Antiretroviral Guidelines

US DHHS Guidelines with Australian commentary


Virologic Failure


Panel’s Recommendations


  • Assessing and managing a patient who is experiencing failure of antiretroviral therapy (ART) is complex. Expert advice is critical and should be sought.
  • Evaluation of virologic failure should include an assessment of adherence, drug-drug and drug-food interactions, drug tolerability, HIV RNA level and CD4 T lymphocyte (CD4) cell count trends over time, ART history, and prior and current drug-resistance test results.
  • Drug-resistance testing should be performed while the patient is taking the failing antiretroviral (ARV) regimen (AI) or within 4 weeks of treatment discontinuation (AII). Even if more than 4 weeks have elapsed since ARVs were discontinued, resistance testing can still provide useful information to guide therapy, although it may not detect previously selected resistance mutations (CIII).
  • The goal of treatment for ART-experienced patients with drug resistance who are experiencing virologic failure is to establish virologic suppression (i.e., HIV RNA levels below the lower limits of detection of currently used assays) (AI).
  • A new regimen should include at least two, and preferably three, fully active agents (AI). A fully active agent is one that is expected to have uncompromised activity on the basis of the patient’s ART history and his or her current and past drug-resistance test results. A fully active agent may also have a novel mechanism of action.
  • In general, adding a single ARV agent to a virologically failing regimen is not recommended, because this may risk the development of resistance to all drugs in the regimen (BII).
  • For some highly ART-experienced patients with extensive drug resistance, maximal virologic suppression may not be possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and delay clinical progression.
  • It is crucial to provide continuous adherence support to all patients before and after regimen changes due to virologic failure.
  • Preliminary data suggest that there is an increased risk of neural tube defects in infants born to individuals who were receiving dolutegravir (DTG) at the time of conception. In patients with virologic failure who are of childbearing potential, pregnancy testing should be performed before starting DTG (AIII).
  • For patients who are pregnant and within 12 weeks post-conception, or those who are of childbearing potential and who are not using effective contraception or who are contemplating pregnancy, the following factors should be considered:
    • If an alternative active ARV option to DTG exists, DTG should not be prescribed (AII).
    • If no alternatives exist, providers and individuals of childbearing potential should discuss the possible association between neural tube defects and DTG use during conception, and the risks of persistent viremia in the patient and HIV transmission to the fetus if pregnancy occurs while the patient is not on effective ART. The decision of whether to initiate or continue DTG should be made after careful consideration of these risks.
  • When it is not possible to construct a viable suppressive regimen for a patient with multidrug-resistant HIV, the clinician should consider enrolling the patient in a clinical trial of investigational agents or contacting pharmaceutical companies that may have investigational agents available.
  • When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs that are active against HBV should be continued as part of the new regimen. Discontinuation of these drugs may lead to the reactivation of HBV, which may result in serious hepatocellular damage.
  • Discontinuing or briefly interrupting therapy may lead to a rapid increase in HIV RNA, a decrease in CD4 cell count, and an increase in the risk of clinical progression. Therefore, this strategy is not recommended in the setting of virologic failure (AI).
    Rating of Recommendations: A = Strong; B = Moderate; C = Optional
    Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion