• Evaluate adherence, compliance, tolerability, drug-drug interactions, drug-food interactions, psychosocial issues
  
• Perform resistance testing on failing therapy (usually reliable with plasma HIV RNA levels >500-1000 copies/ml) and obtain historical resistance testing for archived mutations
  
• Consider TDM
  
• Review antiretroviral history
  
• Identify treatment options, active, potentially active drugs/combinations

If plasma HIV RNA > 50 and <500-1000 copies/ml

• Check for adherence
  
• Check plasma HIV RNA 1 to 2 months later
  
• Improve boosted PI's PK (if applicable)

If plasma HIV RNA confirmed > 500/1000 copies/ml, change regimen as soon as possible: what to change will depend on the resistance testing results:

• No resistance mutations found: re-check for adherence, perform TDM
  
• Resistance mutations found: switch to a suppressive regimen based on drug history; multidisciplinary experts discussion advised

Goal of new regimen: plasma HIV RNA < 400 c/ml after 3 months, plasma HIV RNA < 50 c/ml after 6 months

General recommendations:

• Use 2 or preferably 3 active drugs in the new regimen (including active drugs from previously used classes)
  
• Any regimen should use at least1 fully active PI/r (e.g. darunavir/r) plus 1 drug from a class not used previously e.g. fusion, integrase or CCR inhibitor (if tropism test shows R5 virus only), or 1 NNRTI (e.g. etravirine), assessed by genotypic testing
  
• Defer change if < 2 active drugs available, based on resistance data, except in patients with low CD4 count (<100/mm3) or with high risk of clinical deterioration for whom the goal is the preservation of immune function through partial reduction of Plasma HIV RNA (> 1 log reduction) by recycling.
  
• If limited options, consider experimental and new mechanistic drugs, favouring clinical trials (but avoid functional monotherapy)
  
• Treatment interruption is not recommended

Optimisation of new regimen:

• If demonstrated NRTI multiple resistance, avoid NRTI but
  
• Consider continuation of 3TC or FTC even if documented resistance mutation (M184V/I)
  
• Select 1 active ritonavir-boosted PI. If at all possible avoid double boosted PIs
  
• Etravirine potentially active in selected NNRTI-mutation profiles
  
• Always check for drug-drug-interactions, and when necessary perform TDM of drugs of new regimen if available

If many options are available, criteria of preferred choice include: simplicity of the regimen, toxicity risks evaluation, drug-drug-interactions, future salvage therapy