When to Change HIV Suppression Therapy
You need to change HIV therapy when virologic failure occurs (confirmed HIV RNA >200 copies/mL on two consecutive tests), when drug toxicity develops, or when switching to a more convenient/safer regimen while maintaining viral suppression. 1
Virologic Failure: Clear Criteria for Switching
Definition and Monitoring
Virologic failure is definitively established when HIV RNA remains above 200 copies/mL on at least two consecutive measurements 1. The most recent International Antiviral Society-USA guidelines (2024) emphasize this threshold as the action point 1.
Specific Timeframes Requiring Action
- Inadequate initial response: Less than 0.5-0.75 log reduction in HIV RNA by 4-8 weeks after starting therapy 1
- Failure to suppress: HIV RNA remains detectable beyond 24 weeks of treatment initiation 1
- Viral rebound: Repeated detection of virus after initial suppression to undetectable levels 1
- Significant increase: Any reproducible threefold or greater increase from the nadir HIV RNA level (excluding intercurrent infections or vaccinations) 1
What NOT to Change For
Do not change therapy for "blips" or persistent low-level viremia between 20-200 copies/mL 1. This is a critical distinction—these intermittent detections should prompt adherence review and drug interaction assessment, but not regimen change, especially if the patient is on a high-barrier regimen containing bictegravir, dolutegravir, or boosted darunavir 1.
Drug Toxicity or Intolerance
When toxicity occurs with maintained viral suppression, substitute the offending drug with an alternative agent from the same class with a different toxicity profile 1. This is straightforward—you're not dealing with resistance, just tolerability 2.
Switching in Virologically Suppressed Patients
When to Proactively Switch
Even with viral suppression, switching is recommended when patients are on regimens with 1:
- Short- or long-term adverse effects
- Inconvenient dosing or high pill burden
- Anticipated drug-drug interactions
- Progressive kidney disease (particularly TDF-containing regimens)
- Cardiovascular disease risk
- Cost concerns
- Pregnancy or pregnancy planning 1
Specific High-Priority Switches
Patients on older regimens containing stavudine, didanosine, zidovudine, or older protease inhibitors should be switched even if doing well, due to long-term toxicities 1.
Patients on boosted protease inhibitors plus 2 NRTIs can be safely switched to dolutegravir plus tenofovir/lamivudine or emtricitabine, or bictegravir/emtricitabine/TAF, regardless of prior NRTI resistance history, provided there is no InSTI resistance 1. This is a major advance—the high barrier to resistance of these newer InSTIs allows this flexibility.
Critical Caveat
Do not switch from boosted protease inhibitors to NNRTI or first-generation InSTI regimens (raltegravir/elvitegravir) if previous NRTI resistance exists 1. These older agents lack the resistance barrier needed.
Immunologic and Clinical Deterioration
CD4+ Count Decline
Persistently declining CD4+ counts on at least two separate occasions suggests treatment failure, though this is less reliable than viral load 1.
Clinical Progression
A new AIDS-defining diagnosis after treatment initiation suggests failure, but context matters 1:
- If antiretroviral effect was poor (less than tenfold viral RNA reduction), this represents true therapeutic failure
- If viral suppression was good but the patient was severely immunocompromised at baseline, the opportunistic infection may reflect persistent immunodeficiency rather than treatment failure
Resistance Testing Requirements
Obtain genotypic resistance testing while the patient is still taking the failing regimen 1. If HIV RNA is too low for successful genotyping (<1000 copies/mL), proviral DNA analysis using deep sequencing may be used 1.
For InSTI-containing regimen failures, integrase resistance testing is mandatory 1. This is non-negotiable given the cross-resistance patterns within the InSTI class.
Post-Switch Monitoring
Check HIV RNA 4-6 weeks after any regimen change 1, 3. Continue monitoring every 3 months until suppression is sustained for at least 1 year, then every 6 months for adherent, stable patients 1.
For patients with prior NRTI resistance who switch to dual NRTI plus dolutegravir or bictegravir regimens, monitor more closely in the first year, especially if adherence concerns exist 1.
Special Considerations for Treatment-Experienced Patients
When changing therapy after failure, the strategy depends on treatment history 1:
- PI-naive patients: Have more options; can potentially use PI-based regimens
- PI-experienced patients with resistance: Require at least two new PIs due to cross-resistance within the class 1
- Extensive multiclass resistance including InSTIs: Novel agents like ibalizumab, fostemsavir, or lenacapavir are recommended, ideally with two fully active drugs 1
The key principle: change the entire regimen to drugs not previously taken when possible, using at least two and preferably three new drugs 1. Partial regimen changes risk rapid resistance development.