Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions

INTRODUCTION — The goals of antiretroviral therapy (ART) are to reduce HIV-related morbidity and mortality (from both infectious and noninfectious causes) and to prevent transmission of HIV to others. For most treatment-naïve patients, ART regimens contains two different nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent from a different class.

This topic will address the approach to choosing an initial ART regimen for treatment-naïve patients with HIV-1 who have comorbid conditions that impact regimen selection, which represent only a small fraction of those starting ART. The general approach to initial regimen selection and other topics relevant to treatment of individuals with HIV include:

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

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

●(See "Patient monitoring during HIV antiretroviral therapy".)

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

●(See "Overview of antiretroviral agents used to treat HIV".)

●(See "Treatment of HIV-2 infection".)

ANTIRETROVIRAL AGENTS — There are more than 25 antiretroviral medications from six major classes currently available for the treatment of patients with HIV (table 1). The most commonly used antiretroviral agents for treatment-naïve patients include nucleoside reverse transcriptase inhibitors (NRTIs), integrase strand transfer inhibitors (INSTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). These agents are discussed in detail in separate topic reviews. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Antiretroviral agents' and "Overview of antiretroviral agents used to treat HIV".)

CONSIDERATIONS PRIOR TO INITIATING ANTIRETROVIRAL THERAPY — To optimize individual regimens, we evaluate the treatment-naïve patient for the presence or absence of certain conditions, including renal insufficiency, chronic hepatitis B virus infection, heart disease, pregnancy status, and, if abacavir is being considered, the HLA-B*5701 allele. Abacavir is contraindicated if the patient is positive for the HLA-B*5701 allele since persons who test positive for HLA-B*5701 are at high risk for developing an abacavir hypersensitivity reaction. (See "Abacavir hypersensitivity reaction".)

Baseline drug resistance testing should also be performed to detect the presence and/or characteristics of a drug-resistant virus. This testing should include reverse transcriptase (nucleoside and non-nucleoside reverse transcriptase) and protease inhibitor resistance; resistance testing for integrase strand transfer inhibitors (INSTIs) is not required unless the source patient is known to have INSTI treatment failure or resistance.

More detailed discussions of the pretreatment evaluation in patients with HIV are presented elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Considerations prior to initiating treatment'.)

WHEN TO INITIATE ANTIRETROVIRAL THERAPY — Antiretroviral therapy (ART) should be offered to all persons with HIV, including asymptomatic individuals, regardless of their immune status [1,2]. The only individuals in whom the benefits of ART are not proven are the small proportion of untreated patients with preserved CD4 cell counts and undetectable HIV RNA (sometimes referred to as HIV controllers). (See "When to initiate antiretroviral therapy in persons with HIV".)

For many individuals, we initiate ART soon after their initial diagnosis. Initiating therapy at the initial visit can improve virologic outcomes and retention in care. However, there may be special considerations for patients with certain opportunistic infections (eg, tuberculosis, cryptococcal meningitis) or comorbid conditions. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Timing of treatment'.)

APPROACH TO REGIMEN SELECTION

General approach — For most treatment-naïve patients, we suggest an integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) regimen. We typically administer dolutegravir plus tenofovir alafenamide-emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Approach for most patients'.)

However, certain patients will have concurrent conditions that impact the choice of regimen. Although many patients with comorbid conditions can still use one of the preferred regimens described above, some may benefit from a regimen that avoids tenofovir (eg, dolutegravir-lamivudine) or uses a non-nucleoside reverse transcriptase inhibitor (NNRTI) instead of an INSTI (table 2 and table 3). If more than one comorbid condition is present, the clinician should review the options for each relevant scenario and select the most appropriate combination.

In persons who are of childbearing potential or are pregnant, physicians must carefully consider the risks and benefits of the different regimens and share these considerations with the patient. Detailed discussions of the safety of antiretroviral medications in these populations are 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".)

Hepatitis B virus coinfection — We make all efforts to administer a tenofovir-containing ART regimen to patients who have chronic hepatitis B virus (HBV) infection. Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are both effective in suppressing HBV replication and are also included in the preferred HIV ART regimens (table 2).

HIV regimens that use lamivudine or emtricitabine without tenofovir should be avoided. These include regimens that use abacavir-lamivudine as the nucleoside combination or a two-drug regimen such as dolutegravir-lamivudine. Although lamivudine has activity against HBV, lamivudine monotherapy is associated with the rapid emergence of lamivudine-resistant HBV due to mutations within the YMDD motif of HBV reverse transcriptase.

A detailed discussion of the management of individuals with HIV/HBV coinfection is found elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV".)

Reduced kidney function — The approach to treatment in patients with reduced kidney function depends upon the degree of renal insufficiency.

Agents to avoid — For patients with reduced kidney function (estimated glomerular filtration rate [eGFR] <60 min/mL/1.73 m²), we avoid TDF, which is associated with proximal tubular dysfunction. However, TAF, a different formulation of tenofovir, can be used in patients with moderately reduced kidney function (eGFR ≥30 min/mL/1.73 m²). (See 'Moderately reduced kidney function' below.)

The protease inhibitor (PI) atazanavir has also been associated with acute and chronic kidney disease and should generally be avoided in patients with reduced kidney function.

Addition information on nephrotoxicity associated with antiretroviral medications is presented elsewhere. (See "Overview of kidney disease in patients with HIV" and "Overview of antiretroviral agents used to treat HIV".)

Moderately reduced kidney function — In patients with an eGFR ≥30 mL/min/1.73 m² but <60 mL/min/1.73 m², several treatment options exist. These include one of the preferred three-drug regimens, dolutegravir plus tenofovir alafenamide–emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide, as well as the two-drug combination dolutegravir-lamivudine (table 2 and table 3).

●A TAF-containing regimen should be used for those with chronic hepatitis B infection, those with a viral load >500,000 copies/mL, and most patients with transmitted drug resistance or a CD4 count ≤200 cells/microL. (See 'Considerations when using dolutegravir-lamivudine' below and 'Hepatitis B virus coinfection' above and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Patients with transmitted drug resistance'.)

●For others, we use a shared decision-making approach to determine if a TAF-containing regimen or dolutegravir-lamivudine should be used. We discuss how using dolutegravir-lamivudine could reduce the risk that even TAF could contribute to potential nephrotoxicity. However, there are fewer long-term data with the use of this regimen, and unlike one of the preferred three-drug regimens, dolutegravir-lamivudine cannot be initiated until the results of the initial evaluation have returned. Additional information on the use of dolutegravir-lamivudine is found below. (See 'Considerations when using dolutegravir-lamivudine' below.)

Severely reduced kidney function

Patients on hemodialysis — There is limited published experience to guide decisions regarding the preferred regimen for treatment-naïve patients on chronic hemodialysis. Studies evaluating antiretroviral agents in patients on hemodialysis have primarily been in virologically suppressed patients [3-5]. In general, we prefer bictegravir-emtricitabine-tenofovir alafenamide, since it can be administered as a single tablet once daily. Dolutegravir plus tenofovir alafenamide-emtricitabine is also an option and does not require dose adjustment [1]. If TAF is not available, renally dosed lamivudine can also be used with dolutegravir, although it has not been studied in this population. Special considerations when using dolutegravir plus lamivudine are discussed below. (See 'Considerations when using dolutegravir-lamivudine' below.)

Patients not on dialysis — In patients with an eGFR <30 mL/min/1.73 m² who are not on dialysis, both TAF and TDF should generally be avoided; although TAF has less nephrotoxicity compared with TDF, there are only limited data evaluating the safety of TAF in patients with severely reduced kidney function.

●Preferred regimen – When choosing a regimen for patients with severely reduced kidney function not on dialysis, we suggest the combination dolutegravir plus lamivudine if they meet all of the criteria described below. (See 'Considerations when using dolutegravir-lamivudine' below.)

When using dolutegravir plus lamivudine in patients with severely reduced kidney function, the single coformulated tablet should not be used since the dose of lamivudine must be reduced. Thus, the regimen must be administered as two tablets once daily. Additional information on renal dosing is found in the Lexicomp drug information topics within UpToDate.

●Alternative regimens – Some patients cannot take dolutegravir plus lamivudine because they do not meet the criteria described below. (See 'Considerations when using dolutegravir-lamivudine' below.)

Such patients should be managed in conjunction with an expert in HIV care, since the approach must be individualized. As examples:

•For patients with chronic hepatitis B coinfection, the benefits of using TAF at a lower eGFR may outweigh the potential risk of toxicity. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Tenofovir in patients with reduced kidney function'.)

•For patients with high viral loads, the combination of dolutegravir plus abacavir plus lamivudine may be reasonable for those who are HLA-B*5701 negative and are without cardiovascular disease. If this regimen is used, the single-pill coformulated tablet should not be administered, as the dose of lamivudine needs to be reduced.

•For those with nucleoside reverse transcriptase inhibitor (NRTI) resistance, the combination of dolutegravir plus boosted darunavir may be reasonable. Although this specific regimen has not been studied, in a randomized trial of 805 treatment-naïve individuals, darunavir (800 mg) boosted with ritonavir (100 mg) plus raltegravir (400 mg twice daily) was noninferior to an established drug combination of ritonavir-boosted darunavir plus tenofovir disoproxil fumarate-emtricitabine after 96 weeks of treatment [6]. We would expect similar or better results when dolutegravir is used rather than raltegravir, since the former has a higher barrier to resistance.

Cardiovascular disease — For patients who have a history of (or are at high risk for) heart disease, dolutegravir plus tenofovir alafenamide-emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide can be used. If there are contraindications to tenofovir, the two-drug combination dolutegravir-lamivudine is also an option, assuming there are no contraindications, as described below. (See 'Considerations when using dolutegravir-lamivudine' below.)

We avoid abacavir in such patients. Although data are conflicting, several studies have found that abacavir can increase the risk of cardiovascular disease [7-11]. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Abacavir' and "Overview of antiretroviral agents used to treat HIV", section on 'Abacavir'.)

Additional considerations for regimen selection in patients with cardiovascular disease include:

●Impact of ART on lipids – Data from clinical trials show that TAF lowers lipids less than TDF [12,13]; however, the clinical significance of this is unclear. Furthermore, it is unknown whether the lipid-lowering effect of TDF improves clinical outcomes. The INSTIs bictegravir, dolutegravir, and raltegravir have a largely neutral effect on cholesterol and triglycerides compared with efavirenz and PIs.

●If an INSTI cannot not be used – If an INSTI is not appropriate (eg, because of drug interactions), rilpivirine can be used as the third agent for patients with a CD4 ≥200 cells/microL and a viral load <100,000 copies/mL, since rilpivirine is also associated with minimal changes in lipids. However, rilpivirine should be avoided, if possible, in patients at risk for torsades de pointes. Another potential option is doravirine, though there is less experience with this NNRTI. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

●If a PI is used – If a PI is used in patients at high cardiovascular risk, we prefer to use atazanavir over other boosted PIs. With the exception of atazanavir, all of the ritonavir-boosted PIs are associated with an increased risk of cardiovascular disease independent of their lipid effects [14]. Furthermore, atazanavir is associated with a decreased risk of myocardial infarction compared with other antiretroviral agents [15] and was shown in a prospective randomized trial to reduce carotid intima media thickness progression more than either raltegravir or darunavir [16].

More detailed discussions of antiretroviral agents and their role in cardiovascular disease are found elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV" and "Overview of antiretroviral agents used to treat HIV".)

Osteoporosis — For most patients with osteoporosis, we use a TAF-containing regimen (dolutegravir plus tenofovir alafenamide-emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide), since the use of TDF, but not TAF, is associated with bone loss [17]. (See "Bone and calcium disorders in patients with HIV".)

However, some patients may prefer to avoid even TAF. For such patients, dolutegravir-lamivudine is a reasonable choice, assuming there are no contraindications, as described below. (See 'Considerations when using dolutegravir-lamivudine' below.)

Patients with opportunistic infections — For patients with HIV who present with opportunistic infections, regimen selection should take into account potential drug interactions. Information on drug interactions can be found in the Lexicomp drug interaction program within UpToDate and within separate topic reviews. (See "Overview of antiretroviral agents used to treat HIV".)

The treatment of active or latent tuberculosis is one example in which drug interactions may impact the ART regimen, since there are important drug interactions that can be seen with rifamycins and many of the antiretroviral agents used to treat HIV:

●Regimens that contain a boosting agent (eg, cobicistat or ritonavir), PIs, bictegravir, rilpivirine, and doravirine should not be used with rifampin.

●Agents such as dolutegravir and raltegravir require dose adjustment if used with rifampin.

●The combination of TAF plus a rifamycin should be avoided, if possible. Rifamycins appear to reduce TAF levels, although the clinical significance of the interaction with TAF is unclear since intracellular concentrations of tenofovir diphosphate (the active agent) were still 82 percent higher on average than those achieved by standard-dose TDF [18].

For patients who are being treated with a rifampin-containing regimen, dolutegravir can be administered with tenofovir disoproxil fumarate-emtricitabine assuming there are no suspected or documented INSTI-associated resistance mutations; however, dolutegravir should be administered as 50 mg twice daily. Other ART options include raltegravir (800 mg twice daily) with tenofovir disoproxil fumarate-emtricitabine, or efavirenz-emtricitabine-tenofovir disoproxil fumarate. Abacavir-lamivudine plus dolutegravir (50 mg twice daily) is another option, assuming the patient is HLA-B*5701 negative and the patient does not have hepatitis B virus or cardiovascular disease. After completing treatment for active or latent TB, these regimens can be switched to one of the preferred ART regimens. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Two-drug ART regimens (eg, dolutegravir-lamivudine, dolutegravir plus boosted darunavir) should not be used in patients who are being treated with a rifamycin.

More detailed discussions of the treatment of active and latent tuberculosis in patients with HIV are found elsewhere. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection".)

CONSIDERATIONS WHEN USING DOLUTEGRAVIR-LAMIVUDINE — The two-drug regimen dolutegravir-lamivudine may be well suited for patients initiating antiretroviral therapy (ART) with certain comorbid conditions (eg, reduced kidney function, osteoporosis). In clinical trials, this regimen was found to have similar efficacy to dolutegravir plus tenofovir disoproxil fumarate-emtricitabine in treatment-naïve patients [19].

If dolutegravir-lamivudine is being considered, all of the following criteria must be met:

●The HIV viral load must be less than 500,000 copies/mL.

●There must be no evidence of transmitted resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or integrase strand transfer inhibitors (INSTIs; if INSTI resistance testing was obtained as part of the initial evaluation). (See 'Considerations prior to initiating antiretroviral therapy' above.)

●The patient must have no evidence of chronic HBV infection.

●The patient must not be taking any concurrent medications that would significantly reduce the levels of either antiretroviral agent (eg, rifampin reduces dolutegravir levels).

In addition, the patient should ideally have a CD4 count >200 cells/microL [2]. A low CD4 count is not a contraindication to using this regimen, but we generally avoid dolutegravir-lamivudine in such patients if there are other good treatment options. Few patients with advanced immunosuppression have been treated with dolutegravir-lamivudine, and in the comparative trial comparing dolutegravir-lamivudine with dolutegravir plus tenofovir disoproxil fumarate-emtricitabine, those who had a low CD4 count were less likely to achieve a viral load <50 copies at week 48, although the lower results were mostly due to study dropout, not virologic failure [19]. A detailed discussion of the data supporting the use of this regimen is presented elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Use of two-drug regimens in select patients'.)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Starting treatment for HIV (The Basics)" and "Patient education: HIV/AIDS (The Basics)")

●Beyond the Basics topics (see "Patient education: Initial treatment of HIV (Beyond the Basics)" and "Patient education: Tips for taking HIV medications by mouth (Beyond the Basics)" and "Patient education: Testing for HIV (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The management of HIV involves treatment with combination antiretroviral therapy (ART). The use of these multidrug regimens substantially reduces progression to AIDS, opportunistic infections, hospitalizations, and death. They also prevent transmission of HIV to others. (See 'Introduction' above.)

●ART should be offered to all persons with HIV, including asymptomatic individuals, regardless of their immune status. For many individuals, we initiate ART soon after their initial diagnosis, even before the results of baseline testing have returned. (See 'When to initiate antiretroviral therapy' above.)

●For most treatment-naïve patients, we suggest an ART regimen of dolutegravir plus tenofovir alafenamide-emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide (table 2). However, there are special considerations for patients with certain comorbid conditions (eg, chronic hepatitis B virus infection, reduced kidney function, cardiovascular disease, osteoporosis, opportunistic infections) (table 3). (See 'General approach' above.)

●For patients with chronic hepatitis B virus coinfection, a tenofovir-containing regimen should be used. Regimens that include lamivudine without tenofovir (eg, dolutegravir-lamivudine, dolutegravir-abacavir-lamivudine) should be avoided, since lamivudine monotherapy for treatment of hepatitis B virus (HBV) has been associated with the rapid emergence of lamivudine-resistant HBV. (See 'Hepatitis B virus coinfection' above.)

●For patients with reduced kidney function, we generally avoid tenofovir disoproxil fumarate (TDF), which is associated with proximal tubular dysfunction. For such patients, the choice of regimen depends on the severity of kidney disease. (See 'Reduced kidney function' above.)

•For patients with moderately reduced kidney function (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m² but <60 mL/min/1.73 m²), dolutegravir plus tenofovir alafenamide-emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide can be used. Dolutegravir-lamivudine is also an option for many patients, assuming they meet the criteria described below. (See 'Moderately reduced kidney function' above.)

•For most patients with severely reduced kidney function (eGFR <30 mL/min/1.73 m²) who are not on dialysis, we suggest dolutegravir plus lamivudine (Grade 2C). For such patients, both tenofovir alafenamide (TAF) and TDF should be avoided. However, if dolutegravir plus lamivudine cannot be used because the patient does not meet the criteria described below, the approach must be individualized, taking into account the presence of other comorbid conditions. (See 'Severely reduced kidney function' above.)

•If dolutegravir-lamivudine is being considered, it can only be used for patients who meet all of the following criteria: HIV viral load <500,000 copies/mL, no evidence of chronic HBV, no transmitted nucleoside reverse transcriptase inhibitor (NRTI) or integrase strand transfer inhibitor (INSTI) resistance (if INSTI resistance testing was obtained as part of the initial evaluation), and no drug interactions that significantly lower the level of either agent. This regimen should ideally be used in patients with a CD4 count >200 cells/microL, but a low CD4 count is not a contraindication. (See 'Considerations when using dolutegravir-lamivudine' above.)

●For patients who have a history of (or are at high risk for) heart disease, any of the preferred regimens can be used (table 2). In such patients we avoid abacavir, since available data suggest that abacavir can increase the risk of cardiovascular disease. (See 'Cardiovascular disease' above.)

●For patients with osteoporosis, TDF should be avoided. However, regimens that contain TAF or the regimen dolutegravir-lamivudine can be used. (See 'Osteoporosis' above and 'Considerations when using dolutegravir-lamivudine' above.)

●For patients with HIV who present with opportunistic infections, regimen selection should take into account potential drug interactions. As an example, in patients being treated for active or latent tuberculosis, regimen selection can be affected by the risk of clinically important drug interactions with rifamycins. (See 'Patients with opportunistic infections' above.)