Virological Failure

Definition

• INCOMPLETE SUPPRESSION: HIV-VL > 50 copies/mL at 6 months after starting therapy in a person not previously on ART. In persons with very high baseline HIV-VL (> 100,000 copies/mL), achieving viral suppression may take longer than 6 months
• REBOUND: confirmed HIV-VL > 50 copies/mL in someone with previously undetectable HIV-VL

General measures

• Review expected potency of the regimen, taking into account all available historical genotypes
• Evaluate adherence, tolerability, drug-drug interactions, drug-food interactions, psychosocial issues
• Perform resistance testing preferably on failing therapy (usually routinely available for HIV-VL levels > 200-500 copies/mL and in specialised laboratories for lower levels of viraemia) and obtain historical resistance testing for archived mutations
• Tropism testing if considering MVC
• Consider TDM
• Review ART history
• Identify treatment options, active and potentially active drugs/combinations

Management of virological failure (VF)

If HIV-VL > 50 and < 200 copies/mL:

• Check for adherence, reinforce adherence
• Check HIV-VL 1 to 2 months later⁽ⁱ⁾
• If genotype shows no resistance mutations⁽ⁱⁱ⁾: maintain current ART if it contains INSTI with high barrier to resistance (BIC, DTG) or PI/b, otherwise monitor carefully

If HIV-VL confirmed > 200 copies/mL: 

• Check for adherence, reinforce adherence
• Switch for a new ART class pending resistance testing
• Therapeutic decision will depend on the resistance testing (genotype) results:
• If no resistance mutations found: check for adherence, reinforce adherence, perform TDM, discuss change to a different regimen
• If resistance mutations found: switch to a suppressive regimen based on drug and genotype history; multidisciplinary expert discussion advised in case of multiclass resistance
• Goal of new regimen: HIV-VL < 50 copies/mL within 6 months, sooner if possible

In case of demonstrated resistance mutations

General recommendations:

• Use at least 2 and preferably 3 fully active drugs in the new regimen (including active drugs from previously used classes) based on resistance mutations present in current and earlier genotypic analyses
• If genotype shows only limited NRTI mutation(s) e.g. M184V and/or 1-2 TAMs⁽ⁱⁱⁱ⁾: new regimen can include 2 NRTIs (3TC or FTC plus TDF or TAF) and either 1 active PI/b (i.e. DRV/b) or BIC or DTG (RAL or NNRTI not recommended)
• If genotype shows multiclass resistance (i.e. ≥ 2 classes): new regimen will usually use
  • at least 1 fully active PI/b (i.e. DRV/b) or 1 fully active 2nd generation INSTI (BIC, DTG)
  • plus 1 or 2 drugs remaining fully active despite resistance to other drugs from the class (i.e. 1 or 2 NRTIs and/or DOR)
  • and/or from a class not used previously i.e. INSTI, NNRTI, PI/b, assessed by genotypic testing
• When a 2-3 drugs active regimen cannot be constructed with NRTI, NNRTI, PI/b and INSTI, a drug with a new mechanism of action such as lenacapavir, maraviroc, fostemsavir or ibalizumab (where it is available on compassionate use) can be selected to obtain such a 2-3 drugs active regimen
• In any case monotherapy is not recommended
• If < 2 active drugs are available, discuss on case by case situation deferring change, except in persons with low CD4 count (< 100 cells/μL) or with high risk of clinical deterioration for whom the goal is the preservation of immune function through partial reduction of HIV-VL (> 1 log₁₀ copies/mL reduction) by recycling drugs
• Other considerations:
  • Treatment interruption is not recommended
  • Continuation of 3TC or FTC even if documented resistance mutation (M184V/I) might be beneficial
  • Consider enrolling the person in a clinical trial evaluating novel drugs
• If many options are available, criteria of preferred choice include: simplicity of the regimen, toxicity risks evaluation, drug-drug interactions, cost and sparing of future salvage therapy

 Footnotes

1. In the absence of resistance and in persons fully adherent to treatment, consider non-suppressible viremia due to cellular proliferation

2. Take into consideration that certain mutations may have reverted and/or no longer be detectable in the absence of drug pressure. Always refer to cumulative genotype

3. Thymidine Analog Mutations (TAMs) are non-polymorphic mutations selected by the thymidine analogs ZDV and/or d4T. For more detailed information on NRTI Resistance, see HIV Drug Resistance Database hivdb.stanford.edu/ or French ANRS resistance web page www.hivfrenchresistance.org