Version May 2024
INTRODUCTION — For persons with human immunodeficiency virus (HIV) who have a stably suppressed plasma viral load (eg, HIV RNA below the limit of detection for at least 6 to 12 months) on antiretroviral therapy (ART), the patient and clinician may consider switching the ART regimen because of factors such as side effects or pill burden. In this setting, the goal is to maintain virologic suppression while improving the patient's quality of life and reducing the risk of short- or long-term toxicity. This is distinct from the situation of virologic failure, in which a salvage regimen must be crafted because of poor adherence and virologic rebound, with or without drug resistance.
This topic will describe the approach to making a regimen switch in the setting of virologic suppression in patients with HIV-1 infection. Topic reviews that discuss changing a regimen in the setting of virologic failure are presented elsewhere. (See "Evaluation of the treatment-experienced patient failing HIV therapy" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
REASONS FOR CHANGING A REGIMEN
Tolerability of current regimen — There are several reasons why patients who are virologically suppressed may benefit from a switch of their antiretroviral therapy (ART) regimen. These include:
●Side effects
●Pill burden
●Drug-drug interactions
In a study of 246 patients who changed ART between January 2011 and July 2012, the most common reasons were toxicity and regimen simplification [1].
Other reasons might include new or worsening medical comorbidities (eg, chronic kidney disease), cost issues or changes in insurance, desire to match a partner's regimen, difficulty with food requirements, desire to conceive, or pregnancy. Considerations for regimen selection in these settings are discussed below. (See 'Other considerations for regimen selection' below.)
Risk of long-term complications — Some patients may be tolerating their regimen but are at risk for long-term toxicity with the antiretroviral agents they are receiving.
●Patients receiving TDF – For patients with normal renal function, we have a low threshold to switch patients off of tenofovir disoproxil fumarate (TDF) to reduce the risk of TDF-associated nephrotoxicity. This is particularly important for patients who have risk factors for renal disease (eg, diabetes), are over 50 years of age, and/or take other nephrotoxic medications. Options typically consist of switching TDF to tenofovir alafenamide (TAF) or using a tenofovir-sparing regimen, as discussed below. (See 'Eligibility for two-drug regimens' below and 'Kidney disease not related to ART' below.)
For some patients, insurance may not cover TAF-based options. If this is the case and the person has normal renal function and none of the risk factors mentioned above for TDF-associated renal disease, we continue the TDF-based option with regular monitoring for renal adverse effects (see "Patient monitoring during HIV antiretroviral therapy"). If a person taking TDF has abnormal renal function and/or significant risk factors for TDF-associated renal disease, we petition insurance for the TAF-based option.
The combination of TDF plus a boosted protease inhibitor (PI) carries a higher risk of TDF-induced renal toxicity than other combinations; so, for patients with risk factors for renal disease, we often change the boosted PI and TDF if the change can be done safely [2-4]. As an example, if a patient has multiple risk factors for renal disease and is taking TDF-emtricitabine plus a boosted PI, we often switch TDF to TAF and/or the boosted PI to dolutegravir or bictegravir (recognizing that the switch to dolutegravir or bictegravir may lead to a mild increase in serum creatinine after the regimen change). If these agents cannot be changed, we continue careful renal monitoring. (See 'Ensuring the potency of the new regimen' below and "Patient monitoring during HIV antiretroviral therapy", section on 'ART-associated toxicity'.)
We also have a low threshold to switch patients from TDF to TAF to reduce the risk of TDF-associated bone disease. This may be particularly beneficial for individuals with osteopenia or multiple risk factors for osteoporosis (eg, low body weight, tobacco smoking, family history of osteoporosis). (See 'Osteopenia/osteoporosis' below.)
It is important to inform patients that they may experience weight gain following a switch from TDF to TAF, although the mechanism and cardiometabolic implications of this are unclear. (See 'Risk of weight gain' below.)
●Patients receiving abacavir – For patients with ischemic cardiovascular events, we always change abacavir since abacavir may raise the risk of ischemic cardiovascular disease [5-10]. For a patient at high risk of cardiovascular disease, we also prefer to change abacavir to TAF or another option if there are no contraindications. (See "Management of cardiovascular risk (including dyslipidemia) in patients with HIV", section on 'Role of antiretroviral therapy'.)
●Elvitegravir-containing regimens – If a patient is taking an elvitegravir-containing regimen (eg, elvitegravir-cobicistat-emtricitabine-TDF or elvitegravir-cobicistat-emtricitabine-TAF) and the regimen is well tolerated with a routinely suppressed viral load, it is not necessary to change to a different option. However, we have a low threshold to make a change because other regimens tend to have fewer side effects and drug-drug interactions. In addition, the boosted elvitegravir options have a relatively low barrier to resistance, and virologic failure on one of the boosted elvitegravir options can lead to significant multiclass drug resistance.
For individuals taking one of these elvitegravir-containing regimens, we regularly assess tolerability (especially gastrointestinal symptoms) and drug-drug interactions (including with over-the-counter medications), and we emphasize the importance of adherence to daily dosing. If any issues are apparent, we switch to a regimen that includes an unboosted integrase strand transfer inhibitor (INSTI) with a high barrier to resistance, such as dolutegravir or bictegravir. (See 'Choosing a regimen' below.)
●First-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs; efavirenz or nevirapine) – If a patient has a suppressed viral load on efavirenz, we inquire about depression and other mental health and central nervous system (CNS) side effects. We then adjust the regimen if these symptoms are present. (See 'Neuropsychiatric side effects' below.)
If the patient is tolerating efavirenz, it is not essential to change the medication, although we have a low threshold to recommend a change because newer regimens have a higher barrier to resistance and tend to be better tolerated. Patients may feel better after a change of therapy even if they did not report significant pre-switch side effects with efavirenz. The change also may benefit lipids and vitamin D levels. (See "Bone and calcium disorders in patients with HIV", section on 'Vitamin D'.)
Similar to efavirenz, a change in regimen is not necessary in virologically suppressed patients taking nevirapine so long as they are tolerating the regimen. However, we discuss the potential advantages of an update (newer options have a higher barrier to resistance and may also provide a slightly lower pill burden). For those considering a switch, we do discuss the potential risk of serious immune-mediated toxicity if nevirapine should be resumed, especially for those with a high CD4 count (>250 cells/microL for females, >400 cells/microL for males), as discussed below. (See 'Can a patient resume a prior regimen' below.)
If a patient wants to stay on nevirapine and is taking it twice daily, updating to the extended-release, once-daily version is also an option. (See "Overview of antiretroviral agents used to treat HIV", section on 'Nevirapine'.)
●Older nucleoside reverse transcriptase inhibitors (NRTIs) or older PIs – There are certain antiretroviral agents that we always try to change because of increased long-term risk of metabolic and other toxicities. These include older NRTIs (eg, zidovudine) or older PIs such as lopinavir-ritonavir, fosamprenavir, indinavir, nelfinavir, or saquinavir. Changing these older antiretroviral drugs to newer options also reduces pill burden.
For those receiving boosted atazanavir, the decision to switch agents is less clear. Guideline panels no longer recommend boosted atazanavir as a first-line treatment option because of reduced tolerability compared with newer agents [11-13]; in addition, atazanavir is associated with unique side effects such as indirect hyperbilirubinemia (which can lead to jaundice), kidney stones, and gallstones. However, it is not essential to change the medication if there are no tolerability issues. Atazanavir is also the only boosted PI that is not linked to a higher risk of cardiovascular events, and it may actually reduce cardiovascular risk since it causes elevated bilirubin levels and bilirubin is an antioxidant [14]. (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Cardiovascular disease'.)
Regimen has a low barrier to resistance — Some patients may be tolerating their regimen, but it has a relatively low barrier to resistance (this includes NNRTI-based regimens or regimens with raltegravir or boosted elvitegravir plus two NRTIs). We do not always switch regimens in this setting. However, we carefully assess adherence and drug-drug and drug-food interactions, and if any appear problematic, we recommend switching to an option with a relatively higher barrier to resistance (usually dolutegravir- or bictegravir-based therapy or sometimes a boosted darunavir-based option). (See 'Ensuring the potency of the new regimen' below.)
EVALUATION PRIOR TO SWITCHING REGIMENS — When switching a regimen, the goal is to maintain a suppressed plasma viral load (HIV RNA) while improving the patient's quality of life and reducing the risk of short- or long-term toxicity. To determine if this is feasible, it is important to evaluate the patient's antiretroviral history (especially history of any virologic failures, antiretroviral drug resistance, or antiretroviral drug intolerances), comorbid conditions, and barriers to taking the current regimen. Every discussion about switching antiretroviral therapy (ART) should include an explanation of the potential risks and benefits as well as a discussion of the potential to resume the pre-switch regimen if unanticipated side effects occur. (See 'Ensuring the potency of the new regimen' below and 'Other considerations for regimen selection' below and 'Can a patient resume a prior regimen' below.)
ENSURING THE POTENCY OF THE NEW REGIMEN
General principles — For a patient who has a suppressed viral load, switching antiretroviral therapy (ART) can involve a single- or multi-drug switch. In either case, it is important to ensure that the new regimen will maintain virologic suppression. The likelihood that a patient will maintain virologic suppression depends upon:
●The presence of prior resistance mutations.
●If the new regimen has a relatively high or low barrier to resistance; this is particularly important if the switch involves a change from a regimen with a higher barrier to resistance to a regimen with a lower barrier to resistance (which carries more risk) or a switch to a regimen with fewer active drugs.
A regimen with a relatively high barrier to resistance includes a boosted protease inhibitor (PI) or the integrase inhibitors dolutegravir or bictegravir as the third agent. Most other regimens (eg, those that include doravirine, rilpivirine, efavirenz, raltegravir, or elvitegravir as the third agent) have a lower barrier to resistance.
If switching from a regimen with a high-resistance barrier to a regimen with a low barrier, it is essential to ensure that there are no resistance mutations that could compromise the activity of the nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone. This was demonstrated in the SWITCHMRK 1 and 2 trials, in which participants with suppressed HIV RNA levels taking ritonavir-boosted lopinavir plus two NRTIs either continued their current regimen or switched to raltegravir plus two NRTIs [15]. These trials were halted at week 24 because fewer participants in the switch arm maintained virologic suppression and results failed to meet noninferiority criteria. However, in an analysis limited to participants with no history of virologic failure or NRTI-associated resistance mutations, those who switched to raltegravir maintained virologic suppression at a rate noninferior to those who continued the boosted PI.
Some providers may be concerned about switching to rilpivirine if the pretreatment HIV RNA was above 100,000 copies/mL or the CD4 count was below 200 cells/microL since rilpivirine should not be used in such patients who are treatment naïve. However, we generally feel comfortable changing to a rilpivirine-containing ART option if the patient has had no prior virologic failures or significant NRTI or non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations and the viral load is suppressed at the time of the switch. Clinical trial data suggest that a switch to rilpivirine is safe in this setting [16].
Single-drug regimens should not be used, as studies have demonstrated an increased risk of virologic failure with monotherapy, even with drugs that have a high barrier to resistance (eg, ritonavir-boosted PIs or dolutegravir) [11,17-20]. As an example, in a randomized trial of 158 patients with virologic suppression on dolutegravir-abacavir-lamivudine, the cumulative incidence of virologic breakthrough (viral load >50 copies/mL on two occasions) was 9.7 percent over 48 weeks in those who switched to dolutegravir monotherapy, and two patients developed integrase strand transfer inhibitor (INSTI) resistance; by contrast, patients who stayed on dolutegravir-abacavir-lamivudine remained virologically suppressed [20].
Evaluating for prior resistance — To assess for prior resistance, it is important to know whether the patient has experienced past instances of virologic failure and if there is a history of documented antiretroviral drug-resistance mutations (either pretreatment or secondary to virologic failure).
A composite of past RNA genotypes is the preferred method for assessing resistance. However, a common clinical challenge arises when past resistance results are not available or if the test was performed when the patient was not taking ART (resistance testing may not detect all the viral mutations if the patient has not taken medications for more than four weeks or so). In this setting:
●We review the patient's past ART regimens and viral load results as best we can to determine if resistance mutations are likely. We consider individuals to have suspected resistance if they switched ART because of virologic rebound on their prior regimen, received previous suboptimal ART (eg, mono- or dual-NRTI regimens), or have a suppressed HIV RNA level on what appears to be a salvage regimen but have an unknown resistance mutation history. A discussion of salvage regimens is presented separately. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Patients who have failed multiple regimens'.)
●We also assess if obtaining a proviral DNA ("archive") genotype test would be helpful since traditional RNA genotypes are not feasible with a suppressed HIV RNA. If past RNA genotype results are not available, we consider checking a proviral DNA genotype, particularly for patients who take a complex salvage ART regimen, who have taken multiple past regimens, and who wish to simplify ART to fewer active drugs or a combination with a relatively lower barrier to resistance [11]. This test can detect resistance mutations in proviral HIV DNA archived within peripheral blood mononuclear cells and may provide clinically useful information to help guide ART changes [21,22]. However, the best use of this test remains unclear since results often do not show complete concordance with traditional RNA genotypes and may either miss historical mutations or detect mutations not present on RNA genotyping (these are of unclear clinical significance) [11,23-26]. Loss of information on DNA genotyping has been associated with longer duration of ART usage [27,28]. Additional information on proviral DNA assays is presented elsewhere. (See "Overview of HIV drug resistance testing assays", section on 'HIV-1 proviral DNA assays'.)
Choosing a regimen
Patients with no history of resistance — If the patient has no history of resistance-associated mutations, we generally switch to any of the preferred ART regimens after a review of comorbid conditions, drug-drug interactions, potential side effects, food requirements, and insurance access; alternative treatment options include doravirine, raltegravir-, or rilpivirine-based regimens (table 1 and table 2). In this setting, in which we feel confident there is no resistance that will compromise the new regimen (especially the NRTI combination), we are comfortable with a switch to a regimen with a greater, equal, or lower barrier to resistance. As examples:
●If a patient reports central nervous system (CNS) or mental health side effects while taking efavirenz-emtricitabine-tenofovir disoproxil fumarate (a regimen with relatively low barrier to resistance), we feel comfortable switching to any of the preferred regimens or to raltegravir-, rilpivirine-, or doravirine-based ART, assuming the viral load is suppressed and there are no other contraindications (since these regimens have a similar barrier to resistance). Considerations for regimen selection in the setting of neuropsychiatric side effects are presented below. (See 'Neuropsychiatric side effects' below.)
●If a patient taking a regimen with a relatively high barrier to resistance (eg, ritonavir or cobicistat-boosted darunavir plus two NRTIs) needs to change regimens because of potential drug interactions, but has had past ART regimen switches, we generally prefer switching to a new regimen with a similarly high barrier to resistance (such as dolutegravir or bictegravir-based therapy). If this is not possible, we would feel comfortable switching to a regimen with a lower barrier to resistance (eg, rilpivirine, doravirine, raltegravir, or elvitegravir-based therapy) only if it is well documented that the viral load remained suppressed through all of the switches. If it is not clear whether this is the case, a DNA (archive) genotype should be obtained before making the switch. The approach to treatment in patients with suspected drug resistance is described below. (See 'Patients with known or suspected drug resistance' below.)
For certain patients with stable HIV RNA suppression (eg, at least 6 to 12 months), a two-drug regimen may be an option if there are concerns about toxicity or pill burden and one of the preferred three-drug regimens cannot be used. (See 'Eligibility for two-drug regimens' below.)
Patients with known or suspected drug resistance — For patients who have a suppressed viral load (HIV RNA) and have known or suspected resistance, we typically switch their regimen only if we are able to create one that has an equal or greater barrier to resistance. We determine if a patient has known resistance by reviewing past resistance test results, and we determine if a patient has suspected antiretroviral resistance by reviewing past regimens and viral load results for evidence of episodes of virologic failure; this is discussed in greater detail above. (See 'Evaluating for prior resistance' above.)
For patients with known or suspected resistance, selecting a new regimen depends upon the type and number of prior resistance mutations and available active agents. As examples:
●If a patient with known NRTI resistance has a suppressed HIV RNA on a regimen such as tenofovir alafenamide-emtricitabine plus boosted darunavir but is bothered by side effects associated with the boosted PI, the patient could continue the NRTI combination, and the boosted PI could be switched to the INSTI dolutegravir or bictegravir. This switch would not significantly change the relative barrier to resistance and is generally effective as long as the patient has at least one active NRTI and there is no history of INSTI resistance. However, in this scenario, we would not switch to a third agent of relatively lower barrier to resistance, such as rilpivirine, doravirine, raltegravir, or boosted elvitegravir, without adding additional active agents.
Patients with NRTI mutations who are virologically suppressed on a PI-based regimen are able to switch to a dolutegravir- or bictegravir-containing regimen and maintain virologic control [29-33]. In a randomized trial of 795 patients with HIV who were on a second-line regimen after failing an initial NNRTI-containing regimen, switching from a boosted PI to dolutegravir was effective, even without knowledge of prior resistance [33].
●By contrast, a single-drug switch may not be feasible in a patient with multi-class resistance who is taking agents from several different classes. In this setting, we generally switch multiple agents to craft a regimen with at least three active drugs (or at least two active drugs if a boosted PI or dolutegravir or bictegravir can be included). To help ensure the potency of a new regimen, patients with a history of complex drug resistance who are virologically suppressed should preferably have their regimens switched only in consultation with an HIV specialist.
Eligibility for two-drug regimens — Two-drug regimens may be suitable for certain virologically suppressed patients who have developed or are at risk of developing toxicity from NRTIs like tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and abacavir [34-36].
●Eligibility – Prior to switching to a two-drug regimen:
•We ensure there are no drug-resistance mutations that would compromise either agent in the two-drug option. If records are not available or the resistance history is not clear and the patient must change regimens (eg, due to toxicity), obtaining a proviral DNA ("archive") genotype is reasonable. (See 'Evaluating for prior resistance' above.)
•When considering two-drug oral ART, we ensure that at least one of the agents in the two-drug regimen has a high barrier to resistance (eg, dolutegravir or boosted darunavir). (See 'Ensuring the potency of the new regimen' above.)
•We confirm that there are no significant drug-drug interactions that might reduce the concentration of either drug. (See 'Reducing drug-drug and drug-food interactions' below.)
•We confirm there is no evidence of chronic hepatitis B virus (HBV) infection (TDF or TAF should be part of the ART regimen in patients with chronic HBV). (See 'Chronic HBV infection' below.)
●Preferred regimens – Once-daily options for two-drug maintenance ART include dolutegravir-lamivudine and dolutegravir-rilpivirine (both available as single, coformulated tablets) as well as the long-acting injectable regimen cabotegravir-rilpivirine (table 3). Of the oral two-drug options, we generally prefer dolutegravir-lamivudine because it avoids the full meal requirement and added drug-drug interactions of dolutegravir-rilpivirine, but both are suitable options to replace three-drug oral ART for select patients who have long-term virologic suppression and no hepatitis B coinfection, as described above. The decision to use injectable versus oral therapy and details regarding administration of cabotegravir-rilpivirine are presented below and in a separate topic review. (See 'Long-acting injectable therapy' below and "Use of long-acting cabotegravir-rilpivirine in people with HIV".)
Several clinical trials have supported the use of dolutegravir-lamivudine as maintenance therapy [37-40]. As an example, in an open-label randomized trial of 743 patients with a plasma HIV RNA <50 copies/mL for at least six months, participants who switched to dolutegravir-lamivudine maintained virologic suppression at a rate similar to those who continued a three- or four-drug TAF-containing regimen at 48 weeks [40]. Participants had no history of INSTI or NRTI resistance or virologic failure requiring a change in regimen, no evidence of virologic failure within one year of switching regimens, and no evidence of hepatitis B coinfection. In this trial, there were improvements in certain metabolic parameters (total and low-density lipoprotein [LDL] cholesterol, triglycerides, insulin resistance) in those who switched to dolutegravir-lamivudine, but these results were largely driven by participants receiving regimens with pharmacokinetic boosters (in particular, elvitegravir-cobicistat-emtricitabine-TAF) at baseline.
The use of dolutegravir-rilpivirine was supported by the open-label SWORD-1 and SWORD-2 trials [41]. In these trials, 1028 individuals taking a standard three-drug ART regimen were randomized to either continue current therapy or simplify to dolutegravir plus rilpivirine. Subjects were required to have a suppressed HIV RNA for at least six months prior to the switch, be taking their first or second ART regimen only, and have no history of virologic failure or hepatitis B coinfection. The proportion of participants in the two-drug maintenance arm with suppressed HIV RNA at 48 weeks was similar to those on the three-drug ART arm (95 percent in both arms; adjusted treatment difference of -0.2 percent [95% CI -3.0 to 2.5 percent]). Observational and retrospective studies have also demonstrated that carefully selected treatment-experienced individuals can safely simplify their regimen to dolutegravir-rilpivirine dual maintenance therapy [42,43].
Several clinical trials have supported the use of long-acting injectable therapy with cabotegravir-rilpivirine. These are discussed in a separate topic review. (See "Use of long-acting cabotegravir-rilpivirine in people with HIV".)
●Alternative regimens – There is limited experience using two-drug combinations that include a boosted PI. The combination of ritonavir-boosted darunavir plus lamivudine was evaluated in 249 patients with an HIV RNA <50 copies/mL for at least six months on a three-drug regimen that included ritonavir-boosted darunavir plus two NRTIs [44]. At 48 weeks, the proportion of participants with a suppressed viral load was 90 percent in those randomized to dual therapy and 93 percent in those randomized to continue triple therapy (difference -3.8 percent; 95% CI -11.0 to 3.4). Other studies have also supported the use of ritonavir-boosted atazanavir or lopinavir-ritonavir with lamivudine; however, these PIs are generally not as well tolerated as boosted darunavir [45-47].
A switch to the two-drug combination boosted darunavir plus dolutegravir was compared with continuation of boosted darunavir plus two NRTIs in a randomized, open-label trial of 263 individuals with an HIV RNA level below 50 copies/mL for at least 24 weeks and no hepatitis B infection [48]. After 48 weeks, those who switched to the two-drug regimen maintained a suppressed viral load at a similar rate as the group who continued their three-drug combination (86.3 versus 87.9 percent, respectively).
Other two-drug combinations, such as dolutegravir plus doravirine and boosted darunavir plus doravirine or rilpivirine, may be considered in select situations when the above regimens cannot not be used [49-52], but these have not been well studied.
OTHER CONSIDERATIONS FOR REGIMEN SELECTION — This section will discuss factors to consider when switching to a new antiretroviral therapy (ART) regimen in nonpregnant adults and adolescents. Specific considerations during pregnancy are discussed below and in a separate topic review. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'ART selection and management'.)
In general, it is best to switch to the new regimen and not interrupt or discontinue therapy. A discussion of how to ensure the potency of a new regimen is discussed above. (See 'Ensuring the potency of the new regimen' above.)
Side effects — When changing a regimen due to intolerance, it is important to understand the types and severity of side effects the patient is experiencing. We assess the following:
●If a specific agent in the regimen is most likely to be causing the side effects
●If an agent less likely to cause the side effects can be substituted for the offending agent
●If there is a benefit to replacing or updating more than one agent in the regimen
Side effects are frequent reasons for modifying an ART regimen and can often be managed by single-drug substitutions. However, newer ART regimens, such as those that include unboosted integrase inhibitors, are generally better tolerated and require fewer treatment modifications compared with other options [53,54]. In addition, tenofovir alafenamide (TAF) is associated with reduced nephrotoxicity compared with tenofovir disoproxil fumarate (TDF), and ritonavir-boosted darunavir is generally better tolerated than other protease inhibitors (PIs), including boosted atazanavir [12].
Gastrointestinal intolerance — Gastrointestinal (GI) side effects may occur with any antiretroviral agent, but among the commonly used drugs, PIs and pharmacokinetic boosters (ie, cobicistat) are the most likely causes. We have occasionally seen GI intolerance with TDF. GI side effects with other agents are much less common.
For patients taking a boosting agent (usually a ritonavir- or cobicistat-boosted PI or cobicistat-boosted elvitegravir), GI symptoms and signs may improve with a switch to a nonboosted integrase strand transfer inhibitor (INSTI), such as dolutegravir or bictegravir. For patients who are already taking an unboosted INSTI, careful consideration should be given to possible nonantiretroviral causes for the GI symptoms before changing the regimen. If an acid suppressing agent is required, drug-drug interactions should be assessed. (See 'Reducing drug-drug and drug-food interactions' below.)
Occasionally, a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen may be considered in patients with GI intolerance, but several factors should be reviewed before making this change. (See 'Eligibility for two-drug regimens' above.)
Neuropsychiatric side effects — The antiretroviral agent that most frequently causes neuropsychiatric adverse effects is efavirenz [55]. The non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine and the INSTIs (especially dolutegravir) can also cause central nervous system (CNS) side effects but are less likely to do so. A more detailed description of these adverse reactions is found elsewhere. (See "Overview of antiretroviral agents used to treat HIV", section on 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)' and "Overview of antiretroviral agents used to treat HIV", section on 'Integrase strand transfer inhibitors (INSTIs)'.)
●NNRTIs – We generally have a low threshold to switch efavirenz to a different agent to improve CNS side effects. This is particularly important for patients with depression, as efavirenz use has been associated with an increased risk of suicidal ideation [55]. Mental health side effects frequently diminish with a switch from efavirenz to an INSTI, such as raltegravir, elvitegravir, or bictegravir or to another NNRTI, such as rilpivirine or doravirine.
Studies that compared efavirenz with an INSTI or with rilpivirine generally found fewer CNS side effects with the nonefavirenz-based option [56-60]. In addition, switching from efavirenz to one of these agents can lead to resolution of CNS manifestations [61-64].
●INSTIs – Although efavirenz is the antiretroviral agent most commonly associated with CNS side effects, 5 to 10 percent of patients do not tolerate dolutegravir. Multiple studies have found that dolutegravir can cause insomnia, headache, and other CNS symptoms [65-70]. There are also rare reports of severe depression with the INSTIs raltegravir and dolutegravir, and it has been suggested that the neuropsychiatric side effects may be a class effect of the integrase inhibitors in some individuals [71-73].
There are limited data to guide treatment decisions in these settings. For those with severe mental health side effects, we switch from an INSTI-containing regimen to one that includes a third agent from a different class (eg, the NNRTI doravirine if there are no concerns for resistance). In contrast, for those with milder adverse reactions (eg, insomnia or headache), we usually try to switch to a different INSTI. Although some patients may ultimately require a switch to a different antiretroviral class, in our experience mild CNS symptoms sometimes resolve after switching dolutegravir to an INSTI like bictegravir.
Transaminitis/hepatic events — Most aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations that occur secondary to ART are mild and asymptomatic, and many improve or remain stable without modification of ART. Severe hepatotoxicity occurs rarely and generally occurs before the patient has a stably suppressed viral load. In a cohort of over 10,000 individuals with HIV, significant elevation in aminotransferase levels occurred within one year of starting ART in 2 percent [74]. Thus, for patients stably suppressed on an ART regimen, it is important to consider other causes of transaminase flares (alcohol, nonantiretroviral medication-induced, nonalcoholic fatty liver disease, hepatitis C or hepatitis C immune reconstitution inflammatory syndrome, and other etiologies). (See "Evaluation of the patient with HIV and hepatobiliary complaints".)
Weight gain
Risk of weight gain — ART regimens that include TAF and/or an INSTI (especially dolutegravir) are associated with greater increases in weight as compared with other classes or agents; this association with greater weight change has been demonstrated after a regimen switch, such as from an NNRTI to an INSTI or from TDF to TAF [75-84].
For individuals switching to TAF or an INSTI from an older agent, we counsel about the potential for weight gain and the importance of healthy eating and exercise, and we monitor weight and metabolic parameters. In general, we do not see this issue as a reason to avoid TAF or INSTIs, but decisions for patients should be individualized, particularly for those who also have metabolic syndrome. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
The weight increase after a switch of ART generally occurs early after the switch and stabilizes by approximately 48 weeks after the switch for most individuals [79]. Greater likelihood of weight gain has also been associated with certain social determinants of health and demographic factors, such as Black race and female gender [76].
The mechanism and long-term cardiometabolic consequences of weight change between different antiretrovirals have not been confirmed. The difference in weight change between TDF and TAF appears to stem from weight suppressive effects of TDF. Studies have not established that TAF directly causes weight gain, and in clinical trials, individuals who stop TDF gain weight even in the absence of a switch to TAF [40,85]. Other NRTIs, such as abacavir and zidovudine, may also suppress weight, and individuals tend to gain weight after a switch from one of these agents to TAF as well [79].
There may be an INSTI class effect that impacts weight and/or glycemic control [86]. Although most studies have found an association between dolutegravir or bictegravir and weight gain after switching from an NNRTI or PI [76,80,83], some have implicated raltegravir or boosted elvitegravir as well. INSTI usage may also lead to an excess risk for diabetes or cardiovascular disease, but these effects and predictors of such effects for individual patients have not been fully elucidated [87,88]. Further research to better understand and confirm the cardiometabolic effects of INSTIs is needed. In the meantime, the possible association between INSTIs and such comorbidities must be weighed against evidence that INSTIs demonstrate greater long-term durability, tolerability, and virologic suppression rates compared to agents from other classes. (See "Overview of antiretroviral agents used to treat HIV".)
Managing weight gain on ART — In patients who experience substantial weight gain on TAF or an INSTI, it is unclear if changing TAF and/or the INSTI will lead to reversal of the weight change. It is also unclear whether returning to an alternate agent that may have weight suppressive effects (eg, TDF or an NNRTI) is better for an individual's health or not. In cases in which weight gain while taking TAF and/or an INSTI has occurred, we emphasize lifestyle modifications for weight loss and discuss the pros and cons of switching therapy.
If a person has a suppressed viral load while taking dolutegravir or bictegravir with TAF-emtricitabine, yet weight gain on the regimen has caused or contributed to mental distress or medical complications (such as glucose intolerance, hypertension, or cardiovascular disease), we consider switching to an NNRTI with TAF-emtricitabine or TDF-emtricitabine (as long as these agents are fully active) but counsel that it is not clear that this will reverse the weight gain, the NNRTI-based regimen has a relatively lower barrier to resistance, and the new regimen may have other potential adverse effects. Clinical trials to help guide clinicians and patients about these options and optimal ART management following INSTI and TAF-associated weight gain are ongoing.
Mitochondrial toxicity — Older NRTIs, such as zidovudine, stavudine, and didanosine, can cause significant mitochondrial toxicity, leading to pancreatitis, lipoatrophy, lactic acidosis, and other adverse events. We always try to switch these agents. In rare instances, zidovudine may be used to maintain viral suppression (such as with the K65R NRTI resistance mutation, which increases zidovudine susceptibility); however, even in this setting, there are usually enough other agents available that zidovudine can be switched to a better-tolerated option. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
Comorbid conditions — Patients may have certain comorbid conditions that require a change in or impact selection of their ART regimen. These conditions may have been present prior to initiating ART (eg, hepatitis B virus [HBV] infection), have resulted from their ART regimen (reduced kidney function due to TDF), or have developed due to other causes (eg, reduced kidney function due to diabetes).
Reduced kidney function — When switching a regimen in patients with or at risk for reduced kidney function, it is important to consider if the patient's current antiretroviral regimen is the cause of the kidney disease.
Renal events due to ART regimen — TDF is the antiretroviral agent that most frequently causes nephrotoxicity (eg, proximal tubule wasting) [2-4], although atazanavir has also been associated with adverse renal events (eg, kidney stones). (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir disoproxil fumarate' and "Overview of antiretroviral agents used to treat HIV", section on 'Atazanavir'.)
If renal toxicity develops with one of these agents, it should be changed. For patients who develop TDF-associated proximal tubulopathy, we use the following approach:
●Patients without chronic HBV – For patients without chronic HBV, the regimen can be switched to a two-drug regimen that does not include tenofovir (TDF or TAF). As an example, if a person who has a suppressed HIV RNA level and no history of virologic failures or resistance develops TDF-induced renal toxicity, a switch to a maintenance regimen such as dolutegravir-lamivudine or dolutegravir-rilpivirine may be an option (see 'Eligibility for two-drug regimens' above). However, if the patient is taking a more complex regimen when TDF-associated proximal tubulopathy occurs, TDF may need to be replaced with an alternate agent.
We generally avoid switching to TAF while the patient is experiencing acute renal dysfunction related to TDF. Although TAF is associated with less renal toxicity and switching to TAF may be safe [89,90], there is limited experience using TAF in the setting of active TDF-induced renal dysfunction [91].
●Patients with chronic HBV – For patients with chronic HBV, changing TDF to TAF with close renal monitoring may be considered since TDF and TAF are first-line treatment for HBV. However, the risk of continued renal dysfunction must be weighed against the potential benefits of TAF. Switching TDF to entecavir is the other principal option to consider. The management of patients with HIV/HBV coinfection with reduced kidney function is discussed elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Renal insufficiency on tenofovir'.)
It is important that antiretroviral-induced renal toxicity be differentiated from benign effects on estimated glomerular filtration rate (eGFR). Rilpivirine, cobicistat, ritonavir, dolutegravir, and bictegravir all block tubular secretion of creatinine, leading to an expected small increase in serum creatinine (and decrease in eGFR), which is noticeable in the first four to eight weeks of therapy [92]. This change in eGFR is benign and does not warrant a change to ART; however, if the patient is also taking TDF, one must monitor for TDF toxicity (such as with regular urinalysis to screen for new proteinuria or glycosuria) [93]. (See "Patient monitoring during HIV antiretroviral therapy", section on 'ART-associated toxicity'.)
Kidney disease not related to ART — Some patients will have pre-existing kidney disease or develop new kidney disease not related to their ART regimen. In such patients, TDF should be avoided. TAF can be used for those with moderately reduced kidney function (eg, creatinine clearance between 30 to 60 mL/min). Alternatively, a tenofovir-sparing regimen may be reasonable for select patients. (See 'Eligibility for two-drug regimens' above.)
Osteopenia/osteoporosis — TDF reduces bone mineral density more than other antiretroviral options [5,94-97]. Thus, we switch patients with low bone density who are receiving a TDF-containing regimen to an alternative one [6].
One option is to switch TDF to TAF since switching TDF to another agent may lead to improvement in bone mineral density [7-10,89]; however, long-term post-switch data are lacking, especially for TAF. Another option is switching to an NRTI-sparing/limiting regimen, but this approach should only be used in select patients. (See 'Eligibility for two-drug regimens' above.)
In patients receiving a PI, consideration should also be given to switching the boosted PI to an alternate agent, such as dolutegravir or bictegravir, if possible. Some studies have also implicated PIs in reducing bone mineral density [5,94,97]. (See 'Ensuring the potency of the new regimen' above.)
Efavirenz affects vitamin D metabolism and reduces vitamin D levels, and switching efavirenz to an alternative drug may lead to increased vitamin D levels [98-100]. However, the clinical benefit of switching for this indication has not been established.
Chronic HBV infection — In patients with HIV/HBV coinfection, all efforts should be made to use a regimen that includes TAF or TDF. Patients with HIV/HBV who cannot take tenofovir as part of their regimen (eg, patients with a creatinine clearance below 30 mL/min) should be managed in consultation with an expert in HIV and viral hepatitis. (See "Treatment of chronic hepatitis B in patients with HIV".)
Hyperlipidemia — Certain antiretroviral agents affect lipids more than others [101]. Boosted PIs and older NRTIs (eg, zidovudine) are the worst offenders in terms of metabolic side effects. The NNRTI efavirenz also raises lipids, especially triglycerides. Thus, if a patient with significant hyperlipidemia is receiving one of these agents, we change to an alternative regimen if we can ensure virologic suppression will be maintained. (See 'Ensuring the potency of the new regimen' above.)
Among the integrase inhibitors, a nonboosted INSTI (raltegravir, dolutegravir, or bictegravir) is preferred over cobicistat-boosted elvitegravir if lipids are a concern. If an NNRTI is used, rilpivirine or doravirine is generally preferred over efavirenz. For patients who require a boosted PI, atazanavir and darunavir are better than older PIs, such as lopinavir [102,103]. Studies have found that there are benefits to changing from a boosted PI to bictegravir, dolutegravir, raltegravir, elvitegravir, rilpivirine, or doravirine [103-110]. Updating efavirenz to newer options (eg, an INSTI, rilpivirine, or doravirine) can also lead to improvement [111,112].
TDF has lipid-lowering properties, though the clinical implications are unclear (especially because it tends to lower both low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) [113]. Although switching from TDF to TAF may lead to increased lipids because of lower circulating plasma tenofovir levels, this worsening is generally mild and the clinical significance is unknown [7,8]. A switch from TDF to abacavir can also lead to an increase in lipids [114].
A more detailed discussion of how to manage cardiovascular risk in patients with HIV is found elsewhere. (See "Management of cardiovascular risk (including dyslipidemia) in patients with HIV", section on 'Role of antiretroviral therapy'.)
Reducing pill burden
Single-pill regimens — Patients often inquire about switching to a single-pill regimen. Patients may be bothered by the number of pills they take, the frequency of dosing, and/or the size of the pill. Reducing pill burden promotes adherence and improves a patient's quality of life.
Before switching to a single-pill option, we review resistance and virologic failure history and ensure that the new regimen will maintain virologic suppression. Many single-pill regimens fit the category of relatively low barrier to resistance (such as those that include an NNRTI or the INSTI elvitegravir). Single-pill regimens that we consider to have high barrier to resistance include bictegravir-emtricitabine-TAF, darunavir-cobicistat-emtricitabine-TAF, and dolutegravir-abacavir-lamivudine. (See 'Ensuring the potency of the new regimen' above.)
A potential concern when switching to a single-pill regimen is the large size of some of these tablets. Options that include TAF are smaller in size than options that include TDF or abacavir. As an example, the dolutegravir-abacavir-lamivudine tablet is quite large. If feasible, it helps to show a patient the various pill sizes of the single-pill regimens and compare with the size of the two-tablet options to help inform the switch decision.
Several clinical trials have examined switches to various single-pill regimens, and patients have generally maintained virologic suppression [8,16,61,63,115-118]. Most of these trials have required enrollees to be taking their first or second ART regimen only, to have no history of virologic failure or drug resistance, and to have a suppressed viral load for a predefined period of time. However, we typically feel fine switching to dolutegravir plus TAF-emtricitabine or to bictegravir-emtricitabine-TAF if a person has a routinely suppressed viral load, no INSTI resistance, and limited NRTI resistance mutations (such as only the M184V/I mutation). Emerging data suggest individuals with this resistance pattern can remain virologically suppressed after a switch to a bictegravir- or dolutegravir-containing regimen [32,119].
If switching to a single-pill regimen does not seem possible due to drug resistance, insurance barriers, or other concerns, other potential switches that can reduce pill burden or reduce dosing frequency include a shift from darunavir plus ritonavir to darunavir-cobicistat (assuming the individual is taking once-daily dosing darunavir); a change from once-daily boosted darunavir plus two NRTIs to darunavir-cobicistat-emtricitabine-TAF; simplification from atazanavir plus ritonavir to atazanavir-cobicistat; or a switch from twice-daily raltegravir to the once-daily, high-dose option. (See "Overview of antiretroviral agents used to treat HIV", section on 'Raltegravir'.)
Long-acting injectable therapy — Several two-drug regimens are available for maintenance ART, including an injectable regimen (cabotegravir-rilpivirine), which is administered intramuscularly (IM) every four or every eight weeks [120]. However, only certain patients are eligible for two-drug injectable therapy, as discussed above and in a separate topic review. (See 'Eligibility for two-drug regimens' above and "Use of long-acting cabotegravir-rilpivirine in people with HIV", section on 'Determining eligibility'.)
Injectable therapy may be a good option to replace oral therapy in select patients who have difficulty swallowing pills, difficulty storing their medications at home due to concerns around confidentiality or stigma, or a preference for nondaily dosing or injectable therapy. However, injectable therapy must be used with caution in patients who have not been adherent to their ART regimens or medical visits in the past; patients may experience prolonged periods of subtherapeutic ART levels if doses are missed, which puts them at risk for developing NNRTI and INSTI resistance. A more detailed discussion of long-acting cabotegravir-rilpivirine, including selecting eligible patients, is presented separately. (See "Use of long-acting cabotegravir-rilpivirine in people with HIV".)
Reducing drug-drug and drug-food interactions — Some ART regimens may need to be modified to avoid drug-drug or drug-food interactions.
The pharmacokinetic boosting agents ritonavir and cobicistat have more drug-drug interactions than other options because they inhibit cytochrome p450-mediated drug metabolism. As examples:
●For a patient requiring regular intranasal or inhaled corticosteroids or corticosteroid injections, we generally avoid ritonavir or cobicistat in order to avoid potentially dangerous interactions. This requires selecting an active agent that does not require pharmacokinetic boosting, such as dolutegravir or bictegravir.
●Similarly, for a patient with HIV/hepatitis C virus (HCV) coinfection, it is important to review interactions between antiretroviral agents and HCV direct-acting antivirals to ensure there are no significant interactions. In general, the unboosted integrase inhibitors dolutegravir, bictegravir, and raltegravir are the safest options. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)
●Both atazanavir and oral rilpivirine require stomach acidity for maximal absorption. As a result, clinicians should avoid these agents in patients who require proton-pump inhibitors. While H2-blockers may sometimes be used if separated from rilpivirine or atazanavir by a specified number of hours, caution should still be employed with this strategy, and in this setting, we typically try to switch the antiretroviral agent if other effective options are available.
●Rifamycins carry a significant risk of drug-drug interactions. Tenofovir disoproxil fumarate-emtricitabine or abacavir-lamivudine can be used as the nucleoside combination when rifampin is used (TAF should be avoided with rifampin). Efavirenz, dolutegravir, or raltegravir are preferred as the third active drug; however, both raltegravir and dolutegravir require doubling of the daily dose when combined with rifampin. Bictegravir should not be combined with rifampin. Similarly, doravirine should not be combined with rifampin, though it may be acceptable at a higher dose when combined with rifabutin. More detailed information on drug interactions can be found in the drug interaction program within UpToDate and in separate topic reviews. (See "Overview of antiretroviral agents used to treat HIV" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
●The integrase inhibitors raltegravir, elvitegravir, dolutegravir, and bictegravir all have potential interactions with cation-containing compounds (such as calcium or iron supplements and certain antacids and laxatives). The ART regimen and cation-containing compounds may need to be separated and should be reviewed. Specific information is in the drug information topics within UpToDate.
Interactions can also be seen with psychiatric drugs, anti-epileptics, statins, agents that cause QTc prolongation, and others. Refer to the drug interaction program within UpToDate to assess specific interactions.
Some antiretroviral agents also have food requirements (eg, regimens containing oral rilpivirine and regimens requiring boosting with cobicistat or ritonavir should be taken with food). If a patient is struggling with this requirement, a switch to an option that does not have food requirements (eg, dolutegravir, bictegravir, or doravirine-based therapy) should be considered.
Cost or insurance coverage changes — Changes in ART regimens may trigger insurance barriers or other challenges. As an example, they may cover bictegravir-TAF-emtricitabine, but not TAF-emtricitabine. Similarly, a patient's insurance coverage may change, resulting in one or more antiretroviral agents no longer being covered.
In such situations, we generally petition the insurance company to provide the clinically optimal regimen. If this is not possible, we review the factors described above to find an alternative regimen that will be safe and effective. (See 'Ensuring the potency of the new regimen' above.)
PERSONS OF CHILDBEARING POTENTIAL/PREGANCY — When switching a regimen in individuals who are of childbearing potential, it is important to determine if the person is pregnant, and if not, whether they are committed to using effective contraception (eg, oral, injectable, or intrauterine contraception). In persons who may conceive or who become pregnant and are taking an effective antiretroviral regimen, physicians must consider the risks and benefits of continuing the current regimen or making a switch and share these considerations with the patient. Detailed discussions of regimen selection and the safety of antiretroviral medications in these populations are found 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", section on 'Regimen management'.)
LABORATORY MONITORING AFTER REGIMEN CHANGE — After prescribing any new antiretroviral therapy (ART) regimen, we typically check in with the patient by phone after one to two days to confirm there were no pharmacy fill issues and they have received the new regimen correctly, and then we check in again after one to two weeks to ensure that the new regimen is well tolerated. We then recheck the HIV RNA along with a comprehensive metabolic panel four to eight weeks after the switch (four weeks preferred) [11]. It is important to remember that certain agents, such as rilpivirine, cobicistat, dolutegravir, and bictegravir, block tubular secretion of creatinine, and these agents can cause an expected mild rise in serum creatinine in the first four to eight weeks which should then stabilize. (See 'Renal events due to ART regimen' above.)
In the absence of any new symptoms, laboratory abnormalities, or evidence of viral rebound at this initial post-switch check, clinical and laboratory monitoring of the patient may resume on a regularly scheduled basis. (See "Patient monitoring during HIV antiretroviral therapy".)
CAN A PATIENT RESUME A PRIOR REGIMEN — It is common for patients to feel concerned that if they switch from an effective antiretroviral medication or regimen they can never switch back. In general, a change back to the pre-switch regimen is acceptable for virologically suppressed patients who were switched to reduce pill burden, improve mild side effects, or update or simplify the regimen. (See 'Reasons for changing a regimen' above.)
One exception is a switch off the non-nucleoside transcriptase inhibitor (NNRTI) nevirapine. For patients with a high CD4 count (>250 cells/microL for females, >400 cells/microL for males), if we switch nevirapine to another option, we do not switch back to nevirapine if an equally effective regimen is available.
Nevirapine is contraindicated in treatment-naïve patients with a high CD4 count because of serious immune-mediated hepatotoxicity, and given the potential risk for severe toxicity, there are insufficient data to support switching back to nevirapine in such patients who are treatment experienced. In addition, a meta-analysis found an increased risk of hepatotoxicity leading to drug discontinuation among virologically suppressed patients who switched from a protease inhibitor (PI)-based regimen to a nevirapine-containing regimen when compared with those who stayed on their PI (pooled risk difference 7 percent; 95% CI 3-12 percent) [121].
INVESTIGATIONAL APPROACHES — Treatment options using agents with novel mechanisms of action are being examined. One approach is the use of broadly neutralizing monoclonal antibodies (bNAbs) as an alternative or an adjunct to antiretroviral therapy (ART) [122].
Early studies using bNAbs demonstrated the rapid selection of resistant HIV and viral rebound in the absence of suppressive ART [123,124]. However, the field has advanced since then, and several other broadly neutralizing antibody approaches are under development or in clinical trials [125].
The use of a bNAb that blocks the virus-binding site on human CD4 cells (UB-421) was evaluated in a nonrandomized trial of 29 patients taking ART with a CD4 count of >350 cells/microL and a viral load of <20 copies/mL [126]. Patients received eight infusions of UB-421 dosed as either 10 mg/kg every week or 25 mg/kg every two weeks; ART was stopped one week after initiating UB-241 and resumed upon completion of the eighth dose. Patients maintained virologic suppression while receiving UB-241, although eight patients experienced viral blips (21 to 142 copies) of unclear significance. Rash was the most common adverse event but only led to treatment discontinuation in one person. Despite the antiviral activity of bNAbs demonstrated in these studies, there is no clear leading candidate or strategy for bNAb-based therapy, and their eventual role in clinical practice remains uncertain.
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
●Reasons for changing a regimen – For persons living with HIV who have a stably suppressed viral load (eg, at least 6 to 12 months) on antiretroviral therapy (ART), there are times when it may be reasonable to switch the ART regimen because of factors such as side effects, pill burden, new or worsening medical comorbidities, drug-drug interactions, or the risk of long-term toxicity. (See 'Reasons for changing a regimen' above.)
●Evaluation prior to switching – Prior to switching a regimen, it is important to evaluate the patient's antiretroviral history (especially history of any virologic failures, antiretroviral drug resistance, or antiretroviral drug intolerances), comorbid conditions, and barriers to taking the current regimen. If considering a switch off of tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), it is especially important to review the hepatitis B status. (See 'Evaluation prior to switching regimens' above.)
●Ensuring potency of the new regimen – In a patient who has a suppressed viral load, switching therapy can involve a single- or multi-drug switch. In either case, it is important to ensure that the new regimen will maintain virologic suppression. The likelihood that a patient will maintain virologic suppression depends upon prior resistance mutations and the new regimen's relative barrier to resistance.
Regimens with a relatively high barrier to resistance include the integrase inhibitors dolutegravir or bictegravir or a pharmacologically boosted protease inhibitor (PI). Regimens without one of the agents (eg, those that include rilpivirine, doravirine, raltegravir, or elvitegravir with a nucleoside reverse transcriptase inhibitors [NRTI] combination) have a lower barrier to resistance. (See 'Ensuring the potency of the new regimen' above.)
●Additional considerations when switching regimens – Additional considerations for regimen selection include ART-related side effects, risk of long-term toxicity, pill burden, and drug interactions. Other factors, such as cost, insurance access, food requirements, and the use of contraception in persons of childbearing potential, may also impact regimen selection. (See 'Other considerations for regimen selection' above.)
●Use of two-drug oral or injectable therapy – In select patients with virologic suppression, certain two-drug regimens (eg, dolutegravir-lamivudine, dolutegravir-rilpivirine, boosted darunavir plus lamivudine, boosted darunavir plus dolutegravir, or long-acting, injectable cabotegravir-rilpivirine) can maintain virologic suppression. We typically consider a transition to one of these two-drug options in individuals if they have or are at risk for toxicity from NRTIs like TDF, TAF, or abacavir, assuming they have routinely undetectable HIV RNA levels, no hepatitis B coinfection, and no confirmed or suspected resistance to the two-drug regimen. (See 'Eligibility for two-drug regimens' above.)
Injectable therapy may be ideally suited for eligible patients who have difficulty swallowing pills, difficulty storing their medications at home due to concerns around confidentiality or stigma, or a preference for nondaily dosing or injectable therapy. However, such patients must be able to commit to regular clinic visits for injections since patients may experience prolonged periods of subtherapeutic ART levels if doses are missed, which puts them at risk for developing non-nucleoside reverse transcriptase inhibitors (NNRTI) and integrase strand transfer inhibitor (INSTI) resistance. Use of long-acting cabotegravir-rilpivirine, including how to select eligible patients for this option, is discussed in detail elsewhere. (See "Use of long-acting cabotegravir-rilpivirine in people with HIV".)
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