Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Management of the Treatment-Experienced Patient

Virologic Failure

Last Updated: December 18, 2019; Last Reviewed: December 18, 2019

Key Considerations and Recommendations Regarding Virologic Failure
Key Considerations and 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 ARV drugs 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 based on the patient’s ART history and 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 that are designed to minimize toxicity, preserve CD4 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.
  • Data from an observational study in Botswana suggest that there is an increased risk of neural tube defects (NTDs) in infants born to individuals who were receiving dolutegravir (DTG) at the time of conception; however, the risk of these defects is still low. In patients with virologic failure who are of childbearing potential and who are not using effective contraception or who are contemplating pregnancy, the following factors should be considered:
    • Clinicians should review Table 6b for information to consider when choosing to initiate or continue an integrase strand transfer inhibitor.
    • If there is an active ARV agent that can be used in place of DTG, DTG should not be prescribed (AII).
    • If no alternatives exist, providers and patients should discuss the possible risk of NTDs and weigh that risk against 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 carefully considering 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 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

Table 11. Antiretroviral Options for Patients with Virologic Failure

Designing a new regimen for patients who are experiencing treatment failure should always be guided by ARV history and results from current and past resistance testing. This table summarizes the text above and displays the most common or likely clinical scenarios seen in patients with virologic failure. For more detailed descriptions, please refer to the text above and/or consult an expert in drug resistance to assist in the design of a new regimen. It is also crucial to provide continuous adherence support to all patients before and after regimen changes.

Table 11. Antiretroviral Options for Patients with Virologic Failure
Clinical Scenario Type of Failing Regimen Resistance Considerations New Regimen Optionsa,b Goal
First Regimen Failure NNRTI plus two NRTIs Most likely resistant to NNRTI +/- 3TC or FTC (i.e., NNRTI mutations +/- M184V/I).c Additional NRTI mutations may also be present. Boosted PI plus two NRTIs (at least one active) (AIII); or

DTGd plus two NRTIs (at least one active) (AI); or

Boosted PI plus INSTI (AIII)
Resuppression
Boosted PI plus two NRTIs Most likely no resistance, or resistance only to 3TC or FTC (i.e., M184V/I, without resistance to other NRTIs)c Continue same regimen (AII); or

Another boosted PI plus two NRTIs (at least one active) (AII); or

INSTI plus two NRTIs (at least one active; if only one of the NRTIs is fully active, or if adherence is a concern, DTGd is preferred over other INSTIs) (AIII); or

Another boosted PI plus INSTI (BIII)
Resuppression
INSTI plus two NRTIs No INSTI resistance (can have 3TC or FTC resistance, i.e., only M184V/I, usually without resistance to other NRTIs)c Boosted PI plus two NRTIs (at least one active) (AIII); or

DTGd plus two NRTIs (at least one active) (AIII); or

Boosted PI plus INSTI (BIII)
Resuppression
EVG or RAL +/- 3TC or FTC resistance

Resistance to first-line BIC or DTG is rare.
Boosted PI plus two NRTIs (at least one active) (AIII); or

DTGd,e twice daily (if HIV is sensitive to DTG) plus two active NRTIs (AIII); or

DTGd,e twice daily (if HIV is sensitive to DTG) plus a boosted PI (AIII)

BIC has not been studied in this setting and cannot be recommended.
Resuppression
Second Regimen Failure and Beyond Drug resistance with active treatment options Use past and current genotypic +/- phenotypic resistance testing and ART history when designing new regimen. At least two, and preferably three, fully active agents (AI)

Partially active drugs may be used when no other options are available.

Consider using an ARV drug with a different mechanism of action.
Resuppression
Multiple or extensive drug resistance with few treatment options Use past and current genotypic and phenotypic resistance testing to guide therapy.

Consider viral tropism assay when use of MVC is considered.

Consult an expert in drug resistance, if needed.
Identify as many active or partially active drugs as possible based on resistance test results.

Consider using an ARV drug with a different mechanism of action.

Consider enrollment into clinical trials or expanded access programs for investigational agents, if available.

Discontinuation of ARV drugs is not recommended.
Resuppression, if possible; otherwise, keeping viral load as low as possible and CD4 count as high as possible.
ART-Experienced Patients with Suspected Drug Resistance and Limited or Incomplete ARV and Resistance History Unknown Obtain medical records, if possible.

Resistance testing may be helpful in identifying drug resistance mutations, even if the patient has been off ART. Keep in mind that resistance mutations may not be detected in the absence of drug pressure.
Consider restarting the old regimen, and obtain viral load and resistance testing 2–4 weeks after reintroduction of therapy.

If no ARV history is available, consider initiating a regimen with drugs with high genetic barriers to resistance (e.g., DTGd,e and/or boosted DRV).
Resuppression
a There are insufficient data to provide a recommendation for the continuation of 3TC or FTC in the presence of M184V/I.

b When switching an ARV regimen in a patient with 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.

c If other NRTI resistance mutations are present, use resistance test results to guide NRTI usage in the new regimen.

d Data from an observational study in Botswana suggest that there is an increased risk of NTDs in infants born to individuals who were receiving DTG at the time of conception; however, the risk of these defects is still low. Please refer to the discussion in the text and in Table 6b before prescribing DTG in persons of childbearing potential.

e Response to DTG depends on the type and number of INSTI mutations.

Key: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; CD4 = CD4 T lymphocyte; DRV = darunavir; DTG = dolutegravir; EVG = elvitegravir; FTC = emtricitabine; HBV = hepatitis B virus; INSTI = integrase strand transfer inhibitor; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; RAL = raltegravir

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