Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy

INTRODUCTION — The standard of care in HIV management is to maximally suppress plasma HIV RNA to prevent HIV disease progression and the emergence of drug-resistant virus. Achieving virologic suppression can be difficult for HIV-infected patients with drug-resistant virus; however, advances in drug development have enabled great progress in the treatment of this patient population, even among those who have resistance to one or two classes of antiretroviral agents.

This topic will discuss how to select a combination antiretroviral therapy regimen for treatment-experienced patients who are failing therapy. Topic reviews that provide an overview of drug resistance testing and discuss how to evaluate treatment-experienced patients failing therapy are presented elsewhere. (See "Overview of HIV drug resistance testing assays" and "Interpretation of HIV drug resistance testing" and "Evaluation of the treatment-experienced patient failing HIV therapy".)

GOALS OF THERAPY — The goal of antiretroviral therapy (ART) is to suppress the viral load to below the level of detection using most commercial assays. Maintaining an undetectable viral load helps prevent disease progression, improve survival, prevent the emergence of drug-resistant virus, and reduce the risk of transmitting HIV to others.

Minimizing the viral load is best achieved with the use of an ART regimen that consists of two to three fully active agents from at least two different classes of drugs [1]. Among patients with virologic failure and drug-resistant virus, this goal can still be achieved even if fewer than two to three active agents are used; however, the likelihood of virologic suppression depends upon the drugs used and number and types of drug-resistant mutations that are present.

Patients with drug-resistant virus who are failing an initial regimen that includes a first-line nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), an integrase strand transfer inhibitor (INSTI), or a pharmacologically boosted protease inhibitor (PI) are likely to achieve viral suppression with their subsequent regimen. These first-line regimens are less likely to result in highly resistant virus compared with older regimens that were less potent. For patients with drug-resistant virus who have failed multiple regimens, the treatment goal is still to decrease the viral load to below the level of detection, and if this is not attainable, to the lowest level possible.

DRUGS BY CLASS AND ABBREVIATIONS USED — The common names and abbreviations of currently available antiretroviral agents are listed by class in a separate table (table 1).

INITIAL EVALUATION — The initial evaluation of a patient with virologic failure includes an assessment of adherence to the failing regimen as well as the HIV resistance profile. The presence of resistant virus is determined through the results of resistance tests (eg, genotype, phenotype) and the ART treatment history. For patients requiring a change in their regimen, the resistance profile and the patient's underlying comorbidities (eg, kidney, cardiovascular disease, and mental health disorders) impact which agents to use. These patients should be managed in consultation with an expert HIV provider. A detailed discussion of the initial evaluation of patients failing their ART regimen is found elsewhere. (See "Evaluation of the treatment-experienced patient failing HIV therapy", section on 'Initial evaluation'.)

PATIENTS WITHOUT DRUG-RESISTANT VIRUS — Certain patients will have virologic failure without the presence of drug-resistant virus. These patients should first be assessed for adherence, drug-drug interactions (eg, proton pump inhibitors with atazanavir or rilpivirine), or drug-food interactions (eg, rilpivirine needing to be taken with food). If necessary, the regimen can be modified to another first-line regimen. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

If there are no concerns regarding drug-drug or drug-food interactions, the patient is most likely non-adherent to their regimen. Every effort should therefore be made to enhance adherence with the drug regimen (table 2 and table 3 and table 4).

●For some patients, this may require modifying the initial antiretroviral therapy regimen to minimize toxicity and/or ease of dosing.

●For others, appropriate treatment should be initiated to address behavioral barriers to adherence (eg, depression, substance use).

Until the time when the patient is adequately adherent with their antiviral regimen, we prefer a regimen that includes a pharmacologically boosted protease inhibitor (PI) since boosted PIs are less likely to select for drug-resistant virus in the face of continued poor adherence. There is increasing evidence that dolutegravir with two NRTIs may have similar properties, allowing this regimen to be considered as well. The single-pill regimen bictegravir/emtricitabine/tenofovir alafenamide may also have this low risk of treatment-emergent resistance, though there are fewer data than with dolutegravir. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Patients with adherence concerns'.)

PATIENTS WITH DRUG-RESISTANT VIRUS — Most patients with drug-resistant virus will require a change in their regimen. The selection of HIV therapy in the context of drug resistance can be challenging and should generally be undertaken in consultation with an HIV specialist. When choosing a new regimen, it is important to evaluate the patient's past antiretroviral therapy (ART) history, as well as the results of previous and current genotype and/or phenotype drug resistance tests, to determine which agents are likely to be fully or partially active. A detailed discussion of HIV resistance mutations is found elsewhere. (See "Interpretation of HIV drug resistance testing".)

General principles — We follow these general principles to help guide the selection of a regimen that will result in sustained viral suppression:

●For most patients, the integrase strand transfer inhibitor (INSTI) dolutegravir and/or a pharmacologically boosted protease inhibitor (PI) should be used as part of the new regimen. (See 'Patients failing their initial regimen' below and 'If a fully active PI is available' below and 'Protease inhibitors' below.)

•Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) can contribute to a suppressive regimen when used with dolutegravir or a fully active pharmacologically boosted PI. The choice of dolutegravir or a pharmacologically boosted PI depends in part upon the availability of at least one active NRTI. (See 'Nucleoside/nucleotide reverse transcriptase inhibitors' below.)

•Dolutegravir plus a pharmacologically boosted PI can be used together as dual therapy if the drugs are sufficiently active, especially if an NRTI cannot be used (eg, toxicity). (See 'Patients failing their initial regimen' below and 'If a fully active PI is available' below.)

●If dolutegravir or a pharmacologically boosted PI is not an option, we administer a regimen consisting of three active agents from at least two drug classes. For such patients, NRTIs are not necessarily needed if there are sufficiently active drugs from other classes included in the regimen [2]. (See 'If a fully active PI is NOT available' below.)

●We do not add a single active agent to a failing regimen. (See 'Management of patients with incomplete viral suppression' below.)

●Treatment interruption is not recommended as an option for the management of virologic failure. (See 'Management of patients with incomplete viral suppression' below.)

There are additional factors that can influence the choice of regimen, such as kidney or cardiovascular disease, osteoporosis, and the presence of chronic hepatitis B virus infection. However, if treatment choices are limited due to multidrug-resistant virus, these comorbidities may have less impact on the choice of regimen as compared with those who have more treatment options. (See 'Overview of specific antiretroviral agents' below.)

Patients failing their initial regimen — Many patients with drug-resistant virus are failing an initial first-line regimen that includes an NRTI combination (eg, tenofovir-emtricitabine or abacavir-lamivudine) and one of the commonly used third agents (eg, an NNRTI, an INSTI, or a pharmacologically boosted PI). (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".).

Patients who receive an NNRTI or an INSTI (other than dolutegravir and probably bictegravir) as part of their initial regimen typically have virus that has become resistant to lamivudine or emtricitabine (ie, have the M184I/V mutation) [3-5]. These patients may also have resistance to the other NRTI in the regimen. As an example, in low and middle income regions, the prevalence of tenofovir resistance (eg, K65R/N or K70E/G/Q) in patients failing an initial tenofovir-based regimen can be as high as 57 percent [3].

Some patients will also have NNRTI or INSTI resistance, although the latter is rare for patients receiving a first-line regimen that includes dolutegravir or bictegravir plus two NRTIs. Those treated with an initial regimen that includes an NRTI combination plus a pharmacologically boosted PI, dolutegravir, or bictegravir often experience virologic failure with either no resistance or, occasionally in those on boosted PIs, the M184V mutation; PI, dolutegravir, and bictegravir resistance is rare. (See "Interpretation of HIV drug resistance testing".)

This section provides guidance for the management of treatment failure in select scenarios.

NNRTI-containing regimens — For patients who experience virologic failure with drug-resistant virus while receiving an initial NNRTI-containing regimen, we typically recommend a new regimen that includes an NRTI combination plus either dolutegravir or a pharmacologically boosted PI:

●If there is evidence that at least one of the preferred NRTIs (ie, tenofovir, abacavir, emtricitabine/lamivudine) is active based upon both treatment history and genotype testing, we administer an NRTI combination (tenofovir-emtricitabine or abacavir-lamivudine) with dolutegravir as the third agent. If abacavir and tenofovir are both active, we prefer tenofovir-emtricitabine as the NRTI combination since there is more experience with tenofovir-emtricitabine plus dolutegravir in treatment-experienced patients [6,7]. We do not use tenofovir and abacavir together. (See 'Nucleoside/nucleotide reverse transcriptase inhibitors' below.)

●If a genotype test is not available, we continue the patient's NRTI combination and use a pharmacologically boosted PI as the third agent. If there are no viable active NRTIs, we will typically use a pharmacologically boosted PI plus an INSTI with or without NRTIs.

•In this setting, the decision regarding which NRTIs to use is based upon issues of convenience and tolerability rather than resistance patterns. We also modify the NRTI combination if a more potent combination is available. (See 'Nucleoside/nucleotide reverse transcriptase inhibitors' below.)

•We generally prefer pharmacologically boosted darunavir as the PI for tolerability reasons, even though clinical trials in this setting have most often included lopinavir/ritonavir [8,9]. (See 'Protease inhibitors' below.)

●An NRTI-sparing regimen that includes a pharmacologically boosted PI plus an active INSTI (eg, pharmacologically boosted darunavir plus dolutegravir) is an alternative for patients who cannot take either first-line NRTI combinations. Although lopinavir/ritonavir plus raltegravir has been tested in prospective clinical trials of treatment failure, we prefer the combination of boosted darunavir plus dolutegravir, since this combination includes the two drugs from these classes with the highest resistance barriers.

If the preferred regimen or the NRTI sparing regimen described above cannot be used, a regimen that includes at least two, and preferably three, fully active agents should be constructed. (See 'If a fully active PI is NOT available' below.)

For patients failing an initial NNRTI regimen, clinical trial data support the use of a pharmacologically boosted PI with either an NRTI combination or an INSTI. In two randomized studies, which together evaluated over 1000 patients, individuals failing an initial regimen that included an NRTI backbone plus an NNRTI were switched to a new regimen consisting of pharmacologically boosted lopinavir plus either two to three NRTIs or raltegravir [8-10]. Approximately 80 percent of these patients were able to achieve a viral load <400 copies/mL, regardless of which regimen they received, and in one study, approximately 75 percent had a viral load <50 copies/mL [9]. Virologic suppression was achieved among those receiving the NRTI regimen even when no fully active NRTIs were included in the regimen [8,9,11]. The latter observation makes a regimen that includes a pharmacologically boosted PI the preferred option for those with extensive NRTI resistance or when resistance data are not available.

A trial in patients failing an initial NNRTI plus two NRTIs found that dolutegravir had superior efficacy to pharmacologically boosted lopinavir when used in combination with two NRTIs, at least one of which was fully active [12]. In this open-label randomized study that was conducted in 13 countries, 624 patients without evidence of resistance to PIs or INSTIs received two NRTIs (at least one was fully active) with either dolutegravir or pharmacologically boosted lopinavir. At 24 weeks, significantly more patients who received dolutegravir had virologic suppression (82 versus 69 percent, adjusted difference 13.8 percent, 95% CI: 7.3 to 20.3 percent). In addition, those who received dolutegravir were less likely to have virologic failure (6 versus 18 patients), which was defined as a viral load >400 copies/mL on two occasions. Based upon these findings, the data safety monitoring board recommended that pharmacologically boosted lopinavir be discontinued as the third agent. The overwhelming majority of patients in this trial received tenofovir-emtricitabine, zidovudine-lamivudine, or tenofovir plus zidovudine, with only 2 percent receiving abacavir-lamivudine. Although abacavir plus lamivudine may be an effective NRTI combination for this strategy, the limited data from the trial would make it a secondary option if other NRTI combinations are available.

INSTI-containing regimen — For patients with drug-resistant virus failing an initial INSTI-containing regimen, we typically prefer a regimen that contains:

●Two nucleoside reverse transcriptase inhibitors plus

●A pharmacologically boosted protease inhibitor

Most studies of first-line failures that support the use of a pharmacologically boosted PI plus an NRTI combination have evaluated patients failing an initial NNRTI-containing regimen [8,9,11]; however, virologic suppression should also be observed in patients failing an initial INSTI-containing regimen. When choosing specific agents, the approach is similar to the one described above (eg, the NRTIs can be continued and the INSTI can be switched to pharmacologically boosted darunavir). (See 'NNRTI-containing regimens' above and 'Protease inhibitors' below.)

Although data are limited, dolutegravir may also have a role for certain patients failing an initial INSTI-containing regimen if genotypic testing for integrase resistance is performed:

●If no INSTI mutations are detected, patients can be switched to dolutegravir (50 mg once daily) plus either two NRTIs (with at least one being fully active) or a pharmacologically boosted PI.

●In patients with resistance to raltegravir or elvitegravir, dolutegravir should not be used if there are integrase mutations at codon Q148 along with two or more secondary mutations, since the level of dolutegravir activity is decreased in this setting. For others, dolutegravir (50 mg twice daily) can be used if the regimen includes a pharmacologically boosted PI or at least two other fully active drugs from other classes.

Additional information on the use of INSTIs in patients failing therapy is found below. (See 'Integrase strand transfer inhibitors' below.)

A pharmacologically boosted PI — Patients rarely develop drug-resistant virus while taking an initial regimen that contains a pharmacologically boosted protease inhibitor (PI) with NRTIs. A minority of individuals will develop virus with resistance to emtricitabine or lamivudine. For such patients, the principal reason for failure is likely to be a lack of adherence. Thus, we typically continue their initial regimen and work with the patient to improve their ability to take daily therapy. We switch to an alternative pharmacologically boosted PI or dolutegravir if there are problems with tolerability or drug-drug interactions. This approach is similar to that used for patients without drug-resistant virus. (See 'Patients without drug-resistant virus' above.)

Patients who have failed multiple regimens — Our approach to patients who have failed multiple regimens is defined by the activity of a pharmacologically boosted PI and dolutegravir. Decreased drug susceptibility to a pharmacologically boosted PI generally requires the accumulation of multiple mutations. Thus, a pharmacologically boosted PI can have full or partial activity depending upon the number and type of mutations present. PI-associated mutations are classified as either primary (major) or secondary (minor), and resistance to one PI does not necessarily confer resistance to all of the PIs. More detailed discussions of PI resistance are found elsewhere. (See 'Protease inhibitors' below and "Interpretation of HIV drug resistance testing", section on 'Protease inhibitors'.)

The management of patients with drug-resistant virus who have failed multiple regimens, especially those who have PI resistance, can be complicated. These patients should be managed in conjunction with an experienced HIV provider.

If a fully active PI is available — Many patients who have failed multiple regimens will still have virus that is fully sensitive to first-line pharmacologically boosted protease inhibitors (PIs), since these agents have a high barrier to resistance. The management of these patients is similar to the management of patients failing their initial regimen. (See 'Patients failing their initial regimen' above.)

For such patients, we administer a pharmacologically boosted PI and add an NRTI combination such as tenofovir-emtricitabine or abacavir-lamivudine. We use a NRTI combination even if there is evidence of nucleoside resistance since the addition of these agents appears to improve the durability of virologic suppression when a fully active pharmacologically boosted PI is used to treat patients with virologic failure [9,13]. The choice of which NRTI to use depends on resistance pattern and upon the presence or absence of certain patient characteristics (eg, reduced kidney function, presence of the HLA-B*5701 allele). (See 'Nucleoside/nucleotide reverse transcriptase inhibitors' below.)

For patients who cannot tolerate nucleosides, we use a pharmacologically boosted PI with an INSTI if there is no evidence of resistance to these agents. Although data are limited, a pharmacologically boosted PI with etravirine (if susceptible) may be an alternative regimen for these patients if an INSTI is not an option due to intolerance or resistance. (See 'Integrase strand transfer inhibitors' below and 'Non-nucleoside reverse transcriptase inhibitors' below.)

There have been limited data treating those with PI resistance who have genotypically or phenotypically predicted susceptibility to newer agents in the class (eg, boosted darunavir). In one open-label study, 545 INSTI-naïve patients who were failing a boosted lopinavir regimen underwent drug resistance testing, and 224 had resistance to boosted lopinavir but predicted susceptibility to boosted darunavir [14]. Approximately 90 percent of these patients achieved virologic suppression to <200 copies/mL when they were switched to boosted darunavir with raltegravir and either best available NRTIs or etravirine (if the latter was predicted to be susceptible).

If a fully active INSTI is available — Some patients who have failed multiple regimens, especially those treated in the 1990s and early 2000s, may still be INSTI naïve. The management of these patients is similar to the management of patients failing their initial regimen. (See 'Patients failing their initial regimen' above.)

This includes the use of dolutegravir, in combination with either:

●Two NRTIs if one of the NRTIs is fully active (based upon treatment history and drug resistance testing), or

●A fully active pharmacologically boosted PI

The approach to patients who have failed multiple regimens and are INSTI experienced is less clear. If there are no INSTI mutations detected, one might be able to extrapolate from the experience with NNRTI failures (ie, dolutegravir plus two NRTIs if one of them remains fully active) (see 'INSTI-containing regimen' above). However, experience is limited, and this approach would be less optimal if there is an effective alternative until more data are available.

If a fully active PI is NOT available — Although uncommon, there are certain individuals who have drug-resistant virus where a fully active protease inhibitor (PI) may not be available. This scenario is typically seen in patients who were treated with unboosted PIs in the past. Patients treated with amprenavir and fosamprenavir may present a particular challenge, as these drugs selected for resistance to darunavir. (See "Interpretation of HIV drug resistance testing", section on 'Protease inhibitors'.)

In this setting, the best data suggest that virologic suppression is most likely achieved if the patient is INSTI naïve and dolutegravir can be combined with two NRTIs (with at least one being fully active). Alternatively, a regimen that includes at least two, and preferably three, fully active agents from at least two drug classes can be used. (See 'Overview of specific antiretroviral agents' below.)

For such patients, additional testing may be needed to determine if fully or partially active drugs in existing classes are available. As examples:

●For those who are treatment-naïve to NNRTIs, INSTIs, and/or T-20, these agents would be considered to be fully active options for a subsequent regimen, unless they are known to have transmitted resistance. (See "Interpretation of HIV drug resistance testing".)

However, if a patient has received these agents in the past, resistance may be present. Genotypic and phenotypic resistance testing can be useful to determine their potential role in a subsequent regimen if the patient is receiving these drugs when resistance testing is performed. Not all routine resistance tests will assess INSTI or T-20 resistance; thus, it is important to specifically request that these tests be performed if these agents are being considered.

●If a CCR5 antagonist is being considered as part of the next regimen, we obtain a tropism assay to exclude the presence of CXCR4-using viruses that would render this class of drugs inactive. (See 'CCR5 antagonists' below.)

When combining agents from different classes of drugs, it is important to assess for drug-drug interactions. As examples, the dose of dolutegravir should be increased to 50 mg twice daily if used with tipranavir/ritonavir, and if dolutegravir is used with etravirine, a pharmacologically boosted PI should be included in the regimen (see 'Overview of specific antiretroviral agents' below). Additional information on drug interactions can be obtained by using the Lexi drug interaction program within UpToDate.

On rare occasions, there are patients with extensive resistance to multiple classes, including boosted PIs, NRTIs, and even NNRTIs. These patients often have CXCR4-using viruses and may have only an INSTI as a fully active agent. When looking for an active drug in another class to use along with the INSTI and potentially recycled NRTIs, it may be reasonable to use the monoclonal antibody ibalizumab. This agent should be used in combination with other antiretrovirals and is administered intravenously every two weeks [15]. In one trial that evaluated 40 patients with multidrug-resistant virus, approximately 50 percent achieved a viral load <200 copies/mL at week 25 [16].

If full suppression is unlikely in patients with multidrug-resistant virus, care should be used to design a regimen that will provide partial suppression, but not necessarily select for resistance to agents that may be important in the future when new drugs (eg, attachment inhibitors, maturation inhibitors, neutralizing antibody) become available. Some of the new agents may be accessed through clinical trials or expanded access programs; a listing of these trials can be found at www.clinicaltrials.gov. The management of patients with incomplete viral suppression is discussed below. (See 'Management of patients with incomplete viral suppression' below.)

Considerations in persons of childbearing potential/persons who are pregnant — When changing a regimen in persons with virologic failure who are of childbearing potential or are pregnant, physicians must carefully consider the risks and benefits of the different regimens and share these considerations with the patient. As an example, there appears to be a small but increased risk of neural tube defects in infants of mothers who use dolutegravir around the time of conception, and there are limited data on the use of bictegravir and tenofovir alafenamide in pregnancy. Detailed discussions of the safety of antiretroviral medications in these populations are presented elsewhere. (See "HIV and women", section on 'Individuals of childbearing potential' and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Integrase inhibitors' and "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'ART selection and management' and "Prevention of vertical HIV transmission in resource-limited settings".)

VIRAL LOAD MONITORING — It is important to closely monitor the patient's plasma HIV RNA level, also known as viral load, after starting a new antiretroviral regimen to determine its ability to adequately suppress the virus. For treatment-experienced patients with drug-resistant virus, we obtain viral load testing four weeks after initiating the new regimen. We then continue to monitor the viral load at four- to eight-week intervals until the level falls below the assay's limit of detection.

●If there is <1 log₁₀ drop in viral load by week 4 and/or if it is not declining over the ensuing months to <200 copies/mL by 12 to 24 weeks, we inquire about the patient's adherence, and review potential drug-drug or drug-food interactions. (See 'Patients without drug-resistant virus' above.)

●If the viral load is >200 copies/ml after 12 weeks (and certainly by 24 weeks), it is possible that the virus is or will become resistant to the new regimen [17,18]. However, resistance testing cannot be done unless the viral load is >500 copies/mL. (See "Overview of HIV drug resistance testing assays".)

For such patients with a viral load >200 copies/mL and <500 copies/mL at 24 weeks, we reassess their prior resistance tests as well as their previous antiretroviral regimens. For such patients:

•We modify the individuals ART regimen if a more potent regimen can be constructed.

•If a more potent regimen is not available, we follow the viral load every two to three months and perform drug resistance testing when the viral load reaches >500 copies/mL.

●If the HIV RNA is >500 copies/mL by week 12 to 24, we test for new resistance mutations. (See "Overview of HIV drug resistance testing assays".)

A more general overview of patient monitoring for individuals receiving ART is found elsewhere. (See "Patient monitoring during HIV antiretroviral therapy".)

MANAGEMENT OF PATIENTS WITH INCOMPLETE VIRAL SUPPRESSION — On rare occasion, full virologic suppression is not achievable due to multiple drug resistance mutations or intolerance. Incomplete suppression is defined as two viral loads >200 copies/mL, at least 4 weeks apart, 24 weeks after initiating a new regimen [1]. For such patients, we continue ART even if a new fully suppressive regimen is not available.

Studies have found that treatment discontinuation in patients with incomplete viral suppression is associated with negative clinical and virologic outcomes [19-22]. The benefit of continuing a partially suppressive regimen may be due, in part, to highly resistant virus often being less fit. Less fit virus replicates slower than wild type virus, resulting in a lower viral load [23], and is usually seen in patients taking nucleoside/tide reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) [19,24-26]. As an example, in patients with the M184V mutation, higher levels of viremia are observed if lamivudine or emtricitabine is stopped. This is due, at least in part, to drug-resistant virus with the M184V mutation being replaced by wild-type virus that has an increased replication capacity [19,24].

Most patients with incomplete viral suppression are maintained on a regimen consisting of one or more NRTIs plus a pharmacologically boosted PI. We generally discontinue non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and T-20 if they are being used. These agents are unlikely to make the virus less fit, and their continued use can result in toxicity, or the emergence of additional resistance mutations that may prevent the use of future novel treatments [27]. It is important to perform resistance testing prior to discontinuing these agents in a partially suppressed patient in order to assess their potential utility as part of a future regimen when new options become available.

We typically do not add a single active agent in the setting of incomplete viral suppression. We prefer to retain the single active agent for use as part of a future, more active treatment regimen. Instead, we continue to administer a partially suppressive ART regimen if there are no other satisfactory treatment options available. These decisions are complex and should be made in close consultation with an expert in managing highly treatment-experienced patients.

OVERVIEW OF SPECIFIC ANTIRETROVIRAL AGENTS — For treatment-experienced patients failing therapy, commonly used classes of drugs include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), pharmacologically boosted protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Certain classes of drugs are less commonly used, but at times are necessary depending upon the amount of drug resistance present; these include the fusion inhibitor T-20, the CCR5 antagonist maraviroc, and the post-attachment inhibitor ibalizumab. A more detailed discussion of the antiretroviral agents used to treat HIV is found elsewhere. (See "Overview of antiretroviral agents used to treat HIV".)

When combining agents from different classes of drugs, it is important to assess for drug-drug interactions. These can be evaluated using the Lexi drug interaction program within UpToDate.

Nucleoside/nucleotide reverse transcriptase inhibitors

●Available agents – The two most commonly used NRTI combinations are tenofovir-emtricitabine and abacavir-lamivudine. If abacavir and tenofovir are both active, we prefer tenofovir-emtricitabine as the NRTI combination since there is more experience with tenofovir-emtricitabine in treatment-experienced patients. Furthermore, the most common NRTI resistance mutation, M184V, reduces susceptibility to abacavir, while improving activity of tenofovir. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

There are two NRTI combinations that include tenofovir, tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) and a newer formulation, tenofovir alafenamide-emtricitabine (TAF-FTC). When using a tenofovir-containing regimen, we typically use TAF-FTC, since TAF is associated with less bone and kidney toxicity compared with TDF and appears to be equally effective in maintaining virologic suppression [28-30]. Exceptions include pregnancy (where there is not enough clinical experience with the newer tenofovir formulation), and in the setting of certain drug interactions (eg, some anticonvulsants and maybe rifamycins) that can lower TAF, but not TDF, levels. (See "Safety and dosing of antiretroviral medications in pregnancy" and "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

In an open-label, randomized study of 135 virologically suppressed patients with a history of drug-resistant virus, patients were continued on their current regimen (which typically included TDF) or were switched to a TAF-containing regimen [28]. None of the patients who were switched to a TAF-containing regimen had virologic breakthrough. This study, as well as other larger switch studies in virologically suppressed patients, have noted improvements in renal and/or bone parameters when TAF was used as part of the NRTI combination [29].

●Choice of NRTI combination – Several factors can influence the decision regarding which NRTI combination to use. As examples:

•HLA-B*5701-positive – Abacavir is contraindicated in patients who are positive for the HLA-B*5701 allele. (See "Abacavir hypersensitivity reaction".)

•Reduced kidney function – In general, the NRTI combination tenofovir disoproxil fumarate-emtricitabine should not be used for patients with an estimated glomerular filtration rate <60 mL/min/1.73 m², and the NRTI combination tenofovir alafenamide-emtricitabine should not be used for patients with an estimated glomerular filtration rate <30 mL/min/1.73 m². However, in a patient with multidrug-resistant virus, the risk of further renal insufficiency must be weighed against the likelihood of achieving virologic suppression. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

•Chronic hepatitis B virus – In the setting of chronic hepatitis B virus infection, the NRTI combination tenofovir (disoproxil fumarate or alafenamide) -emtricitabine should be used unless contraindicated. (See "Treatment of chronic hepatitis B in patients with HIV".)

•Other considerations include cardiovascular risk (some data suggest this may be increased with use of abacavir) and osteopenia/osteoporosis, which is more negatively affected by tenofovir disoproxil fumarate (although not tenofovir alafenamide). (See "Overview of antiretroviral agents used to treat HIV", section on 'Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)'.)

We typically do not use zidovudine (it is less potent than the other NRTIs and has more toxicity). However, there may be a benefit of using zidovudine in the presence of the K65R mutation in select patients who have difficulty achieving viral suppression with other available options. (See "Interpretation of HIV drug resistance testing", section on 'Nucleoside reverse transcriptase inhibitors'.)

We also avoid using tenofovir and abacavir together, since there are insufficient data to recommend the use of this combination in treatment-experienced patients. In addition, data in treatment-naïve patients suggest this combination may be associated with an increased risk of virologic failure [31].

Protease inhibitors — The choice of which PI to use in the setting of treatment failure depends upon the number of PI mutations present in the patient's virus:

●If a genotype shows no PI mutations, any PI can be used. We prefer pharmacologically boosted darunavir since it is as active as other PIs and is generally better tolerated [32,33]. For patients without darunavir resistance mutations, darunavir can be administered once daily.

There are additional important factors when considering which PI to use:

•We do not administer darunavir to treatment-experienced patients with a severe sulfa allergy (eg, rash with systemic symptoms, immediate-type allergy, Stevens-Johnson syndrome) since darunavir contains a sulfonamide moiety. Although most patients with a sulfonamide allergy are reportedly able to tolerate darunavir (it lacks one or both essential functional groups implicated in sulfonamide antibiotic hypersensitivity), for such patients, we prefer using a different PI. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Cross-reactivity'.)

•An alternative PI to darunavir is pharmacologically boosted atazanavir. This agent should not be used in patients who require a proton pump inhibitor using a dose equivalent to >20 mg omeprazole per day since this lowers the level of atazanavir. It should also be used cautiously in those with renal disease since adverse reactions include the development of renal stones and chronic renal impairment. (See "Overview of kidney disease in patients with HIV", section on 'Medication nephrotoxicity'.)

Either ritonavir or cobicistat can be used as a pharmacological-boosting agent with once-daily darunavir or atazanavir. Both ritonavir and cobicistat have significant drug interactions. A more detailed discussion on pharmacokinetic boosting is found elsewhere.

●If the patient has ≥2 PI mutations, darunavir or tipranavir are the agents that are most likely to have activity. If possible, we avoid tipranavir since this agent can be associated with hepatotoxicity and intracranial hemorrhage. The optimal antiviral activity of these agents depends upon the number of mutations:

•Optimal antiviral activity with darunavir is seen in patients with <3 of the following mutations: 11I, 32I, 33F, 47V, 50V, 54L/M, 73S, 76V, 84V, and 89V [34].

•Optimal antiviral activity with tipranavir is seen in patients with less <2 of the following mutations: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V [35].

The dose of darunavir also depends upon which drug resistance mutations are present.

•We administer darunavir twice daily (600 mg darunavir plus 100 mg ritonavir) if any of the following darunavir resistance mutations are present: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, or L89V. Cobicistat should not be used as a boosting agent for patients who require twice-daily dosing of darunavir.

•Darunavir can be given once daily (800 mg darunavir with 100 mg ritonavir or 150 mg cobicistat) if there are no darunavir mutations, even if there is resistance to other agents [36].

We do not administer two PIs within a combination regimen; this approach is associated with substantial toxicity, complex drug-drug interactions, and no clinical benefit [37].

Integrase strand transfer inhibitors — If an INSTI is used, we generally prefer dolutegravir or bictegravir (bictegravir is only available as bictegravir/emtricitabine/tenofovir alafenamide single-tablet regimen), although any of the INSTIs can be used for treatment-experienced patients if they are INSTI naïve [6,38-43]. If the regimen is going to include an INSTI with one active NRTI, we prefer dolutegravir since there are more data in this setting. Dolutegravir, bictegravir, and raltegravir can be used as part of a regimen with or without a pharmacologically boosted PI; however, elvitegravir requires a boosting agent regardless of what it is combined with.

We prefer dolutegravir over raltegravir and elvitegravir for the following reasons:

●In treatment-experienced patients, dolutegravir is more likely to result in virologic suppression compared with twice-daily raltegravir when used in combination with up to two other antiretroviral drugs [6]. In addition, for treatment-experienced patients failing therapy, raltegravir requires twice-daily dosing. Although a once-daily formulation of raltegravir has been approved (two 600 mg tabs once daily), this dosing schedule is recommended only for those who are initiating therapy for the first time and those who are virologically suppressed on a regimen containing raltegravir 400 mg twice daily.

●Dolutegravir has a higher barrier to resistance compared with raltegravir and elvitegravir. Integrase resistance can be seen in patients who experience virologic failure on raltegravir- or elvitegravir-containing regimens [39,40,44-46]. However, integrase mutations have been rarely reported in experienced patients receiving dolutegravir [6,47,48]. Bictegravir may share similar properties to dolutegravir; however, there are much less data in this setting.

●Dolutegravir can be used to treat certain patients whose virus is resistant to raltegravir and elvitegravir. For such patients, dolutegravir must be dosed as 50 mg twice daily [7,38,49]. In general, dolutegravir should not be used if there are integrase mutations at codon Q148 along with two or more secondary mutations, where its level of activity is decreased. There are very limited data using bictegravir in those with underlying INSTI resistance.

Special considerations regarding the use of these agents in persons who are of childbearing potential or are pregnant are discussed above. (See 'Considerations in persons of childbearing potential/persons who are pregnant' above.)

Bictegravir is a nonboosted INSTI available as part of a fixed-dose combination (bictegravir-emtricitabine-tenofovir alafenamide). This once-daily regimen was approved in February 2018 by the US Food and Drug Administration for those who are treatment naïve or virologically suppressed and are considering switch options. There are no available data using this drug in patients who are experiencing virologic failure.

A more detailed discussion of these agents is found elsewhere. (See "Overview of antiretroviral agents used to treat HIV", section on 'Integrase strand transfer inhibitors (INSTIs)'.)

Non-nucleoside reverse transcriptase inhibitors — For individuals with multidrug-resistant virus, first generation NNRTIs, such as efavirenz and nevirapine, are not typically used since most patients will have resistance to these agents. Rilpivirine, another NNRTI, is only recommended for treatment-naïve individuals. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

The most commonly used NNRTI for patients with drug-resistant virus is etravirine. The likelihood that etravirine will be active against a particular virus can be determined via a weighted mutation score based upon the specific NNRTI mutations (table 5). (See "Interpretation of HIV drug resistance testing", section on 'Non-nucleoside reverse transcriptase inhibitors'.)

●If the overall weighted mutation score is less than or equal to 2.0, we consider etravirine to be a fully active agent.

●If the overall weighted mutation score is between 2.5 and 3.5, we may include etravirine and consider it a partially active agent.

●If the overall weighted mutation score is greater than 3.5, we do not consider it to have any activity and would not include it in a new regimen.

If etravirine is part of the new regimen, it should be used with at least one, and ideally two other fully active drugs; if this is not possible, it should be used with multiple partially active agents. Increasing the number of active antiretroviral agents used in combination with etravirine increases the likelihood of obtaining the desired treatment response [50,51]. As an example, in a study of 243 patients with multidrug resistance, the use of two or more active agents in combination with etravirine increased the likelihood of achieving HIV RNA suppression by more than eightfold [51].

Ideally, etravirine is combined with a pharmacologically boosted PI (eg, darunavir); clinical trials of etravirine in patients with resistant virus have found that the boosted PI contributed to virologic outcomes [52,53]. However, it is important to assess if any PI mutations are present since this will help determine the likelihood that the new regimen will result in virologic suppression. As an example, in a study of treatment-experienced patients receiving etravirine plus darunavir, the number of NNRTI and darunavir mutations predicted the response to therapy [54]. Overall response rates were as high as 93 percent among patients who had only two etravirine mutations and one darunavir mutation. This is in contrast to individuals with more than three etravirine mutations plus more than three darunavir mutations; none of these patients achieved viral suppression by 24 weeks.

There are significant drug-drug interactions with etravirine and other antiretroviral medications which can limit its use. As examples:

●Etravirine cannot be used with tipranavir

●If etravirine is used with dolutegravir, the regimen must also include a boosted PI

Doravirine is an NNRTI that appears to have a unique resistance pattern. However, it is only approved for those initiating therapy for the first time or switching while virologically suppressed without underlying resistance. There are very little data for using this drug in those with underlying NNRTI resistance.

A detailed review of drug interactions can be found in the Lexicomp interactive program within UpToDate

CCR5 antagonists — Maraviroc is a CCR5 co-receptor antagonist and is the only approved drug in this class. This drug can only be used in patients who do not have virus that utilizes the CXCR4 coreceptor for HIV entry. Tropism testing is required prior to the initiation of this agent to determine if a virus utilizes CXCR4. (See "Overview of HIV drug resistance testing assays".)

Tropism testing done in the past must be repeated if maraviroc is going to be used as part of a new regimen. Patients who initially have no detectable CXCR4-utilizing virus can develop such strains over time if they are not maintained on a fully suppressive drug regimen. CXCR4-using virus is fairly common in treatment-experienced patients and in those with lower CD4 cell counts (<200 cells/microL) [55,56].

In patients without detectable virus that utilize CXCR4, maraviroc can be used in combination with two other fully active drugs from other classes. In two clinical trials (MOTIVATE 1 and 2), treatment-experienced patients without detectable CXCR4-using virus were randomly assigned to an optimized background regimen with or without maraviroc [57]. Individuals who received maraviroc had significantly greater reductions in plasma HIV RNA compared with patients who received optimized background therapy alone. In contrast, little antiviral activity has been seen with maraviroc among patients who had detectable CXCR4-using virus at screening [58].

In patients who develop virologic failure on a maraviroc-containing regimen, a substantial number had detectable CXCR4-using virus with a small number having true maraviroc drug resistance [59]. (See "Overview of HIV drug resistance testing assays".)

Fusion inhibitors — We only use enfuvirtide (T-20) when a potent two- or three-drug oral regimen is not available (see 'If a fully active PI is NOT available' above). Enfuvirtide, a 36 amino acid peptide, is an injectable agent that is effective in treatment-experienced patients who have not been exposed to this medication. However, this agent is difficult to administer for long periods of time due to the need for twice-daily injections, which often lead to local cutaneous reactions.

Enfuvirtide is considered to be a fully active agent among those who are enfuvirtide-naïve. Data suggest that enfuvirtide is highly effective in patients with multidrug resistance. As an example, in two clinical trials (TORO 1 and TORO 2), patients were randomly assigned to receive optimized background therapy, based on resistance testing, with or without enfuvirtide [60,61]. Those receiving enfuvirtide had a significantly greater viral load decline (0.8 to 1.0 log difference in HIV RNA) and a significantly higher CD4 cell count increase compared with those who received placebo.

Resistance to enfuvirtide emerges fairly quickly, and a single mutation can confer high level resistance and lead to virologic failure [62,63]. Therefore, those with a history of viremia on this drug are likely to have selected for an enfuvirtide-resistant virus. Genotypic and phenotypic testing is available for enfuvirtide resistance in select cases where this issue is being considered.

Attachment inhibitors — Fostemsavir is an attachment inhibitor that was approved for use in the United States in July 2020 for patients with HIV-1 infection. Fostemsavir is a prodrug, which is converted to the active metabolite temsavir. Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and prevents viral attachment and subsequent entry of virus into host T cells. Fostemsavir should be used in combination with other active antiretroviral agents for treatment-experienced patients who are failing therapy and have limited treatment options [64]. In a study that evaluated 272 patients who each had at least one fully active antiretroviral agent to include as part of an optimized background regimen that contained fostemsavir, 54 percent achieved an HIV viral load <40 copies/mL at 48 weeks [65], and by 96 weeks, 60 percent of participants had HIV RNA suppression [66]. In a separate cohort of 99 patients who had no active drugs but had fostemsavir added to an optimized antiretroviral regimen, 38 percent achieved an HIV viral load <40 copies/mL at 48 weeks [65]. Additional information on fostemsavir is presented in a separate topic review. (See "Overview of antiretroviral agents used to treat HIV", section on 'Attachment inhibitors'.)

Post-attachment inhibitor — Ibalizumab is a monoclonal antibody that is given as an intravenous infusion every two weeks and binds the CD4 cell in such a way that it does not block viral attachment, but does block entry. It is indicated for the treatment of heavily antiretroviral-experienced HIV-1-infected adults with multidrug-resistant virus who are failing their current regimen. It should be used as part of a regimen with other potentially active agents whenever possible. In a study of 40 patients with multidrug-resistant HIV, 43 percent of patients who received ibalizumab plus an optimized background had a viral load of <50 copies/mL at 25 weeks [67].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents".)

SUMMARY AND RECOMMENDATIONS

●The goal of antiretroviral therapy (ART) is to maximally suppress plasma HIV RNA to prevent HIV disease progression and the emergence of drug-resistant virus. Achieving virologic suppression can be difficult for HIV-infected patients with drug-resistant virus; however, advances in drug development have enabled great progress in the treatment of this patient population, even among those who have resistance to one or two classes of antiretroviral agents. (See 'Introduction' above and 'Goals of therapy' above.)

●Many patients will have virologic failure without the presence of drug-resistant virus. In this setting, it is important to assess adherence, drug tolerability, and the possibility of drug-food or drug-drug interactions. (See 'Patients without drug-resistant virus' above.)

●Most patients with drug-resistant virus will require a change in their regimen. When choosing a new regimen, we evaluate the patient's past antiretroviral therapy (ART) history, as well as the results of previous and current genotype and/or phenotype drug resistance tests to determine which agents are likely to be fully or partially active. Additional factors that can influence the choice of regimen include comorbid conditions, commitment to using effective contraception, and the risk of drug interactions. (See 'Patients with drug-resistant virus' above.)

●For patients who experience virologic failure with drug-resistant virus while receiving an initial regimen that contains a nucleoside reverse transcriptase inhibitor (NRTI) combination plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), we typically continue an NRTI combination. We recommend replacing the NNRTI with either dolutegravir or a pharmacologically boosted protease inhibitor (PI) as the new third agent (Grade 1B) (see 'NNRTI-containing regimens' above):

•We recommend dolutegravir as the third agent if there is at least one active NRTI that can be included in the new regimen and there is no evidence of integrase strand transfer inhibitor (INSTI) resistance (Grade 1B). If tenofovir and abacavir are both active, we prefer a tenofovir-containing NRTI combination (ie, tenofovir-emtricitabine).

•If genotype testing is not available, we suggest that a pharmacologically boosted PI be used as the third agent instead of dolutegravir (Grade 2C). High quality clinical trial data support the use of a pharmacologically boosted PI in this setting, while there is limited data regarding dolutegravir in this population. The choice of which NRTIs to use is based upon resistance testing results, convenience, and tolerability.

•For patients failing an initial NNRTI-containing regimen who are unable to tolerate a first-line NRTI combination, we recommend treatment with a pharmacologically boosted PI plus an INSTI (eg, boosted darunavir plus dolutegravir), rather than a pharmacologically boosted PI plus either a second-line NRTI regimen or a different nucleoside-sparing regimen (Grade 1B). Second-line NRTIs are associated with significant toxicity, and there is less clinical trial data supporting a different nucleoside-sparing regimen. If there are no active NRTIs, consideration can also be given to a pharmacologically boosted PI plus an INSTI.

●For patients who experience virologic failure with drug-resistant virus while receiving an initial regimen that contains a first-line NRTI combination plus an INSTI, we suggest the NRTIs be continued, but the INSTI be switched to a pharmacologically boosted PI (Grade 2C). A nucleoside-sparing regimen with a pharmacologically boosted PI plus an INSTI should only be used if there is documented evidence of INSTI susceptibility and close follow up. (See 'INSTI-containing regimen' above.)

●Patients rarely develop drug-resistant virus while taking an initial regimen that contains a pharmacologically boosted PI. However, a minority of individuals will develop virus with resistance to emtricitabine or lamivudine. Most patients failing a pharmacologically boosted PI are doing so because of poor adherence, and we typically continue their initial regimen and work with the patient to improve their ability to take daily therapy. However, if the patient is experiencing side effects, an effort should be made to switch to an alternative regimen that includes a better tolerated pharmacologically boosted PI or dolutegravir. (See 'A pharmacologically boosted PI' above.)

●For patients who have failed multiple regimens, our approach is typically defined by the activity of a pharmacologically boosted PI and dolutegravir. However, for certain patients, additional tests (eg, those that assess for T-20 resistance and/or the presence of CCR5 tropic virus) may be needed. (See 'Patients who have failed multiple regimens' above.)

●For treatment-experienced patients with drug-resistant virus, we obtain viral load testing four weeks after initiating the new regimen. We then continue to monitor the HIV RNA level at four- to eight-week intervals until the level falls below the assay's limit of detection. (See 'Viral load monitoring' above.)

●For a minority of patients, full virologic suppression is not achievable due to multiple drug resistance or intolerance. For such patients, we typically continue ART even if a new fully suppressive regimen is not available. (See 'Management of patients with incomplete viral suppression' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Meena Lagnese, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.