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 multiclass resistant virus.

This topic will discuss how to select a combination antiretroviral 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-1 drug resistance testing assays" and "Interpretation of HIV-1 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 sexually 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 [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 nonnucleoside reverse transcriptase inhibitor (NNRTI), an integrase strand transfer inhibitor (INSTI), or a 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 inferred from the antiretroviral therapy (ART) treatment history. For patients requiring a change in their regimen, the resistance profile and the patient's underlying comorbidities (eg, kidney, cardiovascular disease, chronic hepatitis B virus infection, 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 divalent cations with integrase inhibitors), 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 nonadherent 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 ART 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).

In such patients, we ensure that the patient is on a regimen with a high barrier to resistance. For many patients, the single-pill regimen bictegravir-emtricitabine-tenofovir alafenamide is a good choice. Other options include two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in combination with either dolutegravir or boosted darunavir.

We typically reserve boosted darunavir for those with a detectable viral load on an INSTI-containing regimens. Although boosted PIs are unlikely to select for drug-resistant virus in the face of continued poor adherence, they are generally associated with an increased risk of side effects compared to second-generation INSTIs such as dolutegravir or bictegravir. (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 experiencing virologic failure 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-1 drug resistance testing".)

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. (See 'Overview of specific antiretroviral agents' below.)

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

Patients failing an initial regimen with a low-barrier to resistance — In the past, most patients experiencing virologic failure with drug-resistant virus on an initial regimen were taking an nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) combination (eg, tenofovir-emtricitabine or abacavir-lamivudine) and a third agent with a low barrier to resistance (eg, a nonnucleoside reverse transcriptase inhibitor [NNRTI] or a first generation integrase strand transfer inhibitor [INSTI] such as raltegravir or elvitegravir). (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Patients who experienced virologic failure on an NNRTI or a first-generation INSTI as part of their initial regimen typically had virus that had become resistant to lamivudine or emtricitabine (ie, have the M184I/V mutation) [2-4]. These patients may also have had 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 [2]. In this setting, some patients will also have NNRTI or INSTI resistance.

By contrast, those treated with an initial regimen that includes an NRTI combination plus a boosted PI, dolutegravir, or bictegravir often experience virologic failure with either no resistance or, occasionally in those on boosted PIs, the M184V mutation; PI and INSTI resistance is rare. (See 'Patients failing an initial regimen with a high barrier to resistance' below.)

Those failing a first-line regimen containing an NNRTI — Several regimens have been found to be effective for patients failing an initial NNRTI-containing regimen [5-13]. These include an NRTI pair plus a third agent with a high barrier to resistance (a second-generation INSTI or a boosted PI), or an NRTI sparing regimen (eg, dolutegravir plus boosted darunavir). Our choice of regimen depends in part upon the presence of an active NRTI on resistance testing.

●If at least one NRTI active – For patients who experience virologic failure while receiving an initial NNRTI-containing regimen and have an active NRTI available, we suggest a new regimen that includes a tenofovir-containing NRTI combination plus a second-generation INSTI (bictegravir-tenofovir alafenamide-emtricitabine (TAF) or dolutegravir plus tenofovir-emtricitabine (or lamivudine). In clinical trials, patients who switched to a regimen containing dolutegravir with two NRTIs were able to achieve virologic suppression when one of the NRTIs were active, and often even when the new regimen did not include any fully active NRTIs [5-7]. Although clinical trials of patients failing an NNRTI containing regimen have not evaluated bictegravir, we assume the efficacy of bictegravir-tenofovir alafenamide-emtricitabine, would be similar to regimens that contain dolutegravir plus tenofovir-emtricitabine (or lamivudine).

A regimen that includes boosted darunavir with either an NRTI combination or dolutegravir is also reasonable. However, we prefer to use regimens without a boosted PI when possible since boosted PIs are more difficult to tolerate than INSTIs and have more drug interactions.

Similarly, we prefer to use tenofovir-emtricitabine (or lamivudine) as the NRTI pair rather than abacavir-lamivudine or zidovudine-lamivudine since there are fewer side effects. In addition, in clinical trials of salvage regimens, there is the most experience with a tenofovir-containing NRTI combination. If a tenofovir-containing regimen cannot be used, then we typically prefer an NRTI sparing regimen such as boosted-darunavir plus dolutegravir.

There are three key clinical trials that have informed our approach. The DAWNING trial evaluated 627 patients failing an initial regimen that included an NNRTI plus two NRTIs [5]. In this open-label randomized study that was conducted in 13 countries, patients without evidence of resistance to PIs or INSTIs received two NRTIs (at least one was fully active) with either dolutegravir or boosted lopinavir. At 48 weeks, significantly more patients who received dolutegravir had virologic suppression (84 versus 70 percent, adjusted difference 13.8 percent, 95% CI: 7.3 to 20.3 percent). In addition, serious adverse events occurred more frequently in the boosted lopinavir than dolutegravir group (14 versus 4, respectively). However, of those evaluated for resistance, 2 of 11 who received dolutegravir developed INSTI resistance whereas none in the boosted lopinavir arm developed PI resistance.

The NADIA trial also enrolled those failing an initial regimen that included an NNRTI plus two NRTIs, but in this trial resistance data were not available to guide NRTI selection [6,7,13]. In this open-label trial of 464 persons with HIV, patients were randomized to either dolutegravir or boosted darunavir, and then randomized again to either zidovudine-lamivudine or tenofovir disoproxil fumarate-lamivudine. Dolutegravir plus zidovudine-lamivudine or tenofovir disoproxil fumarate-lamivudine was as effective as boosted darunavir with similar dual NRTIs [6,7]. In addition, 90 percent of patients with extensive NRTI resistance (including 50 percent who had the K65R mutation that confers tenofovir resistance) achieved a viral load <400 copies/mL. Similar to the DAWNING trial, PI resistance was not identified in those treated with darunavir, while 9 patients who received dolutegravir developed INSTI resistance, six of whom were in the zidovudine-lamivudine group.

In the D2EFT trial, which evaluated 826 patients who failed first-line NNRTI therapy, the combination of dolutegravir plus boosted darunavir was included as a treatment option [14]. The proportion of participants with an HIV RNA <50 copies/mL at 48 weeks in those receiving ritonavir-boosted darunavir plus dolutegravir was 84 percent. Among those receiving a tenofovir-containing NRTI combination with either dolutegravir or ritonavir-boosted darunavir, 78 and 74 percent achieved an HIV RNA <50 copies/mL, respectively.

●If no NRTIs are active or NRTI activity unknow – If no NRTIs are active, we typically suggest dolutegravir plus tenofovir-emtricitabine or dolutegravir plus boosted darunavir. Available data support both options. Boosted darunavir plus two NRTIs is a reasonable alternative if dolutegravir cannot be used.

The rationale for our preferred regimens is as follows:

•Dolutegravir plus tenofovir-emtricitabine – Some experts prefer this regimen since it avoids the drug-drug interactions and the less favorable safety profile that can be seen with PI-based regimens. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)

The use of dolutegravir plus tenofovir-emtricitabine is supported by the NADIA trial, described above [6,7]. In that trial, 90 percent of patients with extensive NRTI resistance (including 50 percent who had the K65R mutation that confers tenofovir resistance) achieved a viral load <400 copies/mL. Although INSTI resistance did occur in patients with virologic failure, it was rare, and most cases occurred in those receiving zidovudine-lamivudine as the NRTI backbone. In addition, should resistance to an INSTI occur, it would still leave boosted darunavir plus tenofovir-emtricitabine as an option.

Bictegravir-emtricitabine-tenofovir alafenamide is likely to be as effective as dolutegravir plus tenofovir-emtricitabine; however, this regimen has not been evaluated in clinical trials.

•Dolutegravir plus boosted darunavir – Some experts prefer dolutegravir plus boosted darunavir if no NRTIs are active or NRTI activity is unknown. In the D2EFT trial discussed above, this regimen appeared to be more effective than NRTI-containing regimens [14]. When dolutegravir plus boosted darunavir was compared with boosted darunavir plus two NRTIs, the difference in virological suppression was 8.6 percent (95% CI 1.7 to 15.5). By contrast, the difference in virologic suppression was 6.7 percent (95% CI -1.2 to 14.4) when dolutegravir plus two NRTIs was compared with boosted darunavir plus two NRTIs.

Those failing a first-line regimen containing a first generation INSTI — Patients who are failing an initial first-line regimen that contains raltegravir or elvitegravir are at risk for developing INSTI resistance. The approach to regimen selection depends upon the results of genotypic testing, which must include testing for integrase resistance. Resistance testing should be performed while the patient is still taking the INSTI.

●No INSTI resistance – If no INSTI resistance is present and at least one NRTI is active, the patient can be switched to dolutegravir (50 mg once daily) plus tenofovir-emtricitabine or bictegravir-tenofovir alafenamide-emtricitabine.

However, boosted darunavir in combination with two NRTIs or dolutegravir is preferred when there may be an increased risk of emerging INSTI resistance. This occurs when there are no fully active NRTIs, poor adherence is an ongoing concern, and/or tenofovir cannot be used as part of the NRTI pair.

●INSTI resistance is present – The approach to regimen selection in this setting depends upon the resistance mutations.

•No mutations at codon Q148 – For patients who have INSTI resistance, but do not have mutations at codon Q148, dolutegravir (50 mg twice daily) can be used if the regimen includes a boosted PI or at least two other fully active drugs from other classes. An INSTI-sparing regimen (boosted darunavir plus two NRTIs) can also be used.

•Mutations at codon Q148 – An INSTI should not be used if there are integrase mutations at codon Q148 along with two or more secondary mutations [15]. The level of dolutegravir activity is decreased in this setting. In this case, a boosted-PI plus two NRTIs or two active agents from a different class should be included in the regimen. Regimen selection should be done in conjunction with an HIV specialist. (See 'If a fully active PI is available' below.)

If there are integrase mutations at codon Q148 but less than two secondary mutations, we still prefer to avoid INSTIs and prescribe a regimen that includes a boosted PI plus two NRTIs. However, if there are contraindications to the components of this regimen, reasonable alternatives include twice daily dolutegravir plus two NRTIs (if at least one is fully active), or twice daily dolutegravir plus a boosted PI. The choice of alternative regimen depends upon the specific contraindications.

●If resistance testing cannot be performed – If resistance testing cannot be performed, the patient should be switched to a regimen that contains:

•Two nucleoside reverse transcriptase inhibitors plus

•A boosted protease inhibitor

Although most studies supporting the use of a boosted PI plus an NRTI combination have evaluated patients failing an initial NNRTI-containing regimen [6,7,9-12], virologic suppression should also be observed in any patient for whom a boosted PI is fully active, including those patients failing an initial INSTI-containing regimen. (See 'Those failing a first-line regimen containing an NNRTI' above and 'Protease inhibitors' below.)

Patients failing an initial regimen with a high barrier to resistance — Patients rarely develop drug-resistant virus while taking an initial regimen that contains an agent with a high barrier to resistance (eg, boosted darunavir, dolutegravir, or bictegravir). The approach to patients failing a regimen without drug-resistance is described above. (See 'Patients without drug-resistant virus' above.)

Although uncommon, if resistance does occur, patients typically develop virus with resistance to emtricitabine or lamivudine. In such patients, poor adherence is likely to be the principal reason for failure, and patients can either continue the initial regimen with enhanced adherence support or switch to a different regimen with a high barrier to resistance that may be better tolerated. The specific approach depends upon why the patient is not taking their medication as prescribed.

On very rare occasion, resistance to a second-generation INSTI or even a boosted PI may occur. Factors that can contribute to resistance in this setting include ongoing adherence challenges, low CD4 counts, high viral loads, recurrent opportunistic infections, and drug-drug interactions. Patients who develop resistance to one of these agents should be managed in conjunction with an HIV specialist. Treatment typically involves switching to a different agent with a high barrier to resistance in combination with two NRTIs or another fully active agent (eg, doravirine and/or agents with a novel mechanism of action). (See 'If a fully active PI is available' below.)

Patients who have failed multiple regimens in the past — Our approach to patients who have failed multiple regimens is defined by the activity of agents with a high barrier to resistance (eg, boosted darunavir, dolutegravir, or bictegravir). The management of patients with drug-resistant virus who have failed multiple regimens, especially those who have PI and second-generation INSTI resistance, can be complicated. These patients should be managed in conjunction with an experienced HIV provider.

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 integrase strand transfer inhibitor (INSTI) naïve or never had documented INSTI resistance. The management of these patients is similar to the management of any patient with a virus that is fully susceptible to second-generation INSTIs, as noted above for those failing first-line NNRTIs, boosted PIs or INSTI without resistance to this class. (See 'Patients failing an initial regimen with a low-barrier to resistance' above.)

In this setting, we typically switch to a regimen that uses dolutegravir or bictegravir, in combination with tenofovir-emtricitabine. If tenofovir-emtricitabine cannot be used (eg, advanced kidney disease), other possibilities include the use of dolutegravir with another fully active agent, eg, abacavir-lamivudine (although data is limited), or boosted darunavir.

The use of cabotegravir-rilpivirine in selected patients who cannot tolerate oral therapy is discussed below. (See 'Patients unable to adhere to oral therapy' below.)

If a fully active PI is available — Many patients who have failed multiple regimens will still have virus that is sensitive to first-line boosted protease inhibitors (PIs). Decreased drug susceptibility to a boosted PI generally requires the accumulation of multiple mutations. Thus, a 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 the PIs. More detailed discussions of PI resistance are found elsewhere. (See 'Protease inhibitors' below and "Interpretation of HIV-1 drug resistance testing", section on 'Protease inhibitors'.)

For such patients who also have a fully active INSTI available, we would generally manage as outlined in previous section. If fully active INSTI is not available, we administer a boosted PI and add an NRTI combination such as tenofovir-emtricitabine, which seems to be effective in almost all patients, even those with extensive NRTI resistance [6,7,9-12]. Studies supporting this approach are described above. (See 'Those failing a first-line regimen containing an NNRTI' above.)

For patients who cannot tolerate tenofovir, we would consider using abacavir-lamivudine (If HLA B*5701-testing is negative) with a boosted PI, regardless of NRTI susceptibility. If NRTIs cannot be used at all, we use a boosted PI with dolutegravir if there is no evidence of resistance to the INSTI. If this is not an option due to intolerance of resistance, we would typically use a boosted PI with a second-generation NNRTI, (eg doravirine), if susceptible, although data are limited. (See 'Integrase strand transfer inhibitors' below and 'Nonnucleoside reverse transcriptase inhibitors' below.)

There have been limited data treating those with PI resistance to early PIs who then switch to newer agents in the class (eg, boosted darunavir). In one open-label study of 545 INSTI-naïve patients who were failing a boosted lopinavir regimen, 224 had resistance to boosted lopinavir but predicted susceptibility to boosted darunavir, and approximately 90 percent achieved virologic suppression to <200 copies/mL when they were switched to boosted darunavir with raltegravir and either the best available NRTIs or etravirine (if the latter was predicted to be susceptible) [16].

If neither a fully active PI or second-generation INSTI are options — Although uncommon, there are certain individuals who have drug-resistant virus and neither a fully active PI nor a second-generation INSTI are options due to intolerance or resistance. This scenario is typically seen in patients with prolonged periods of nonadherence or those who were treated with unboosted Pis and first-generation INSTIs in the distant past. (See "Interpretation of HIV-1 drug resistance testing", section on 'Protease inhibitors'.)

The approach to regimen selection in these patients must be individualized. Data suggest that virologic suppression is most likely achieved if the patient is given a regimen that includes at least two, and preferably three, fully active agents from at least two drug classes [17,18]. This typically involves combining drugs from novel classes, eg, CCR5 antagonists (maraviroc), attachment, post attachment and capsid inhibitors, along with partially active agents with older mechanisms. These are discussed in detail below. (See 'Overview of specific antiretroviral agents' below.)

When combining agents from different classes of drugs, it is important to assess for drug-drug interactions. As an example, if dolutegravir is used with etravirine, a boosted PI should be included in the regimen. Additional information on drug interactions can be obtained by using the drug interaction program within UpToDate.

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 as new drugs 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. Additional considerations for the management of patients with incomplete viral suppression is discussed below. (See 'Management of patients with incomplete viral suppression' below.)

Patients unable to adhere to oral therapy — Long-acting injectable therapy with cabotegravir-rilpivirine may be a treatment option for carefully selected persons with a detectable viral load who are unable to take oral ART as prescribed despite extensive adherence support. (See "Use of long-acting cabotegravir-rilpivirine in people with HIV", section on 'Considerations for persons with a detectable viral load'.)

If cabotegravir-rilpivirine is being considered, patients must have virus that is susceptible to both cabotegravir and rilpivirine and be at high risk for developing AIDS-related complications (ie, CD4 count <200 cells/microL or a prior AIDS-defining illness). When initiating cabotegravir-rilpirivine in this setting, we start with every four-week dosing. If viral suppression is achieved, consideration can be given to switching to every eight-week dosing. If using this regimen, patients must understand that if virologic failure occurs, individuals may be at increased risk for emerging resistance that could limit treatment options in the future.

Although injectable cabotegravir-rilpivirine is only approved for use in virologically suppressed patients, observational studies have demonstrated that with intensive case management, long-acting cabotegravir-rilpivirine can be effective [19,20]. Unpublished data from a randomized trial also supports the use of cabotegravir-rilpivirine in patients who were not able to achieve sustained viral suppression with oral therapy due to poor adherence despite intensive efforts [21]. In this trial, financial incentives were used to help patients achieve virologic suppression on oral therapy; the 294 patients who achieved HIV suppression were then randomized to receive long-acting cabotegravir-rilpivirine every four weeks or continue oral therapy. At 52 weeks, patients who were switched to long-acting cabotegravir-rilpivirine were less likely to experience virologic failure than those who continued oral therapy, though this result was not significant (7.2 versus 25.4 percent; difference -18.2 percent, 98.75%CI -31.1 to 5.4).

In some patients, injectable lenacapavir has been used in combination with cabotegravir [20]. However, data using this combination are extremely limited, and similar to cabotegravir-rilpivirine, it has only been used in selected individuals who are not able to achieve viral suppression despite intensive case management on an oral regimen and have underlying rilpirivine resistance. More detailed information on lenacapavir is found below. (See 'Lenacapavir' 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. 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-abundant settings", section on 'ART selection and management' and "Prevention of vertical HIV transmission in resource-limited settings", section on 'Individuals already on ART prior to pregnancy'.)

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 [22,23]. However, resistance testing cannot be done unless the viral load is >500 copies/mL. (See "Overview of HIV-1 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 antiretroviral therapy (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-1 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 four weeks apart, 24 weeks after initiating a new regimen [1]. For such patients, we continue antiretroviral therapy (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 [24-27]. 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 [28], and is usually seen in patients taking nucleoside/tide reverse transcriptase inhibitors (NRTIs) and protease inhibitors (Pis) [24,29-31]. 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 [24,29].

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 nonnucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, attachment inhibitors, CCR5 antagonists, capsid inhibitors, and fusion inhibitors 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 [32]. It is important to perform resistance testing, when available, 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), boosted protease inhibitors (Pis), integrase strand transfer inhibitors (INSTIs), and nonnucleoside 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, the postattachment inhibitor ibalizumab, the attachment inhibitor fostemsavir, and the capsid inhibitor lenacapavir. 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 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. We typically 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 formulations of tenofovir, tenofovir disoproxil fumarate (TDF)-and tenofovir alafenamide-emtricitabine (TAF). When using a tenofovir-containing regimen, we typically use TAF in combination with emtricitabine or lamivudine. TAF is associated with less bone and kidney toxicity compared with TDF and appears to be equally effective in maintaining virologic suppression [33-35]. Exceptions include the presence of certain drug interactions (eg, some anticonvulsants and 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 [33]. 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 [34].

●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 TDF-FTC should not be used for patients with an estimated glomerular filtration rate <60 mL/min/1.73 m². For patients with more severe kidney disease (eg, estimated glomerular filtration rate <30 mL/min/1.73 m²) the NRTI combination TAF-FTC should generally be avoided as well. 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 TDF (although not TAF). (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). (See "Interpretation of HIV-1 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 [36].

Protease inhibitors — The choice of which protease inhibitor (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 boosted darunavir since it is as active as other Pis and is generally well-tolerated [37,38]. 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 hypersensitivity", section on 'Cross-reactivity'.)

•An alternative PI to darunavir is 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 "Kidney disease in patients with HIV", section on 'Antiretroviral therapy 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 [39].

•Optimal antiviral activity with tipranavir is seen in patients with <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 [40].

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 [41].

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 [42].

Integrase strand transfer inhibitors — In patients who are INSTI- naïve or have no resistance to INSTIs, any of the INSTIs can be used [8,17,18,43-45]. We strongly prefer dolutegravir or bictegravir (bictegravir is only available as bictegravir- TAF- emtricitabine single-tablet regimen) for the following reasons:

●In treatment-experienced patients, dolutegravir is more likely to result in virologic suppression compared with raltegravir when used in combination with up to two other antiretroviral drugs [8]. Although there are no available data evaluating bictegravir in patients who are experiencing virologic failure, it is expected to have similar efficacy to dolutegravir.

●Dolutegravir and bictegravir have higher barriers to resistance compared with raltegravir and elvitegravir. Integrase resistance can be seen in patients who experience virologic failure on raltegravir- or elvitegravir-containing regimens [17,18,46-48]. However, integrase mutations are less likely to be reported in treatment-experienced patients receiving dolutegravir [5,7,8,49,50].

●Dolutegravir and bictegravir have certain pharmacokinetic properties that make them easier to administer than the other INSTIs. As an example, dolutegravir and bictegravir can be used as part of a regimen with or without a boosted PI; however, elvitegravir requires a boosting agent regardless of what it is combined with.

In addition, dolutegravir and bictegravir can be administered once daily. By contrast, raltegravir typically 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 should be used rather than bictegravir in patients whose virus is resistant to raltegravir and elvitegravir and still partially susceptible to dolutegravir. For such patients, dolutegravir should be dosed as 50 mg twice daily [15,51,52]. There are very limited data using bictegravir in those with underlying INSTI resistance. None of the INSTIs should be used if there are integrase mutations at codon Q148 along with two or more secondary mutations, since even dolutegravir’s level of activity is decreased.

Cabotegravir, the newest INSTI, is primarily available as a long acting (LA) injectable formulation which is given with LA RPV to those without underlying resistance to either drug, who have sustained viral suppression on oral therapy and no evidence of chronic HBV. In very select situations, LA cabotegravir-rilpivirine can be considered in those at high risk for disease progression and death who, despite intensive efforts, are unable to achieve viral suppression with oral therapy. (See 'If a fully active INSTI is available' above and "Use of long-acting cabotegravir-rilpivirine in people with HIV", section on 'Considerations for persons with a detectable viral load'.)

More detailed discussions of these agents, including their use in persons who are of childbearing potential or are pregnant, are found elsewhere. (See "Overview of antiretroviral agents used to treat HIV", section on 'Integrase strand transfer inhibitors (INSTIs)' and "Antiretroviral selection and management in pregnant individuals with HIV in resource-abundant settings" and "Prevention of vertical HIV transmission in resource-limited settings".)

Nonnucleoside reverse transcriptase inhibitors — For individuals with multidrug-resistant virus, first-generation nonnucleoside reverse transcriptase inhibitors (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-1 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 [53,54]. 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 [54].

Ideally, etravirine is combined with a boosted PI (eg, darunavir); clinical trials of etravirine in patients with resistant virus have found that the boosted PI contributed to virologic outcomes [55,56]. 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 [57].

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 limited data for using this drug in those with underlying NNRTI resistance.

A detailed review of drug interactions can be found in the drug interaction program within UpToDate.

Other agents

Maraviroc — Maraviroc is a CCR5 coreceptor 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-1 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) [58,59].

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 [60]. 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 [61].

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 [62]. (See "Overview of HIV-1 drug resistance testing assays".)

Enfuvirtide (T-20) — Enfuvirtide (also known as T-20) is a fusion inhibitor. In the past, enfuvirtide was only used when a potent two- or three-drug oral regimen was not available. 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 [63,64]. 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 [65,66]. 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.

In light of the limitations of enfuvirtide, and the availability of several other drugs in novel classes, there are rarely situations where this drug would be used in the current era.

Fostemsavir — Fostemsavir is an attachment inhibitor that was approved for use in the United States in July 2020 for treatment-experienced patients with HIV-1 infection who are failing therapy and have limited treatment options [67]. Fostemsavir is given orally twice per day in combination with other active antiretroviral agents.

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.

Clinical trial data show high rates of virologic suppression in highly treatment-experienced patients. 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 [68], and by 96 weeks, 60 percent of participants had HIV RNA suppression [69]. In a separate cohort of 99 patients who had no active drugs but had fostemsavir added to an optimized antiretroviral regimen, 37 percent achieved an HIV viral load <40 copies/mL at 48 weeks [68,69].

Additional information on fostemsavir is presented in a separate topic review. (See "Overview of antiretroviral agents used to treat HIV", section on 'Attachment inhibitors (Fostemsavir)'.)

Ibalizumab — Ibalizumab is a monoclonal antibody that is given as an intravenous infusion every two weeks [70]. It 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 [71].

Lenacapavir — In 2022, the capsid inhibitor, lenacapavir, was approved for use in the United States as part of a combination regimen for patients with multi-drug resistant HIV-1 [72]. Capsid inhibitors are small molecules that disrupt HIV capsid protein functions [73]. This impacts key protein-protein interactions necessary for viral entry and virion assembly.

Patients initiating treatment should receive an initial induction regimen that includes oral lenacapavir. After that, lenacapavir is given subcutaneously as two injections every six months. Detailed dosing information can be found in the lenacapavir drug information topic within UpToDate.

Clinical trials have evaluated lenacapavir in combination with an optimized background ART regimen in 72 patients with multidrug-resistant HIV [74]. Approximately 80 percent achieved a viral load of less than 50 copies by 26 weeks, and none of the patients developed serious adverse events. Thirty-six patients received lenacapavir or placebo in combination with their failing regimen for 15-days prior to receiving open label lenacapavir; a reduction of ≥0.5 log₁₀ copies/mL in HIV-1 RNA was seen in 88 versus 17 percent of those who received lenacapavir versus placebo, respectively.

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".)

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – 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 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.)

●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.

Most patients with drug-resistant virus will require a change in their regimen. When choosing a new regimen, we evaluate the patient's past 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 and the risk of drug interactions. (See 'Patients with drug-resistant virus' above.)

●Patients without drug-resistant virus – 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.)

As an example, patients infrequently develop drug-resistant virus while taking an initial regimen that contains a boosted PI or second-generation INSTI (dolutegravir or bictegravir). In this setting, we typically continue their initial regimen and work with the patient to improve their ability to take daily therapy or switch to an alternative regimen with a high barrier to resistance that includes a better tolerated. (See 'Patients failing an initial regimen with a low-barrier to resistance' above.)

●Patients failing an initial NNRTI-containing regimen – Some patients will experience virologic failure with drug-resistant virus while receiving an initial regimen that contains a nucleoside reverse transcriptase inhibitor (NRTI) combination plus a nonnucleoside reverse transcriptase inhibitor (NNRTI).

•For patients who have one active NRTI, we suggest a regimen that includes tenofovir-emtricitabine (or lamivudine) plus a second-generation INSTI (dolutegravir or bictegravir) (Grade 2C). Clinical trial data have found that an NRTI combination plus a third agent with a high barrier to resistance is effective suppressing virus, even if there are no active NRTIs. A regimen that contains a boosted PI (eg, boosted darunavir plus dolutegravir or boosted darunavir plus two NRTIs) is a reasonable alternative; however, boosted protease inhibitors (PIs) are more difficult to tolerate and have more drug interaction. (See 'Those failing a first-line regimen containing an NNRTI' above.)

•If genotype testing is not available or if there are no active NRTIs, we suggest dolutegravir plus either tenofovir-emtricitabine or boosted darunavir (Grade 2C). Factors to consider when deciding between these alternatives are discussed above. (See 'Those failing a first-line regimen containing an NNRTI' above.)

●Patients failing an initial INSTI-containing regimen

•If the INSTIs had a low barrier to resistance – For patients who experience virologic failure while receiving an initial regimen that contains a first-line NRTI combination plus an INSTI with a low barrier to resistance (raltegravir or elvitegravir), our approach is dictated by the presence of INSTI resistance. (See 'Those failing a first-line regimen containing a first generation INSTI' above.)

-If no INSTI resistance is present and at least one NRTI is active, we suggest either once-daily dolutegravir plus tenofovir-emtricitabine (or lamivudine) or bictegravir-tenofovir alafenamide-emtricitabine (TAF) (Grade 2C). Regimens such as boosted darunavir plus two NRTIs or boosted darunavir plus dolutegravir are reasonable alternatives, and are generally preferred if there are no fully active NRTIs or if poor adherence is an ongoing concern; there may be an increased risk of emerging INSTI resistance in these settings. (See 'Those failing a first-line regimen containing a first generation INSTI' above.)

-If INSTI resistance is present, the choice of regimen depends upon the specific mutations. As an example, if there are integrase mutations at codon Q148 along with two or more secondary mutations, we suggest the patient be switched to a regimen that includes boosted darunavir plus an NRTI combination (Grade 2C). By contrast, twice daily dolutegravir can used in the regimen if there is no evidence of dolutegravir resistance. Regimen selection should be done in conjunction with an HIV specialist.

•If the INSTIs had a high barrier to resistance – Patients rarely develop drug-resistant virus while taking an initial regimen that contains a second-generation INSTI (dolutegravir or bictegravir) since these agents have a high barrier to resistance. When virologic failure occurs in this setting, efforts should be focused on enhancing adherence to the regimen. If resistance is present, subsequent regimens should include a boosted-PI. (See 'Patients failing an initial regimen with a high barrier to resistance' above and 'Patients without drug-resistant virus' above.)

●Patients failing multiple regimens – For patients who have failed multiple regimens, our approach is typically defined by the activity of a boosted PI and dolutegravir. If neither are available, a regimen is created using at least two and preferably three fully active drugs. In this setting, this might include the use of agents with novel mechanisms of action (ibalizumab, fostemsavir, and/or lenacapavir). (See 'Patients who have failed multiple regimens in the past' above.)

●Monitoring – For treatment-experienced patients with drug-resistant virus changing regimens, 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 UpToDate editorial staff acknowledges Meena Lagnese, MD, and John G Bartlett, MD, who contributed to earlier versions of this topic review.