Virologic Failure

Last Updated: October 25, 2018; Last Reviewed: October 25, 2018

Panel's Recommendations Regarding Virologic Failure of the Treatment-Experienced Patient

Panel’s Recommendations

Designing a new regimen for patients with 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.

Preliminary data from Botswana suggested that there is an increased risk of NTDs in infants born to individuals who were receiving DTG at the time of conception.^47,48 Pregnancy testing should therefore be performed for those of childbearing potential prior to initiation of DTG. If there is an alternative option, DTG should not be prescribed for those who are pregnant and within 12 weeks post-conception or those who are of childbearing potential and who are planning to become pregnant or who are not using effective contraception. When DTG is the only treatment option, or one of few treatment options, providers should counsel individuals who are pregnant or of childbearing potential about the possible association between NTDs and DTG use during conception. The decision of whether to initiate or continue DTG should be made after careful consideration of this risk 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.

Clinical Scenario	Type of Failing Regimen	Resistance Considerations	New Regimen Options^a,b	Goal
First Regimen Failure	NNRTI plus 2 NRTIs	Most likely resistant to NNRTI +/- 3TC/FTC (i.e., NNRTI mutations +/- M184V/I).^c Additional NRTI mutations may also be present.	Boosted PI plus 2 NRTIs (at least 1 active) (AIII); or DTG^d plus 2 NRTIs (at least 1 active)(AI); or Boosted PI plus INSTI (AIII)	Resuppression
	Boosted PI plus 2 NRTIs	Most likely no resistance, or resistance only to 3TC/FTC (i.e., M184V/I, without resistance to other NRTIs)^c	Continue same regimen (AII); or Another boosted PI plus 2 NRTIs (at least 1 active)(AII); or INSTI plus 2 NRTIs (at least 1 active; if only 1 of the NRTIs is fully active, or, if adherence is a concern, DTG^d is preferred over the other INSTIs)(AIII); or Another boosted PI plus INSTI (BIII)	Resuppression
	INSTI plus 2 NRTIs	No INSTI resistance (can have 3TC/FTC resistance, i.e., only M184V/I, usually without resistance to other NRTIs)^c	Boosted PI plus 2 NRTIs (at least 1 active) (AIII); or DTG^d plus 2 NRTIs (at least 1 active)(AIII); or Boosted PI plus INSTI (BIII)	Resuppression
		EVG or RAL +/- 3TC/FTC resistance Resistance to first-line BIC or DTG is rare	Boosted PI plus 2 NRTIs (at least 1 active) (AIII); or DTG^d,e twice daily (if patient is sensitive to DTG) plus 2 active NRTIs (AIII); or DTG^d,e twice daily (if patient is sensitive to DTG) plus a boosted PI(AIII) BIC has not been studied in this setting andcannot 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 in designing new regimen	At least 2, and preferably 3, fully active agents (AI) Partially active drugs may be used when no other options are available Consider using an ARV with a different mechanism of action	Resuppression
Second Regimen Failure and Beyond	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 if 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 with a different mechanism of action Consider enrollment into clinical trials or expanded access programs for investigational agents, if available Discontinuation of ARVs is not recommended.	Resuppression, if possible; otherwise, keeping viral load as low as possible and CD4 cell count as high as possible
Previously on Treatment, Suspected Drug Resistance, Limited or Incomplete ART 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 there is no available ARV history, consider initiating a regimen with drugs with high genetic barriers to resistance (e.g., DTG^d,e and/or boosted DRV)	Resuppression
^a There are insufficient data to provide a recommendation for the continuation of 3TC/FTC in the presence of M184V/I. ^b When switching an ARV regimen in a patient with HIV/HBV 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 Preliminary data from Botswana suggested that there is an increased risk of NTDs in infants born to those who were receiving DTG at the time of conception.^47,48 Pregnancy testing should therefore be performed for those of childbearing potential prior to initiation of DTG. Please refer to the discussion at the beginning of this table for further recommendations. ^e Response to DTG depends on the type and number of INSTI mutations. Key to Acronyms: 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


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. Data from an observational study in Botswana 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: Clinicians should review the table Considerations Before Initiating Dolutegravir and Other Integrase Strand Transfer Inhibitors as Initial Therapy for Persons of Childbearing Potential for information to consider when choosing to initiate or continue an integrase strand transfer inhibitor 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

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.
Data from an observational study in Botswana 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:
- Clinicians should review the table Considerations Before Initiating Dolutegravir and Other Integrase Strand Transfer Inhibitors as Initial Therapy for Persons of Childbearing Potential for information to consider when choosing to initiate or continue an integrase strand transfer
  inhibitor
- 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