Overview of antiretroviral agents used to treat HIV

INTRODUCTION — Antiretroviral therapy (ART) regimens used to treat individuals with HIV have led to dramatic reductions in morbidity and mortality. Drug selection could potentially include at least 25 antiretroviral medications available in six major classes (table 1). For most individuals, an ART regimen consists of a dual nucleoside combination plus a third agent from a different class.

This topic will provide an overview of the different antiretroviral agents used to treat HIV. Topic reviews that discuss the safety of these agents in pregnancy, when to initiate therapy, how to choose a regimen, and antiretroviral resistance are presented elsewhere:

●(See "When to initiate antiretroviral therapy in persons with HIV".)

●(See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

●(See "Antiretroviral selection and management in pregnant women with HIV in resource-rich settings".)

●(See "Safety and dosing of antiretroviral medications in pregnancy".)

●(See "Interpretation of HIV drug resistance testing".)

●(See "Evaluation of the treatment-experienced patient failing HIV therapy".)

●(See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

OVERVIEW OF HIV REPLICATION — The life cycle of HIV can be broken down into 6 steps: (1) entry (binding and fusion), (2) reverse transcription, (3) integration, (4) replication (transcription and translation), (5) assembly, and (6) budding and maturation. The identification and understanding of these processes have provided the basis for antiretroviral drug discovery.

●Entry – The process of entry involves the binding of HIV to receptors on the surface of the CD4 cell. Once initial binding occurs, the intimate association of HIV with the cell is enhanced by further binding to chemokine coreceptors, which promotes membrane fusion and internalization of the viral genetic material and enzymes necessary for replication. Maraviroc, enfuvirtide, and fostemsavir are antiretroviral agents that inhibit binding and fusion, respectively. However, these agents are not commonly used for the treatment of HIV infection. (See 'Entry inhibitors' below.)

●Reverse transcription – The genetic material of HIV is RNA, and the virus uses reverse transcriptase (one of three virally encoded enzymes: reverse transcriptase, integrase, and protease) to convert its RNA into DNA. Following reverse transcription, the double-stranded viral DNA product migrates into the nucleus of the cell. Nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit the process of reverse transcription. There are several agents in each of these classes that are widely used for the treatment of HIV. (See 'Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)' below and 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)' below.)

●Integration – The virus uses the enzyme integrase to integrate (insert) its viral DNA into the DNA of the host CD4 cell. Once viral DNA has been integrated into the cell's DNA, the cell is infected for the remainder of its life. Integrase strand transfer inhibitors (INSTIs) inhibit the process of integration. In many countries, INSTIs are considered the preferred third agent (in combination with two nucleoside analogues) for treatment-naïve individuals. (See 'Integrase strand transfer inhibitors (INSTIs)' below.)

●Replication – After integration, HIV preferentially replicates in activated cells. Proviral DNA is formed by transcription using the machinery of the host CD4 cell to create new viral RNA. This viral RNA is translated into long polyprotein chains, which will become the protein and enzyme components of new viral particles. There are no antiretroviral agents that inhibit this step of the replication cycle.

●Assembly – The new viral proteins and enzymes move to the cell's outer membrane where they assemble into an immature, noninfectious HIV particle or bud. There are no antiretroviral agents that inhibit this step of the replication cycle.

●Budding and maturation – The virus bud is released from the host CD4 cell. The viral enzyme, protease, cuts the long HIV polyprotein chains into smaller functional HIV proteins to make a mature, infectious viral particle. Protease inhibitors are antiretroviral agents that inhibit the HIV protease enzyme, and therefore, prevent this final step in the replication cycle. (See 'Protease inhibitors (PIs)' below.)

CAPSID INHIBITORS — Capsid inhibitors are small molecules that disrupt HIV capsid protein functions [1]. This impacts key protein-protein interactions necessary for viral entry and virion assembly.

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 [2]. Patients initiating treatment should receive an initial induction regimen that includes oral lenacapavir, following by subcutaneous injections of lenacapavir 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 [3]. Approximately 80 percent achieved a viral load of less than 50 copies/mL 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.

ENTRY INHIBITORS

CCR5 antagonists — HIV enters CD4 cells via the CD4 receptor in conjunction with one of its coreceptors: the chemokine coreceptor 5 (CCR5) or the CXC chemokine coreceptor 4 (CXCR4). Viruses that use the CCR5 coreceptor are called "R5 viruses," whereas others that use the CXCR4 coreceptor are called "X4 viruses."

Agents that block CCR5 exert their antiviral activity against HIV by blocking entry of CCR5-tropic viruses into the CD4 T cell. Maraviroc is the only approved CCR5 antagonist. Maraviroc is not commonly used for initial treatment of HIV. However, it may have a role in the treatment-experienced patients with drug-resistant virus. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Patients who have failed multiple regimens'.)

If maraviroc is being considered, a tropism assay is essential prior to initiation of therapy. This assay determines whether a response from a CCR5 antagonist should be expected since maraviroc is not active against X4 or dual-mixed tropic viruses. (See "Overview of HIV drug resistance testing assays", section on 'Tropism assays'.)

Maraviroc is eliminated by both renal and hepatic pathways. The dose should be adjusted in persons with a creatinine clearance <30 mL/min or on dialysis. Increased maraviroc concentrations are expected in persons with significant hepatic dysfunction, though there are no specific guidelines for dose adjustment.

In all settings, the dose of maraviroc must be adjusted when given with concomitant antiretrovirals (or other drugs) that are CYP3A enzyme inducers (eg, efavirenz) or inhibitors (eg, ritonavir). Refer to the Lexicomp drug interactions program within UpToDate for more specific information.

Fusion inhibitors — Fusion inhibitors bind to the envelope glycoprotein 41 (gp41) of HIV to prevent viral fusion to the CD4 T cell. The only approved fusion inhibitor is enfuvirtide (sometimes referred to as T-20), a 36 amino acid peptide. This is an injectable agent that is effective in treatment-experienced patients who have not been exposed to this medication. However, enfuvirtide is difficult to administer for long periods of time due to the need for twice-daily injections, which often lead to local cutaneous reactions. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Fusion inhibitors'.)

Attachment inhibitors — Fostemsavir is an attachment inhibitor that was approved for use in the United States in July 2020 for patients with HIV-1 infection [4]. Fostemsavir is a prodrug, which is converted to the active metabolite temsavir. Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and prevents viral attachment and subsequent entry of virus into host T cells.

Fostemsavir is dosed as 600 mg orally twice daily and should be used in combination with other active antiretroviral agents for treatment-experienced patients who are failing therapy and have limited treatment options [4]. It should not be used in patients taking strong cytochrome P450 (CYP)3A inducers (eg, rifampin, carbamazepine, phenytoin, St John's wort), as they decrease the level of temsavir. The most common adverse reaction to fostemsavir is nausea. Other adverse reactions include elevations in liver enzymes in those with hepatitis B or C infection, as well as QTc prolongation.

The efficacy of fostemsavir was demonstrated in a randomized trial of 272 treatment-experienced patients failing therapy, in which the addition of fostemsavir to a regimen with at least one active agent resulted in a greater reduction of HIV RNA after eight days of treatment compared with a regimen that did not include fostemsavir (0.79 versus 0.17 log₁₀ copies/mL, respectively) [5]. In this trial, open-label fostemsavir was given to the whole study population after the initial eight days of treatment, and 54 percent achieved an HIV viral load <40 copies/mL at 48 weeks. By 96 weeks, 60 percent of participants had a suppressed viral load [6]. In a separate cohort of 99 patients who had no active drugs but had fostemsavir added to an optimized antiretroviral therapy regimen, 38 percent had an HIV viral load <40 copies/mL at 48 weeks [5].

NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

NRTI class characteristics — The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) class includes (listed alphabetically) (table 1):

●Abacavir sulfate, a guanosine analog. (See 'Abacavir' below.)

●Emtricitabine and lamivudine, which are cytosine analogs. (See 'Emtricitabine and lamivudine' below.)

●Tenofovir alafenamide and tenofovir disoproxil fumarate, which are adenosine-derived NRTIs. (See 'Tenofovir' below.)

●Zidovudine, a thymidine analog. (See 'Zidovudine' below.)

Other NRTI agents (eg, didanosine and stavudine) are rarely used because of adverse reactions including neuropathy, lipodystrophy, and mitochondrial toxicity.

NRTIs are usually given in pairs. The commonly used combinations are available as coformulations (eg, tenofovir alafenamide-emtricitabine [Descovy], tenofovir disoproxil fumarate-emtricitabine [Truvada], abacavir-lamivudine [Epzicom]). However, two-drug regimens that include an integrase strand transfer inhibitor (INSTI) or a boosted protease inhibitor (PI) in combination with lamivudine can be used in select patients. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Use of two-drug regimens in select patients' and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

●Mechanism of action – NRTIs undergo intracellular phosphorylation mediated by several host enzymes (eg, cytoplasmic or mitochondrial kinases and phosphotransferases). The active triphosphate form inhibits viral replication through competitive binding to the viral enzyme, reverse transcriptase. DNA chain elongation is terminated after the NRTI triphosphate is incorporated [7,8]. (See 'Overview of HIV replication' above.)

●Spectrum of activity – The spectrum of activity of NRTIs includes HIV-1 and HIV-2 viruses.

Lamivudine, emtricitabine, and tenofovir (tenofovir disoproxil fumarate and tenofovir alafenamide) also have activity against hepatitis B virus (HBV). However, lamivudine and emtricitabine should not be used as monotherapy for the treatment of HBV given the high risk of developing HBV resistance with prolonged use. HBV flares can be seen if agents active against HBV are discontinued. A discussion of the treatment of HBV in HIV-infected patients is found elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV".)

●Resistance – All of the NRTIs can select for resistance mutations. Detailed discussions of HIV drug resistance are found elsewhere. (See "Interpretation of HIV drug resistance testing", section on 'Nucleoside reverse transcriptase inhibitors' and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Patients with drug-resistant virus'.)

●Adverse events – The hallmark toxicity of the NRTI class is mitochondrial toxicity, which may manifest as peripheral neuropathy, pancreatitis, lipoatrophy, and/or hepatic steatosis [9-11]. Although all NRTIs have "black box" warnings in their product labeling because of the possibility of lactic acidosis syndrome, which is potentially fatal, the risk of mitochondrial toxicity is low with the commonly used agents (abacavir, emtricitabine, lamivudine, tenofovir alafenamide, tenofovir disoproxil fumarate). (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors".)

Discussions of adverse reactions seen with specific agents are found below. (See 'Abacavir' below and 'Tenofovir' below and 'Zidovudine' below.)

●Drug interactions – NRTIs have few clinically significant drug-drug interactions because they are not substrates, inhibitors, or inducers of hepatic cytochrome P450 (CYP) enzymes. However, certain important interactions do exist. As an example, tenofovir alafenamide should generally be avoided if the patient is receiving a rifamycin (eg, for the treatment of tuberculosis) since rifamycins reduce the level of tenofovir alafenamide [12]. Additional information on drug interactions can be found in the Lexicomp drug interactions program within UpToDate.

Specific agents (listed alphabetically)

Abacavir — Abacavir is administered as 300 mg twice daily or as 600 mg once daily. It is also available as part of several coformulated tablets, including abacavir-lamivudine, which is a commonly used NRTI combination, and dolutegravir-abacavir-lamivudine (table 1). Prior to initiating treatment with abacavir, all patients must be screened for HLA-B*5701. Abacavir is contraindicated in persons who test positive for HLA-B*5701, as they are at high risk for developing an abacavir hypersensitivity reaction. (See "Abacavir hypersensitivity reaction".)

Although abacavir-lamivudine is considered a first-line NRTI combination, there are concerns about its use in patients with certain comorbidities, as well as those with high viral loads (unless dolutegravir is used as the third agent).

●Heart disease – Abacavir should be generally avoided in individuals with coronary artery disease (CAD) as well as those with multiple risk factors for CAD. Although there is no consensus on whether there is a causal association between abacavir and the risk of myocardial infarction, data suggest that abacavir may be associated with an increased risk of hyperlipidemia and cardiovascular events [13-17]. Additionally, in one trial, more favorable changes in the total and low-density lipoprotein (LDL) cholesterol levels were observed among patients who switched from an abacavir-lamivudine to a tenofovir disoproxil fumarate-emtricitabine-containing NRTI combination [18]. However, other studies have found no association or only a weak association between abacavir and the risk for myocardial infarction [15,19-21]. Additional information on the use of abacavir in patients with, or at risk for, cardiovascular disease is presented in separate topic reviews. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Abacavir' and "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Cardiovascular disease'.)

●Viral load – The use of abacavir-lamivudine in patients with a high viral load depends upon which third agent is used. As an example, the use of a regimen containing abacavir-lamivudine plus dolutegravir in patients with high viral loads is supported by a randomized, placebo-controlled trial of 833 participants treated with abacavir-lamivudine-dolutegravir versus efavirenz-tenofovir disoproxil fumarate-lamivudine [22]. The abacavir-lamivudine-dolutegravir arm had a significantly greater percentage of participants achieve viral suppression to <50 copies/mL (88 versus 81 percent), and higher CD4 counts (267 versus 208 cells/microL), even among individuals with a baseline HIV RNA >100,000 copies/mL.

In contrast, there are conflicting data about the efficacy of abacavir-lamivudine in patients with high HIV RNA levels when dolutegravir is not the third agent [13,23,24]. Clinical trial data indicate that patients receiving a nucleoside combination of abacavir-lamivudine are less likely to achieve virologic suppression compared with those receiving tenofovir disoproxil fumarate-emtricitabine when the third drug is efavirenz or ritonavir-boosted atazanavir [13]. There are limited data with the use of other third agents in combination with abacavir-lamivudine.

Emtricitabine and lamivudine — Emtricitabine and lamivudine are both dideoxycytidine analogues, which have very similar pharmacokinetic and pharmacodynamic characteristics, and are considered interchangeable. Structurally, emtricitabine is very similar to lamivudine, only differing in the addition of a fluorine to emtricitabine. Lamivudine and emtricitabine should not be combined because they will compete for intracellular phosphorylation [25].

These agents are used as components of the preferred dual NRTI combination (tenofovir-emtricitabine, abacavir-lamivudine). In addition, lamivudine has been used in combination with dolutegravir or a boosted PI in certain treatment-naïve and -experienced patients. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Approach for most patients' and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Use of two-drug regimens in select patients' and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

Both emtricitabine and lamivudine are extremely well tolerated. Rare side effects include:

●Pancreatitis – Lamivudine has been associated with pancreatitis, although the risk in adults is quite low at 0.3 percent [26]. The risk of pancreatitis may be higher in children [26].

●Skin changes – Emtricitabine can cause skin discoloration that presents as hyperpigmentation usually on the palms and/or soles. The incidence appears to be approximately 2 percent [27]. The mechanism and clinical significance is unknown.

Tenofovir — Tenofovir is an acyclic nucleotide diester analog of adenosine monophosphate, which is administered orally as the prodrug tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF). Both are converted intracellularly to the pharmacologically active moiety, tenofovir-diphosphate.

TAF is administered at a lower dose than TDF, and plasma concentrations of tenofovir are lower; however, intracellular concentrations of tenofovir-diphosphate are higher. Because of differences in drug transporters involved in TAF versus TDF absorption, there are drug interactions (eg, certain anticonvulsants, rifamycins), which can lower TAF, but not TDF levels. Specific information on drug interactions can be found in the Lexicomp drug interactions program within UpToDate.

Tenofovir alafenamide — Tenofovir alafenamide (TAF) is available as part of several coformulated tablets: elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide (EVG/c/FTC/TAF), rilpivirine-emtricitabine-tenofovir alafenamide (RPV/FTC/TAF), tenofovir alafenamide-emtricitabine (TAF/FTC), bictegravir-emtricitabine-tenofovir alafenamide (BIC/FTC/TAF), and darunavir-cobicistat-emtricitabine-tenofovir alafenamide (DRC/c/FTC/TAF). These coformulated tablets are approved for use in patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². There are insufficient data for dosing recommendations in patients with an eGFR <30 mL/min/1.73 m², unless they are on hemodialysis. Special considerations for patients with HIV/HBV coinfection are presented elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Tenofovir in patients with reduced kidney function'.)

In these coformulated tablets, TAF is used in two different doses: either 10 or 25 mg. When TAF is combined within a pharmacokinetic boosting agent (eg, cobicistat or ritonavir) as in elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide, the reduced dose of 10 mg is used. When TAF is not given with a pharmacokinetic booster, as in rilpivirine-emtricitabine-tenofovir alafenamide and bictegravir-emtricitabine-tenofovir alafenamide, the dose is 25 mg. Pharmacologic boosting agents (eg, cobicistat, ritonavir) inhibit intestinal P-glycoprotein, thereby increasing TAF bioavailability and tenofovir plasma concentrations; the reduced TAF dose of 10 mg is used to manage this interaction. The long-term safety of TAF at the 25 mg dose given with a pharmacokinetic booster has not been established.

Tenofovir can lead to kidney injury and bone loss; however TAF is associated with less renal and bone toxicity compared with TDF since it achieves lower plasma tenofovir concentrations [28]. In two randomized studies that included 1733 patients, elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide was compared with elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate (EVG/c/FTC/TDF) [29]. More than 90 percent of patients achieved a plasma HIV-RNA <50 copies/mL after 48 weeks, regardless of which agent they received. However, those who received the TAF-containing regimen had significantly smaller increases in serum creatinine (0.08 versus 0.12 mg/dL), less proteinuria (median percent change –3 versus 20), and smaller decreases in bone mineral density (median percent change spine: –1·30 versus –2.86; hip –0.66 versus –2.95).

Although TAF has several advantages over TDF, TAF may be associated with greater weight gain [30-32]. In addition, levels of LDL and high-density lipoprotein (HDL) cholesterol, as well as triglycerides, have been found to be higher in patients receiving TAF compared with those receiving TDF in randomized trials [29,30]. However, the total cholesterol-to-HDL ratio did not differ between patients receiving TAF and TDF; thus, the clinical significance of these findings is unclear.

Tenofovir disoproxil fumarate — Tenofovir disoproxil fumarate (TDF) is administered once daily and taken without regard to food. TDF is usually combined with emtricitabine (FTC), which is available as a coformulated tablet (TDF [300 mg]/FTC [200 mg]) [12]. For treatment of HIV infection, tenofovir disoproxil fumarate-emtricitabine must be given with a third agent from a different class, and several combinations of these drugs are available as coformulated tablets (table 1). There are also generic combination tablets that include TDF, such as TDF (300 mg) with lamivudine (300 mg), which are available in resource-limited countries.

The main toxicities of TDF include kidney injury and bone loss:

●Kidney injury – TDF can lead to renal impairment, characterized by increases in serum creatinine, proteinuria, glycosuria, hypophosphatemia, and acute tubular necrosis [33]. Patterns of kidney injury include proximal tubular dysfunction (Fanconi syndrome), acute kidney injury, chronic kidney disease, and nephrogenic diabetes insipidus [34].

Baseline risk factors for the development of kidney injury from TDF include elevated serum creatinine, older age, advanced HIV infection, low body weight, hepatitis C coinfection, and prescription of concurrent nephrotoxic drugs [35]. Concomitant use with a pharmacokinetically boosted regimen (eg, a protease inhibitor plus ritonavir or elvitegravir plus cobicistat) may also increase the risk of renal dysfunction [12]. An additional discussion of tenofovir nephrotoxicity is found elsewhere. (See "Overview of kidney disease in patients with HIV", section on 'Medication nephrotoxicity'.)

Given the potential for nephrotoxicity:

•For patients with HIV, we generally avoid administering TDF to those with a baseline eGFR <60 mL/min/1.73 m². However, if TDF must be used in this setting, the manufacturer recommends the dose be adjusted when the eGFR falls below 50 mL/min/1.73 m². If cobicistat is used as part of the ART regimen, TDF should not be administered to patients with a pretreatment eGFR <70 mL/min/1.73 m². (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Reduced kidney function'.)

•Renal function and proteinuria should be monitored during the use of this agent. (See "Administration of pre-exposure prophylaxis against HIV infection", section on 'Patient monitoring' and "Patient monitoring during HIV antiretroviral therapy".)

In patients with end-stage kidney disease on hemodialysis in whom recovery of renal function is not anticipated, TDF may be a convenient choice because it can be dosed at 300 mg once weekly (every seven days). (See 'Timing of doses for patients on hemodialysis' below.)

●Bone loss – TDF is associated with decreased bone mineral density, which usually stabilizes with continued use [36-38]. In one randomized trial, TDF was associated with a greater reduction in bone mineral density compared with abacavir [38]. (See "Bone and calcium disorders in patients with HIV", section on 'Risk with specific agents'.)

Overall, tenofovir disoproxil fumarate-emtricitabine is very well tolerated, and a number of well-designed studies have found that this combination is effective in suppressing HIV RNA when used with a variety of different third agents. Although data are limited, tenofovir disoproxil fumarate-emtricitabine has generally been superior to other nucleoside combinations [14,23,24,27,39-41]. In addition, the combination of tenofovir disoproxil fumarate-emtricitabine has been found to be effective in reducing HIV transmission when administered as pre-exposure prophylaxis (PrEP) to patients without HIV. A detailed discussion of tenofovir disoproxil fumarate-emtricitabine for PrEP is found elsewhere. (See "Administration of pre-exposure prophylaxis against HIV infection".)

Zidovudine — Zidovudine (also known as AZT) was the first antiretroviral medication used for the treatment of HIV that demonstrated a reduction in the morbidity and mortality associated with HIV infection. Zidovudine is dosed twice daily, as pharmacokinetic and pharmacodynamic studies with once-daily dosing suggest that intracellular trough levels are lower and HIV RNA declines are less robust than with twice-daily dosing [42,43].

Adverse reactions associated with zidovudine include headache, malaise, anorexia, nausea, vomiting, lactic acidosis, and loss of limb fat. Administration of zidovudine with food improves gastrointestinal tolerability. The major dose-limiting toxicities of zidovudine are related to bone marrow suppression (eg, anemia and/or neutropenia).

The coformulation of zidovudine (300 mg) and lamivudine (150 mg) is dosed as one tablet twice daily. This NRTI combination was a preferred choice when it was first introduced in 1997, but is now rarely used. A tenofovir-containing nucleoside combination or abacavir-lamivudine is administered instead of zidovudine-lamivudine for the following reasons:

●Zidovudine requires twice-daily dosing whereas tenofovir disoproxil fumarate-emtricitabine, tenofovir alafenamide-emtricitabine, and abacavir-lamivudine are dosed once daily.

●Zidovudine is associated with more severe adverse reactions [40,44].

●Zidovudine-lamivudine has been shown to have inferior virologic potency compared with tenofovir disoproxil fumarate-emtricitabine-based ART [27,40].

However, there are certain situations where zidovudine may still be indicated. As an example, there may be a benefit of using this drug in the setting of the K65R mutation when patients have difficulty achieving viral suppression with more commonly used regimens. In addition, the intravenous formulation of zidovudine (zidovudine is one of the only agents available in a parenteral form) is administered to certain pregnant women at the time of delivery. More detailed discussions of the management of patients with drug-resistant virus and pregnant women are found elsewhere. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Patients who have failed multiple regimens' and "Antiretroviral selection and management in pregnant women with HIV in resource-rich settings" and "Intrapartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings", section on 'Intrapartum antiretrovirals'.)

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

NNRTI class characteristics — The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are typically administered with a dual nucleoside reverse transcriptase inhibitor (NRTI) combination, although the combination of dolutegravir-rilpivirine is an option for select patients who are virologically suppressed and are switching regimens. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

First-generation NNRTIs include efavirenz and nevirapine; other NNRTIs (doravirine, etravirine, and rilpivirine) have resistance profiles that are distinct from efavirenz and nevirapine. Most NNRTIs are used for treatment-naïve patients and those with suppressed viral loads switching regimens, except for etravirine, which is generally used for individuals with evidence of drug-resistant virus.

●Mechanism of action – NNRTIs prevent HIV-1 reverse transcriptase from adding new nucleotides to the growing DNA chain. The NNRTIs block viral cDNA elongation at a site that is separate from the active site targeted by the NRTI class. The NNRTIs bind to a hydrophobic pocket in the palm subdomain of p66, approximately 10 angstroms from the polymerase active site [45]. This causes a stereochemical change in the protein, which reduces the ability of naturally occurring nucleosides to bind to the active site pocket. Reverse transcriptase becomes less flexible and DNA polymerization is inhibited. In addition, cDNA elongation is reduced, which ultimately leads to a decline in viral replication [46]. (See 'Overview of HIV replication' above.)

●Spectrum of activity – The NNRTIs are active against HIV-1 but are not active against HIV-2.

●Resistance – The first-generation NNRTIs (ie, efavirenz and nevirapine) have a low barrier to resistance and require only a single mutation to confer drug resistance. A major mutation (eg, K103N) leads to cross resistance to other first-generation NNRTIs. In some cases, the second-generation NNRTI, etravirine, can be used in the treatment of patients with resistance to first-generation NNRTIs [12,47]. Virologic failure on rilpivirine may also compromise the anti-HIV activity of other NNRTIs, including etravirine. (See "Interpretation of HIV drug resistance testing", section on 'Non-nucleoside reverse transcriptase inhibitors' and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'NNRTI-containing regimens'.)

Oral NNRTIs have a long plasma half-life, typically >24 hours in adults, with the exception of doravirine, which has a half-life of 15 to 21 hours. The long half-life allows all NNRTIs to be administered once daily. Importantly, when an NNRTI-containing antiretroviral regimen is discontinued, a period of functional NNRTI monotherapy may occur if the concentrations of the NNRTI decline slower than those of the other antiretrovirals. This period of functional monotherapy or "NNRTI tail" increases the risk of developing NNRTI resistance [48,49]. Thus, some experts suggest that if a regimen containing an NNRTI is stopped, the concomitant nucleoside backbone should be continued for three to seven days after the NNRTI is discontinued. An alternative strategy is for a boosted protease inhibitor to be substituted for the NNRTI for one week before discontinuing the nucleoside backbone. These relatively cumbersome stop strategies have not been well studied, and it is difficult to recommend any one approach. Specific considerations regarding the injectable formulation are presented elsewhere. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

●Drug interactions – Drug interactions can result in increased or decreased NNRTI levels, and NNRTIs may be a perpetrator of drug interactions. Detailed information about specific interactions is available by using the Lexicomp drug interactions program included with UpToDate.

●Adverse events – There are no specific class-related adverse events. However, the two most commonly used NNRTIs (efavirenz and rilpivirine) can result in neurologic and psychiatric side effects. They are also associated with QT prolongation.

Specific agents (listed alphabetically)

Doravirine — Doravirine became available in the United States in August of 2018. This agent is approved for use in treatment-naïve patients and is available alone or in combination with tenofovir disoproxil fumarate-lamivudine. Doravirine may be administered with or without food, and there are no viral load or CD4 count parameters to initiate therapy.

Doravirine is metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect plasma concentrations. As an example, rifampin decreases doravirine exposure by >70 percent, and coadministration is contraindicated. By contrast, rifabutin decreases doravirine exposure by 50 percent, and this interaction may be managed by increasing the doravirine dose from 100 mg once daily to 100 mg twice daily. Detailed information about specific interactions is available by using the Lexicomp drug interactions program within UpToDate.

Doravirine was found to be non-inferior to efavirenz- and darunavir-based regimens in randomized trials [50,51]. In addition, it appears to be well tolerated. Although it may cause neurologic and psychiatric side effects similar to efavirenz (eg, dizziness, sleep disturbances, and altered sensorium), these are much less common. In the trial that compared doravirine-lamivudine- tenofovir disoproxil fumarate with efavirenz-emtricitabine-tenofovir disoproxil fumarate, the rates of neuropsychiatric adverse events at 48 weeks were 12 versus 22 percent, respectively [50]. Clinical trial data also suggest that it has better lipid profiles than both efavirenz and darunavir [50,51]. Additional information on the adverse events associated with efavirenz and darunavir are presented elsewhere. (See 'Efavirenz' below and 'Darunavir' below.)

Despite the favorable clinical trial data, there is limited experience with this agent, and doravirine has never been directly compared with integrase strand transfer inhibitors (INSTIs), the preferred third agent for most patients. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Approach for most patients'.)

Efavirenz — Efavirenz is given at a dose of 600 mg once daily. It is also available as part of coformulated tablets (efavirenz-emtricitabine-tenofovir disoproxil fumarate and efavirenz-lamivudine-tenofovir disoproxil fumarate) (table 1). Since efavirenz is a potent inducer of hepatic cytochrome P450 (CYP) enzymes, drug interactions can be seen with certain medications that are commonly used in patients with HIV. These include rifabutin, clarithromycin, atorvastatin, simvastatin, methadone, carbamazepine, and other anticonvulsants. Detailed information about specific interactions is available by using the Lexicomp drug interactions program included with UpToDate.

Efavirenz has been used extensively and has excellent potency and durability in treatment-naïve patients, including those with high pretreatment viral loads and low CD4 cell counts [11,27,52-59]. However, INSTIs are preferred, due in part to fewer adverse events [12,22,60-63]. (See 'Integrase strand transfer inhibitors (INSTIs)' below.)

Side effects seen with efavirenz include central nervous system (CNS) toxicity, elevated hepatic transaminases (including fulminant hepatitis), and QT interval prolongation. Thus, this agent is typically avoided in patients with psychiatric illness, moderate to severe liver disease (Child Pugh B and C), and those at risk for torsade de pointes. Other side effects include rash and hyperlipidemia. The safety of efavirenz during pregnancy is discussed elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Efavirenz'.)

The CNS symptoms, which are one of the most frequently seen side effects, commonly include vivid dreams, confusion, dizziness, and a "hungover" feeling the following day. Higher rates of intolerance are noted in Black patients due to slower metabolism that is genetically determined. Taking efavirenz on an empty stomach may reduce the risk of these side effects since high-fat/high-caloric meals increase the absorption of efavirenz.

Although many CNS side effects are restricted to the first few weeks after initiation, there are data that suggest long-term mental health consequences (eg, irritability, anxiety, mood changes, depression) and increased suicidality (combined endpoint of suicidal ideation, suicide attempts, and completed suicides) can be seen with efavirenz [64-67]. A combined analysis of 5332 HIV-infected individuals from four clinical trials evaluated the risk of suicidality among those receiving an efavirenz-containing regimen [66]. There was a significantly increased incidence of suicidality among those who received efavirenz compared with those who did not (8.08 versus 3.66 per 1000 person-years; hazard ratio 2.28; 95% CI, 1.27-4.10). The increased risk of suicidality appears to be greatest in patients who have genotypes that predict higher plasma efavirenz exposure [68]. This may help explain why an increase in suicidality is not seen in all patient groups [69].

A fixed-dose combination of tenofovir disoproxil fumarate-lamivudine-efavirenz using a lower dose of efavirenz (400 mg) is available. Clinical trial data in antiretroviral-naïve persons suggest that this lower dose of efavirenz is noninferior to the 600 mg dose with regards to virologic efficacy [70,71] and may be associated with fewer adverse events [70]. In one study, the 400 mg dose of efavirenz appeared to be noninferior to dolutegravir at 48 weeks, with 69 and 75 percent of patients achieving a viral load <50 copies, respectively [72]. However, the 400 mg dose of efavirenz is not routinely used in clinical practice.

Etravirine — The most commonly used NNRTI for patients with drug-resistant virus is etravirine [73]. 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 2). (See "Interpretation of HIV drug resistance testing", section on 'Non-nucleoside reverse transcriptase inhibitors'.)

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 [18,19]. 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 [19].

The most common adverse event after etravirine administration is rash, which is generally mild. In clinical trials, rash occurred primarily in the second week of therapy and was infrequent after week four. Rash generally resolved within one to two weeks of continued dosing. As with other NNRTIs, severe rashes (including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and erythema multiforme) have been reported in the postmarketing experience. Etravirine should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.

There are significant drug-drug interactions with etravirine and other antiretroviral medications that can limit its use. As an example, if etravirine is used with dolutegravir, the regimen must also include a boosted PI. A detailed review of drug interactions can be found in the Lexicomp drug interactions program within UpToDate.

Nevirapine — In the United States, nevirapine is no longer recommended for the initial treatment of HIV infection in treatment-naïve patients [12,63]. Compared with other NNRTIs, nevirapine is associated with increased toxicity, especially during the first three months of therapy. Complications include hepatic necrosis and serious cutaneous reactions, including deaths due to hepatic necrosis or Stevens-Johnson Syndrome [74-81].

If nevirapine is being considered, it should not be initiated in females with a baseline CD4 count >250 cells/microL or in males with a CD4 count >400 cells/microL since these CD4 cell thresholds represent major risk factors for hepatotoxicity. Caution should also be used when nevirapine is initiated in males with CD4 cell counts between 250 to 400 cells/microL. A study of 566 patients from China showed that a CD4 cell count of >250 cells/microL was an independent predictor of hepatotoxicity in both males and females initiated on a nevirapine-containing regimen [82].

Nevirapine should also be avoided in patients with moderate to severe liver disease (Child-Pugh Class B or C) (calculator 1). As described above, nevirapine has been associated with hepatotoxicity, and data on its use in this population are limited.

If administered, nevirapine should be started at a dose of 200 mg once daily for 14 days; the dose is then increased to the maintenance dose of 200 mg twice daily. We monitor serum aminotransferases at baseline, prior to and two weeks after dose escalation, then monthly for the first three months. Patients should also be counseled about symptoms and signs of hepatotoxicity (eg, nausea, jaundice).

Rilpivirine — Rilpivirine is formulated both as an individual tablet (25 mg once daily) and in three fixed-dose combination tablets (rilpivirine-emtricitabine-tenofovir disoproxil fumarate, rilpivirine-emtricitabine-tenofovir alafenamide, and dolutegravir-rilpivirine), all of which can be administered once daily (table 1). It is also available in an injectable formulation that must be used with cabotegravir. (See 'Cabotegravir' below.)

Rilpivirine can be used in combination with tenofovir-emtricitabine in treatment-naïve patients with a baseline viral load <100,000 copies/mL and a CD4 cell count ≥200 cells/microL [12]. This combination, as well as the two-drug combination of dolutegravir-rilpivirine, can also be used in select virologically suppressed patients who are switching regimens. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

Rilpivirine should be used cautiously or avoided in patients with long QT syndrome or other risks for torsade de pointes [12]. High doses of rilpivirine (ie, 75 mg and 300 mg once daily) were associated with QT interval prolongation [83].

Gastric acid and food are required for optimal absorption; thus, rilpivirine must be administered with a meal, and concomitant use of rilpivirine with proton pump inhibitors is contraindicated. In addition, other drugs that alter the stomach pH (eg, H2 antagonists, antacids) may impair absorption and should be avoided if possible; however, if they are used, they should be dosed separately from rilpivirine.

Important drug interactions can also be seen with certain anti-tuberculosis medications (eg, rifampin and rifabutin), anti-epileptics (eg, phenytoin, phenobarbital), and drugs that may inhibit rilpivirine metabolism and increase plasma concentrations (eg, azole antifungals, macrolide antibiotics). Detailed information about specific interactions is available by using the Lexicomp drug interactions program within UpToDate.

Rilpivirine is generally well tolerated [84]. The most common adverse drug reactions to rilpivirine include depression, insomnia, headache, and rash. Although rilpivirine may cause neurologic and psychiatric side effects similar to efavirenz, they are much less common [85]. In addition, rash led to drug discontinuation in less than 1 percent of study participants in the phase 3 clinical trials [86].

Two controlled trials (ECHO and THRIVE) compared rilpivirine with efavirenz in treatment-naïve patients in combination with two NRTIs; most received tenofovir disoproxil fumarate-emtricitabine as the NRTI combination [87-89]. The pooled results demonstrated that the proportion of patients with viral suppression at 48 weeks was comparable in the rilpivirine and efavirenz-containing arms. Rilpivirine was also well tolerated and associated with minimal changes in lipids.

In a 96-week analysis of 1368 participants, rilpivirine had a lower incidence of any neurologic or psychiatric adverse event compared with efavirenz (38 versus 17 percent and 24 versus 16 percent, respectively) [88]. However, among those subjects with a baseline viral load >100,000 copies/mL, the risk of virologic failure was higher in the rilpivirine arm compared with the efavirenz arm. An increased risk of nucleoside analog resistance mutations (eg, M184V/I) was also noted in these trials [87-89].

The combination of rilpivirine-emtricitabine-tenofovir alafenamide was approved on the basis of pharmacokinetic bioequivalence; comparative clinical trial data have not yet been reported.

INTEGRASE STRAND TRANSFER INHIBITORS (INSTIs)

INSTI class characteristics — Regimens using integrase strand transfer inhibitors (INSTIs), such as raltegravir, elvitegravir, dolutegravir, and bictegravir, are effective and well tolerated. Most INSTIs are administered orally. An injectable, long-acting INSTI (cabotegravir) is also available for treatment and must be used in combination with injectable rilpivirine. (See "Use of long-acting cabotegravir-rilpivirine in people with HIV".)

In many countries, including the United States, INSTIs are considered the preferred third agent for treatment-naïve individuals when used in combination with two nucleoside analogues. These agents are a particularly attractive option for patients with either abnormal lipid profiles or risk factors for coronary artery disease, since they have a neutral effect on cholesterol and triglycerides compared with efavirenz and protease inhibitors. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

●Mechanism of action – HIV integrase is one of three enzymes (reverse transcriptase, protease, and integrase) that are encoded by the virus and are essential for HIV replication. After entry into CD4+ T cells, viral RNA is reverse transcribed into DNA by HIV reverse transcriptase. The integrase enzyme catalyzes the process by which viral DNA is integrated into the genome of the host cell. This process is essential for maintenance of the viral genome and viral gene expression [90-95].

Integrase inhibitors target the strand transfer step of viral DNA integration. These drugs prevent or inhibit the binding of the preintegration complex (PIC) to host cell DNA, thus terminating the integration step of HIV replication. (See 'Overview of HIV replication' above.)

●Spectrum of activity – The integrase inhibitors are active against HIV-1 and HIV-2.

●Resistance – HIV-infected patients who fail an antiretroviral therapy (ART) regimen that contains raltegravir or elvitegravir have a relatively high risk of developing integrase resistance. In addition, there appears to be a high level of cross resistance between raltegravir and elvitegravir, precluding their sequential use [96-98]. As an example, in one study, 13 of the 23 patients who experienced virologic failure while receiving elvitegravir developed the following drug resistance mutations: T66I, E92Q, Q148R, and N155H [99]; three of these mutations (E92Q, Q148R, and N155H) also conferred significant resistance to raltegravir.

By contrast, dolutegravir and bictegravir resistance is very uncommon among patients failing an initial regimen that contains one of these agents [100,101]. It is also uncommon for such individuals to develop resistance to the NRTIs that are administered in combination with dolutegravir or bictegravir.

●Drug interactions – A decrease in INSTI concentrations is possible when administered with polyvalent cation-containing antacids and supplements. With regards to specific agents, there are relatively few problematic drug-drug interactions with raltegravir and dolutegravir because they are primarily metabolized via glucuronidation. Bictegravir, which is cleared by both glucuronidation and hepatic cytochrome P450, also has few problematic drug interactions. By contrast, elvitegravir is associated with more drug-drug interactions since it is administered with the boosting agent cobicistat, which is a potent inhibitor of CYP3A. More specific information on drug-drug interactions is found in the sections below and in the Lexicomp drug interactions program within UpToDate.

●Adverse events – All INSTIs are generally well tolerated. However, INSTIs may be associated with increased weight gain compared with other agents [32,72,102-104]. In one study that evaluated data from eight randomized trials, weight gain at 96 weeks was approximately 3.5 kg, and was similar in those that received bictegravir- and dolutegravir-based regimens. The mechanism for this weight gain is not known.

Insomnia and dizziness can also occur in some patients receiving INSTIs [105,106]. In addition, depression and suicidal ideation have been reported on rare occasion, primarily in patients with a history of psychiatric illnesses [12]. On occasion, elevations in creatine phosphokinase (CPK), rhabdomyolysis, and myopathy or myositis have been reported in patients taking raltegravir and dolutegravir [12].

●Considerations in persons of childbearing potential and those who are pregnant – When deciding whether to use a regimen that includes an INSTI in individuals who are of childbearing potential, it is important to determine if the person is pregnant and, if not, if they are committed to using effective birth control (eg, oral, injectable, or intrauterine contraception). Pregnancy, as well as the desire to become pregnant, may impact the selection of ART agents used for treatment of HIV infection. Detailed discussions of the use of INSTIs in persons who are of childbearing potential and in those who are pregnant are presented elsewhere. (See "HIV and women" and "Safety and dosing of antiretroviral medications in pregnancy" and "Antiretroviral selection and management in pregnant women with HIV in resource-rich settings", section on 'ART selection and management' and "Prevention of vertical HIV transmission in resource-limited settings".)

Specific agents (listed alphabetically)

Bictegravir — Bictegravir was approved for use in February 2018 and is available as a coformulated tablet with emtricitabine and tenofovir alafenamide. It has been approved for use in treatment-naïve patients and in those who are virologically suppressed and are considering a change in their regimen. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

There are limited data using this drug in treatment-experienced patients with a history of virologic failure. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Overall, bictegravir-emtricitabine-tenofovir alafenamide appears well tolerated. Notable drug interactions include rifampin and dofetilide, which are contraindicated for coadministration with bictegravir.

Bictegravir-emtricitabine-tenofovir alafenamide can be used in patients on hemodialysis; it is approved for use in treatment-experienced patients who are virologically suppressed. Similar to most other antiretroviral agents, it has not been evaluated in treatment-naïve patients on hemodialysis.

Cabotegravir — Cabotegravir is available as an oral and injectable preparation, which must be used in conjunction with rilpivirine for treatment of HIV [12,63]. The oral formulation is only approved for use as lead-in therapy prior to initiating injectable therapy or for patients who will miss planned injections of cabotegravir. Injectable cabotegravir-rilpivirine should only be used in treatment-experienced patients who are virologically suppressed, have no resistance to either drug, do not have chronic hepatitis B infection, have no significant drug-drug interactions that might reduce either drug's concentration, and are able to adhere to clinic visits for intramuscular injections. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens' and "Use of long-acting cabotegravir-rilpivirine in people with HIV", section on 'Determining eligibility'.)

The injectable regimen is administered every four or eight weeks. Overall, cabotegravir-rilpivirine is well tolerated; however, when the injectable formulation is used, mild to moderate injection site reactions are common. The most common other adverse reactions are mild and nonspecific, such as pyrexia, fatigue, headache, muscle aches, nausea, sleep disorders, dizziness, and rash. On rare occasion, serious post-injection reactions due to rilpivirine have been reported (dyspnea, flushing, sweating); however, these typically resolve within minutes.

Some drugs are contraindicated for coadministration with intramuscular cabotegravir-rilpivirine, such as the rifamycins (eg, rifampin) and certain anticonvulsants (eg, phenytoin). Information on specific drug-drug interactions can be found in the Lexicomp drug interactions program within UpToDate.

A more detailed discussion of cabotegravir-rilpivirine, including dosing regimens, the approach to missed doses, and the data supporting its efficacy, is presented in the Lexicomp drug information topic and in separate topic reviews. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens' and "Use of long-acting cabotegravir-rilpivirine in people with HIV".)

Dolutegravir — Dolutegravir is approved for use in treatment-naïve and most treatment-experienced individuals [107]. Patients receiving dolutegravir are unlikely to develop drug-resistant virus [108].

●For most patients, dolutegravir is given at a dose of 50 mg once daily without regard to food. It can be administered with a tenofovir-containing nucleoside combination or abacavir-lamivudine. Topic reviews that discuss regimen selection are presented separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

●Dolutegravir is available as part of three coformulated tablets (dolutegravir-abacavir-lamivudine, dolutegravir-lamivudine, and dolutegravir-rilpivirine) (table 1).

Dolutegravir-rilpivirine is only approved for use in virologically suppressed individuals switching regimens. Detailed discussions of the use of these regimens, including contraindications to their use, are presented elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

●The dose of dolutegravir should be increased to 50 mg twice daily for treatment-experienced patients who have previously taken integrase inhibitors and have confirmed or suspected integrase resistance. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Patients with drug-resistant virus'.)

●Dolutegravir should not be used for patients who have the Q148 mutation in addition to two or more secondary integrase mutations, since such patients respond less well to a dolutegravir-containing regimen [109-111]. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Integrase strand transfer inhibitors'.)

Dolutegravir can block tubular secretion of creatinine without reducing renal glomerular function. In some patients, this can lead to an expected small increase in serum creatinine (and decrease in eGFR) [101].

Several trials have shown that dolutegravir is well tolerated [22,112,113]. However, dolutegravir may be associated with more central nervous side effects (CNS) compared with other INSTIs [105]. This was demonstrated in a retrospective review of 1704 patients taking 1950 INSTI-based therapies, where neuropsychiatric adverse events (eg, insomnia and dizziness) resulted in treatment discontinuation more frequently in those receiving dolutegravir versus a different INSTI (5.6 percent for dolutegravir versus 0.7 and 1.9 percent for elvitegravir and raltegravir, respectively). These CNS side effects occurred significantly more frequently in females, and in patients older than 60 years.

Dolutegravir can have significant interactions with agents, such as metformin, rifampin, and antiepileptics (eg, phenytoin, phenobarbital, and carbamazepine). Detailed information can be found in the Lexicomp drug interactions program within UpToDate.

There are no clinically significant drug interactions between dolutegravir and NRTIs or the boosted protease inhibitors atazanavir and lopinavir. This is because dolutegravir does not induce or inhibit CYP or UGT isoenzymes at clinically relevant concentrations [114]. Although dolutegravir trough concentrations are reduced by approximately 38 percent when given with darunavir/ritonavir, this is not considered clinically significant. In addition, it appears there is not a clinically significant adverse interaction if dolutegravir is given with darunavir/cobicistat [115]. However, there are very limited data assessing possible interactions between dolutegravir and cobicistat.

The concentration of dolutegravir can be affected when dolutegravir is administered with drugs that inhibit or induce the UGT family of enzymes and CYP3A4. As an example, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and etravirine reduce dolutegravir trough concentrations by 75 and 88 percent, respectively. Dose adjustments or coadministration with a ritonavir-boosted protease inhibitor are required when these agents are used together; specific recommendations can be found at the United States Department of Health and Human Services (DHHS) Antiretroviral Guidelines for Adults and Adolescents.

Clinical trial data supporting the efficacy of dolutegravir are summarized below:

●Studies of dolutegravir have used both tenofovir disoproxil fumarate-emtricitabine and abacavir-lamivudine as nucleoside backbone therapy [112]. The virologic response rates were comparable to those seen in patients treated with raltegravir, even among patients with baseline HIV RNA >100,000 copies/mL, and there were no differences in the rates of discontinuation for adverse events.

●At 48 weeks, dolutegravir-abacavir-lamivudine was associated with significantly more frequent viral suppression to <50 copies/mL (88 versus 81 percent) and higher CD4 counts (267 versus 208 cells/microL) when compared with efavirenz-emtricitabine-tenofovir disoproxil fumarate [22]. This was seen even among individuals with a baseline HIV RNA >100,000 copies/mL.

●Patients receiving dolutegravir were more likely to have an HIV RNA level <50 copies/mL (90 versus 83 percent) compared with darunavir/ritonavir (800/100 mg once daily) in an open-label, randomized clinical trial [116]. This difference was greatest in those with a baseline HIV RNA >100,000 copies/mL.

Elvitegravir — Elvitegravir can be used for treatment-naïve or treatment-experienced patients. However, it must be administered with a boosting agent (eg, cobicistat or ritonavir), which is a potent inhibitor of CYP3A and thus causes more potential drug-drug interactions. A discussion of pharmacokinetic boosting is found below. (See 'Pharmacokinetic boosting' below.)

Elvitegravir was initially approved for use in treatment-naïve HIV-infected patients as part of a fixed-dose antiretroviral combination, elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate (EVG/c/FTC/TDF). This combination can be administered once daily, but only to patients with a pre-treatment eGFR >70 mL/min/1.73 m². In November 2015, the coformulation of elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide (EVG/c/FTC/TAF) became available for treatment-naïve patients. Elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide can be administered to patients with reduced kidney function who have an eGFR ≥30 mL/min/m².

Elvitegravir, like raltegravir, has a low genetic barrier to resistance. In addition, drug-drug interactions should be thoroughly assessed as it must be administered with a pharmacologic boosting agent. (See 'Pharmacokinetic boosting' below.)

Clinical trials supporting the use of elvitegravir include:

●Two trials that enrolled 1408 treatment-naïve patients with a pre-treatment eGFR >70 mL/min/1.73 m² found that elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate was noninferior to coformulated efavirenz-emtricitabine-tenofovir disoproxil fumarate or ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate-emtricitabine in achieving viral suppression at 48 weeks of therapy [60,117]. The most common adverse events on the elvitegravir regimen were headache and transient diarrhea and nausea; four patients developed proximal tubulopathy in these phase 3 clinical trials.

●Trials have shown elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide has equal efficacy and less nephrotoxicity and bone loss compared with elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate [29,118]. In addition, patients who are virologically suppressed on a tenofovir disoproxil fumarate-containing regimen were able to safely switch to elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide. In an open-label, randomized trial of 1443 patients who were virologically suppressed on a regimen containing tenofovir disoproxil fumarate for 96 weeks, patients were switched to elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide or were continued on their regimen [118]. By 48 weeks, the tenofovir alafenamide-containing regimen was found to be noninferior to a tenofovir disoproxil fumarate-containing regimen, and 97 percent of the 959 patients who were assigned to elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide had an HIV RNA <50 copies/mL.

Raltegravir — Raltegravir is approved for use in treatment-naïve and treatment-experienced patients with HIV as part of a combination ART regimen [61,62,119-121]. It is available in 400 mg and 600 mg tablets. A discussion of how to select an ART regimen is presented separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Raltegravir is generally administered as 400 mg twice daily (800 mg total daily dose). However, once daily dosing with two 600 mg tablets (1200 mg total daily dose) is an option for patients who are treatment naïve or who are virologically suppressed (eg, HIV RNA <50 copies/mL) on an initial regimen of raltegravir 400 mg twice daily. If raltegravir is coadministered with rifampin, it should be administered as 800 mg twice daily (1600 mg total daily dose) regardless of prior ART experience.

Although rare, side effects can be seen with raltegravir, and include nausea, dizziness, and headache. Rare cases of skeletal muscle toxicity and severe systemic cutaneous reaction resembling Stevens-Johnson syndrome have also been reported [122-124].

As with other INSTIs, clinical trial data have found that raltegravir, when used in combination with tenofovir disoproxil fumarate-emtricitabine, is among the most effective agents in suppressing the HIV viral load. Raltegravir has demonstrated superior viral suppression compared with efavirenz [61,62] and was found to be superior to first-line protease inhibitors (ie, boosted atazanavir and boosted darunavir) when combined tolerability and virologic efficacy endpoints were evaluated [125]. In addition, raltegravir achieves meaningful drug concentrations in cerebral spinal fluid and genital compartments [126,127].

One of the main disadvantages of raltegravir is its lower genetic barrier to resistance compared with dolutegravir and protease inhibitors (N155H is its signature mutation) [100,125]. As an example, in one study virologic resistance developed in 3 percent of patients receiving raltegravir versus ≤1.5 percent in those receiving a protease inhibitor [125]. In addition, raltegravir has been studied only in combination with tenofovir disoproxil fumarate-emtricitabine as the NRTI pair.

PROTEASE INHIBITORS (PIs) — Protease inhibitors (PIs) are typically administered in combination with a dual nucleoside combination; however, they can also be used as part of a nucleoside-sparing/limiting regimen. PIs should be administered with a boosting agent, either ritonavir or cobicistat. They can be used for patients who are treatment-naïve, and are often the preferred agent for patients failing their initial antiretroviral therapy (ART) regimen. (See 'Pharmacokinetic boosting' below and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy" and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Eligibility for two-drug regimens'.)

Although boosted darunavir and boosted atazanavir are effective as initial therapy in combination with a nucleoside backbone, boosted darunavir is generally preferred since darunavir appears to be better tolerated than atazanavir [12,128,129]. Ritonavir-boosted darunavir, ritonavir-boosted atazanavir, or raltegravir given with tenofovir disoproxil fumarate-emtricitabine were compared in a randomized study of 1809 ART-naïve patients [125]. There was a 9 percent higher incidence of treatment discontinuation in patients who received boosted atazanavir compared with boosted darunavir (97.5% CI 5.5 to 12.9 percent). This difference was due in large part to clinical jaundice and hyperbilirubinemia associated with atazanavir.

PI class characteristics

●Mechanism of action – Protease inhibitors (PIs) competitively inhibit the cleavage of the Gag-Pol polyproteins in HIV-infected cells, which is a crucial step in the viral maturation process, thereby resulting in the production of immature virions that are not infectious. (See 'Overview of HIV replication' above.)

●Spectrum of activity – PIs are active against HIV-1 and HIV-2.

●Resistance – PIs have a relatively high genetic barrier to resistance compared with non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the integrase inhibitors (INSTIs) raltegravir and elvitegravir. The development of resistance to pharmacologically boosted PIs in previously antiretroviral-naïve individuals is uncommon, even with less than optimal adherence [130]. In clinical trials evaluating the frequency of PI resistance in patients with virologic failure on their initial ART regimen, protease resistance developed in 0 of 76 cases with lopinavir/ritonavir, 0 of 140 cases with atazanavir/ritonavir, and 0 of 46 cases with darunavir/ritonavir. Thus, protease inhibitor-based regimens are a good choice for patients in whom adherence is a concern. (See "Interpretation of HIV drug resistance testing", section on 'Protease inhibitors' and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Patients without drug-resistant virus'.)

●Adverse events – There are several side effects that appear to be PI class effects while others are agent-specific. Some of the class side effects are insulin resistance, hyperglycemia, diabetes, hyperlipidemia, lipodystrophy, hepatotoxicity, bleeding in patients with hemophilia, and PR interval prolongation [131-133]. Adverse reactions can also be a result of drug interactions with other hepatically metabolized drugs [131,134]. Specific adverse reactions related to the commonly used agents are described below. (See 'Darunavir' below and 'Atazanavir' below and 'Other protease inhibitors' below.)

●Drug interactions – It is important to carefully check for potential drug interactions between the PI being considered and other concomitant medications [135]. Under-recognition of these interactions may result in loss of therapeutic effect or excess toxicity. Some studies have demonstrated that unsuspected drug-drug interactions were more common among HIV-infected patients taking PIs compared with those taking antiretroviral medications within other drug classes [135]. Mechanistically, most drug interactions with PIs arise from the pharmacological boosting agents. (See 'Pharmacokinetic boosting' below.)

For detailed drug interaction information, see the United States Department of Health and Human Services (DHHS) Antiretroviral Guidelines for Adults and Adolescents (tables 17, 18, and 19) and the Lexicomp drug interactions program within UpToDate.

Specific agents (listed alphabetically)

Atazanavir — Atazanavir should be administered as atazanavir 300 mg once daily plus ritonavir 100 mg once daily or atazanavir 300 mg once daily plus cobicistat 150 mg once daily. Atazanavir and cobicistat are coformulated as a single tablet (table 1). When atazanavir is administered with cobicistat, it should be avoided in patients with an eGFR <70 mL/min/1.73 m² if tenofovir disoproxil fumarate-emtricitabine is used as the nucleoside combination. Although the US Food and Drug Administration (FDA) has approved unboosted atazanavir at 400 mg (two 200 mg capsules) once a day, unboosted atazanavir is not recommended except in select situations [12,63].

Atazanavir has the advantage of better gastrointestinal tolerance than most other PIs, once-daily dosing, and good potency. Atazanavir is not associated with the development of insulin resistance when compared with some other PIs such as lopinavir-ritonavir. Lipid profiles show mild increases in cholesterol and triglycerides that are mainly related to ritonavir [136].

Disadvantages with atazanavir include the need for gastric acid and food for optimal absorption; thus, concomitant use of drugs that alter stomach pH (eg, proton pump inhibitors) may impair absorption of the drug. Atazanavir should not be used in patients who require a proton pump inhibitor dose equivalent to >20 mg omeprazole per day.

Atazanavir has been associated with the development of renal stones and kidney injury (eg, proximal tubular dysfunction, interstitial nephritis, and acute and chronic kidney injury) [34,137-142]. (See "Overview of kidney disease in patients with HIV", section on 'Causes of AKI in patients with HIV'.)

Adverse reactions also include an increase in the indirect serum bilirubin concentration, which is benign but may cause jaundice. However, in antiretroviral-naïve persons with low cardiovascular risk, the hyperbilirubinemia associated with atazanavir plus ritonavir may be responsible for slower progression of carotid artery intima-media thickening compared with those who received darunavir boosted with ritonavir [143]. In addition, unlike other PIs, atazanavir is not associated with an increased risk of cardiovascular disease [144-146]. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV".)

Darunavir — Dosing of darunavir for treatment-naïve patients is 800 mg once daily plus ritonavir 100 mg once daily or darunavir 800 mg once daily plus cobicistat 150 mg once daily. Darunavir is available in two single coformulated tablets, darunavir-cobicistat and darunavir-cobicistat-emtricitabine-tenofovir alafenamide (table 1).

For patients with drug-resistant virus, the dose of darunavir 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, and L89V). Cobicistat should not be used as a boosting agent for such 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 [147].

Darunavir appears to be the best tolerated PI in randomized studies [125,129]. The principal adverse effects associated with darunavir include nausea, diarrhea, increased transaminases, headache, and rash. However, severe reactions can occur, and darunavir should be discontinued in patients who develop a rash associated with fever, transaminase elevations, eosinophilia, and/or systemic symptoms, as well as those who have severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, exanthematous pustulosis) [148-152].

Darunavir, whether given with ritonavir or cobicistat, should not be used in patients with severe liver disease, as infrequent cases of drug-induced liver injury have been reported. In addition, we generally avoid administering darunavir to patients with a sulfonamide allergy, especially those with a severe 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 able to tolerate darunavir (it lacks one or both essential functional groups implicated in sulfonamide antibiotic hypersensitivity), we prefer using a different third drug for such patients if possible, given the availability of multiple effective alternatives.

Other protease inhibitors

●Lopinavir – Lopinavir boosted with ritonavir is not typically recommended because of issues related to potency, toxicity, and convenience [12,128,129]. However, when it is used, a tenofovir-containing nucleoside reverse transcriptase inhibitor (NRTI) combination is preferred.

Lopinavir-ritonavir can also be given with lamivudine alone for patients who are unable to tolerate a tenofovir or abacavir-containing backbone [12]. In a randomized study of 426 patients, individuals received lopinavir-ritonavir in combination with lamivudine (dual therapy) or tenofovir disoproxil fumarate-emtricitabine (triple therapy). After 48 weeks of treatment, the number of patients who achieved a viral load <50 copies/mL was similar between the two groups (88 versus 83 percent) [153]. However, a nucleoside-limiting regimen such as lopinavir-ritonavir plus lamivudine may not be suitable for all patients. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Use of two-drug regimens in select patients'.)

●PIs rarely used – Several older PIs that were commonly used are either no longer administered or are rarely used because of poor efficacy and/or toxicity. Such agents include indinavir, fosamprenavir, nelfinavir, saquinavir, and tipranavir. As an example, although tipranavir is active against strains of HIV that are resistant to other protease inhibitors, it is avoided when possible since it has high rates of hepatotoxicity and has been associated with intracranial hemorrhage [154-157]. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'Protease inhibitors'.)

POST-ATTACHMENT INHIBITOR — Ibalizumab is a monoclonal antibody that is given as an intravenous infusion every two weeks and binds the CD4 molecule in such a way that it does not block viral attachment, but does block entry [158]. 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. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy", section on 'If a fully active PI is NOT available'.)

SPECIAL CONSIDERATIONS

Pharmacokinetic boosting — Most protease inhibitors (PIs), as well as the integrase inhibitor elvitegravir, are administered in combination with another agent (eg, low-dose ritonavir or cobicistat) to increase trough plasma drug concentrations, increase drug half-lives, and increase maximum plasma concentrations (C_MAX). This improves the potency of the antiviral agent and enables lower and less frequent dosing of the parent drug, thereby decreasing pill burden.

For PIs, pharmacokinetic boosting is done in combination with cobicistat or low-dose ritonavir. Although ritonavir is also a PI, it is not used as an antiviral agent when administered at a low dose but rather as a boosting agent for other PIs. Both cobicistat and ritonavir inhibit the hepatic microsomal enzyme CYP (450) 3A4, a characteristic used to "boost" the concentration of the coadministered PI.

Ritonavir boosting is required for darunavir and lopinavir, and is preferred for atazanavir. As a boosting agent for darunavir and atazanavir, ritonavir is dosed as 100 mg daily; for lopinavir, ritonavir is dosed at 200 mg per day. Ritonavir is available as a tablet, gel cap, and oral solution. Tablets and oral solution do not require refrigeration. The gel capsules should be refrigerated but may be left at room temperature (77°F) for up to 30 days. Full-dose ritonavir (600 mg twice daily) is never used to treat HIV infection because of significant adverse effects at this dose. The major drawbacks of using ritonavir boosting are related to adverse drug interactions, an increased risk of gastrointestinal intolerance, and hyperlipidemia. All of these adverse effects are dose related.

Cobicistat is chemically similar to ritonavir, but has no antiviral activity. Overall, it is well tolerated, but it has been associated with modest increases in serum creatinine (it inhibits tubular secretion of creatinine), and has gastrointestinal toxicity, lipid changes, and drug interactions comparable with ritonavir. It is also used to boost the integrase inhibitor, elvitegravir, and the protease inhibitors, atazanavir and darunavir. Coformulated tablets of cobicistat with these agents are available. Cobicistat-boosted regimens should not be used in females of childbearing age who are not committed to effective birth control and in pregnant females due to decreased drug levels during pregnancy. (See "HIV and women", section on 'Selection of antiretroviral regimens'.)

Patients who have trouble swallowing tablets — Certain patients may have trouble taking combination regimens if they have difficulty swallowing due to other comorbidities, such as candidal esophagitis, or more permanent disabilities, such as stroke. Fortunately, many antiretroviral medications are available as liquid preparations; for other medications, there are methods for dissolving or crushing tablets without losing drug potency [159,160]. The milligram dosing of a liquid preparation may differ from the milligram dose of a tablet formulation, so a direct conversion should not be expected. In addition, some chewable, powder, and liquid formulations are not approved for or conducive to administration to adults. Antiretroviral formulations that can be used for patients who have trouble swallowing pills are described in the table (table 3). Injectable therapy (eg, long-acting cabotegravir-rilpivirine) may also be an option for selected patients. (See 'Cabotegravir' above and "Use of long-acting cabotegravir-rilpivirine in people with HIV".)

Timing of doses for patients on hemodialysis — For patients undergoing hemodialysis, we schedule medications so that at least one of the daily ART doses is taken soon after dialysis on dialysis days. As an example, bictegravir-emtricitabine-tenofovir alafenamide, emtricitabine, lamivudine, tenofovir alafenamide, tenofovir disoproxil fumarate, and zidovudine specifically should be taken after dialysis on dialysis days [12,161]. Although some antiretroviral agents are probably not dialyzed, the logic behind dosing after dialysis is to guarantee therapeutic plasma concentrations in case dialysis removes some of the drug or an important metabolite.

More detailed information on the use of specific antiretroviral agents in the setting of dialysis can be found in the Lexicomp drug monographs included with UpToDate and in the DHHS guidelines [12].

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

●Overview of HIV replication – The life cycle of HIV can be broken down into 6 steps: (1) entry (binding and fusion), (2) reverse transcription, (3) integration, (4) replication (transcription and translation), (5) assembly, and (6) budding and maturation. The identification and understanding of these processes have provided the basis for antiretroviral agents used to treat HIV. (See 'Overview of HIV replication' above.)

●Nucleoside reverse transcriptase inhibitors (NRTIs) – Nucleoside reverse transcriptase inhibitors (NRTIs) are often referred to as the "backbone" of antiretroviral therapy (ART) regimens and are usually given in pairs. The commonly used combinations are available as coformulations (tenofovir alafenamide-emtricitabine, tenofovir disoproxil fumarate-emtricitabine, abacavir-lamivudine). (See 'Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)' above.)

●Non-nucleoside reverse transcriptase inhibitors (NNRTIs) – The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are typically administered with an NRTI combination. For treatment-naïve patients, options include efavirenz, rilpivirine, and doravirine. Etravirine is generally used for individuals with evidence of drug-resistant virus. (See 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)' above.)

●Integrase strand transfer inhibitors – Regimens using integrase strand transfer inhibitors (INSTIs; eg, bictegravir, dolutegravir, elvitegravir, and raltegravir) are effective and well tolerated. In many countries, including the United States, INSTIs are considered the preferred third agent for treatment-naïve individuals in combination with two nucleoside analogues. In addition, a once-monthly, injectable regimen (cabotegravir-rilpivirine) is available as switch therapy for treatment-experienced patients who are virologically suppressed on an oral regimen. (See 'Integrase strand transfer inhibitors (INSTIs)' above.)

●Protease inhibitors – Protease inhibitors (PIs) are typically administered with an NRTI combination; however, they can also be used as part of a nucleoside-sparing/limiting regimen. PIs should be administered with a boosting agent such as ritonavir or cobicistat. They can be used for patients who are treatment-naïve, and are often the preferred agent for patients failing their initial ART regimen. (See 'Protease inhibitors (PIs)' above and 'Pharmacokinetic boosting' above.)

●Other agents – There are several antiretroviral agents available for treatment of persons with multidrug-resistant HIV that are not included in the classes above. These include lenacapavir (capsid inhibitor), fostemsavir (attachment inhibitor), and ibalizumab (post-attachment inhibitor). (See 'Capsid inhibitors' above and 'Attachment inhibitors' above and 'Post-attachment inhibitor' above.)

Other antiretroviral agents, such as maraviroc (a CCR5 inhibitor) and enfuvirtide (a fusion inhibitor), are also available; however, they are not commonly used for the treatment of HIV. (See 'Entry inhibitors' above.)

●Patients who have trouble swallowing pills – Certain patients may have trouble taking combination regimens if they have difficulty swallowing due to other comorbidities, such as candidal esophagitis, or more permanent disabilities, such as stroke. For such patients, alternative antiretroviral agents may be available (table 3). (See 'Patients who have trouble swallowing tablets' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Amy Graziani, PharmD, and Charles Hicks, MD, who contributed to an earlier version of this topic review.

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