximal viral suppression to <50 copies/mL to prevent resistance emergence 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
• Partial viral suppression is superior to no suppression, but incomplete suppression promotes resistance 1

Specific Switching Strategies Based on Failing Regimen

After NNRTI Failure:

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

After Integrase Inhibitor Failure:

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

After Protease Inhibitor Failure:

• Virological failure with PI resistance is rare 1
• Focus on adherence support or switch to an alternative regimen that improves adherence and tolerability 1
• Consider using two new protease inhibitors with one or two new NRTIs, or a PI combined with an NNRTI 1

Special Considerations for NRTI Resistance

• In patients with NRTI resistance mutations who are virologically suppressed on a boosted PI, do not switch to a regimen containing drugs with low genetic barriers to resistance (e.g., NNRTIs or raltegravir) 1

Monitoring After Treatment Change

• Assess HIV 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 within 4-6 months 1
• Monitor CD4+ T cell counts as a complementary marker, though viral load is the primary parameter 1

When Treatment Options Are Limited

• For clinically stable patients with detectable viremia but no optimal treatment options, delaying therapy changes while awaiting newer agents may be prudent 1
• Refer patients without viable options using approved drugs to clinical trials 1
• Consultation with or referral to an experienced HIV clinician is essential when considering treatment changes 1

Common Pitfalls to Avoid

• Do not perform resistance testing in treatment-naïve patients with chronic infection—it is not recommended due to uncertainty about resistance prevalence and inability to detect archived resistant variants 1
• Do not measure viral load during or within 4 weeks after intercurrent infections, symptomatic illness, or immunization 1
• Avoid switching individual drugs in a failing regimen without complete resistance assessment 1
• Do not use monotherapy with boosted PIs or dolutegravir 1
• 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