Adult Antiretroviral Guidelines

US DHHS Guidelines with Australian Commentary

Initial Combination ARV Regimens for People with HIV

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Initial Combination ARV Regimens for People with HIV

DHHS Last Updated: September 2024Australian Commentary Last Updated: December 2024

Long-acting cabotegravir (CAB-LA) for PrEP was TGA approved in 2022 but as of June 2024, the process for listing this medication on the PBS has ceased. However, some patients may have accessed CAB-LA as PrEP while overseas. Clinicians should ensure that integrase genotypic resistance testing is requested to exclude integrase strand transfer inhibitor (INSTI) resistance. If initiating therapy before the result is available, please refer to the latest DHHS recommendations.

The non-nucleoside reverse transcriptase inhibitor doravirine (DOR), was approved by the TGA in 2020 as a single drug or as a fixed dose combination with TDF and lamivudine (3TC). DOR/TDF/3TC is NOT reimbursed under the PBS in Australia.

Key Considerations and Recommendations
  • An initial antiretroviral (ARV) regimen for a person with HIV generally consists of two nucleoside reverse transcriptase inhibitors administered in combination with a third active ARV drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer (also known as a booster; the two drugs used for this purpose are cobicistat and ritonavir).
  • Data also support the use of the two-drug regimen, dolutegravir (DTG) plus lamivudine (3TC), for initial treatment.
  • Before initiating antiretroviral therapy (ART) in a person of childbearing potential, clinicians should discuss the person’s intentions regarding pregnancy and a pregnancy test should be performed (AIII). Clinicians should refer to the Perinatal Guidelines for recommendations on initial ARV treatment around the time of conception and during pregnancy.
  • The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) classifies the regimens below (in alphabetical order) as Recommended Initial Regimens for Most People with HIV.

    For people with HIV who do not have a history of using long-acting cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP), the following regimens are recommended:

    • Bictegravir/tenofovir alafenamide (TAF)/emtricitabine (FTC) (AI)a
    • DTG/abacavir/3TC—only for individuals who are HLA-B*5701 negative and without chronic hepatitis B virus (HBV) coinfection (AI)
    • DTG plus (TAF or tenofovir disoproxil fumarate [TDF])b plus (FTC or 3TC) (AI)
    • DTG/3TC (AI)—except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or when ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available

For people with HIV and a history of using CAB-LA as PrEP, INSTI genotypic resistance testing should be done before the start of ART. If treatment is begun prior to results of genotypic testing, the following regimen is recommended:

    • Boosted darunavir plus (TAF or TDF)b plus (FTC or 3TC)—pending the results of the genotype test (AIII).
  • To address individual patient characteristics and needs, the Panel also provides a list of Recommended Initial Regimens in Certain Clinical Situations (see Table 6 below).
  • Given the many excellent options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug–drug interaction potential, resistance-test results, comorbid conditions, access, and cost. For guidance on choosing an ARV regimen based on selected clinical case scenarios, see Table 7. Also see Table 9 for the advantages and disadvantages of different components in an ARV regimen.
  • Patients without prior ART use who wish to begin long-acting intramuscular CAB and rilpivirine (RPV) should first achieve viral suppression on another regimen before switching to CAB and RPV (see Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression).
Rating of Recommendations: A = Strong; B = Moderate; C = Weak

Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion

a Bictegravir should not be initiated in pregnant people due to insufficient data in pregnancy.

b TAF and TDF are two forms of tenofovir that are approved by the U.S. Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Introduction

More than 30 antiretroviral (ARV) drugs in nine mechanistic classes are U.S. Food and Drug Administration (FDA)–approved for treatment of HIV infection. These nine classes include nucleos(t)ide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), a fusion inhibitor, a CCR5 antagonist, a CD4 T lymphocyte (CD4) cell post-attachment inhibitor, a gp120 attachment inhibitor, and a capsid inhibitor. In addition, two drugs—ritonavir (RTV) and cobicistat (COBI)—are used as pharmacokinetic (PK) enhancers (or boosters) to improve the PK profiles of PIs and the INSTI elvitegravir (EVG).

Over time, incremental improvements in potency, tolerability, safety, convenience, drug interactions and genetic barriers to the emergence of drug resistance have led to streamlined recommendations for initial ARV regimens for most people with HIV. The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) now recommends initial ARV regimens based on an oral second- generation INSTI plus two NRTIs—bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (AI) or dolutegravir (DTG) plus TAF/FTC or tenofovir disoproxil fumarate (TDF)/ FTC or TDF/lamivudine (3TC) (AI)—for most people with HIV. In some people with HIV, the two-drug regimen DTG/3TC can be used (AI). When INSTI resistance is possible, such as after exposure to long-acting injectable cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP) and/or if INSTI genotype results are not yet available, a boosted PI (boosted darunavir [DRV]) in combination with two NRTIs (TAF or TDF with FTC or 3TC) is recommended (AIII). The Panel’s recommendations are summarized in Tables 6a and 6b.

Table 6a. Recommended Initial Regimens for Most People With HIV

Selection of antiretroviral therapy (ART) should be based on the regimen’s virologic efficacy, potential adverse effects, pill burden, dosing frequency, drug–drug interaction potential, cost, access, resistance test results, and the comorbid condition of the person with HIV. A pregnancy test should be performed in people of childbearing potential, and choice of ART for pregnant individuals should be guided by recommendations from the Perinatal Guidelines. Drug classes and regimens within each class are arranged first by evidence rating and, when ratings are equal, in alphabetical order.

Additional initial ARV regimen options for certain clinical scenarios are listed in Table 6b below.

Recommended Initial Regimens for Most People with HIV
Recommended regimens are those with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. Choice of ART during pregnancy should be guided by recommendations from the Perinatal Guidelines.
For people who do not have a history of using CAB-LA as PrEP, one of the following regimens is recommendeda:


  • BIC/TAF/FTC (AI)

  • DTG plus (TAF or TDF)b plus (FTC or 3TC) (AI)

  • DTG/3TC (AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available.



For people who have a history of CAB-LA use as PrEP, INSTI genotype resistance testing should be performed before starting ART. If ART is to be started before results of genotypic testing results, the following regimen is recommended:

  • DRV/cc or DRV/r with (TAF or TDF)b plus (FTC or 3TC)—pending the results of the genotype test (AIII)
Rating of Recommendations: A = Strong; B = Moderate; C = Weak
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion


Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion

a Because of the current low rates of transmitted INSTI resistance in the United States, even when there is suspicion that HIV was acquired from a partner with virologic failure while on an INSTI, an INSTI-based regimen can be started pending the results of the INSTI genotype.

b TAF and TDF are two forms of TFV approved by the U.S. Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

c COBI should be avoided in pregnancy because lower concentrations of COBI and DRV have been reported during the second and third trimesters. For further information, refer to the Perinatal Guidelines.

Note: The following are available as coformulated drugs: BIC/TAF/FTC, DRV/c/TAF/FTC, DTG/3TC, TAF/FTC, TDF/3TC, and TDF/FTC.

Key: 3TC = lamivudine; ART = antiretroviral therapy; BIC = bictegravir; CAB-LA = long-acting cabotegravir; COBI = cobicistat; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; FTC = emtricitabine;

HBV = hepatitis B virus; INSTI = integrase strand transfer inhibitor; PrEP = pre-exposure prophylaxis; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir

Table 6b. Other Initial Antiretroviral Regimens for Certain Clinical Scenarios

Several antiretroviral regimens are found to be effective and tolerable as initial regimens but have some disadvantages or have fewer supporting data from randomized clinical trials compared with the recommended regimens listed in Table 6a. However, one of these regimens may be preferred for an individual with HIV in certain clinical situations (also see Table 7). These regimens are listed below.

Type of RegimenARV RegimenFor Certain Clinical ScenariosOther Considerations
INSTI Plus Two NRTIsDTG/ABC/3TC (BI) (if HLA-B*5701-negative)
When concern about renal- or bone-associated AEs precludes the use of TDF or TAFTest for HLA-B*5701 before prescribing ABC; do not prescribe if HLA-B*5701- positive.

Consider avoiding ABC for people with multiple CV risk factors or known CV disease.

Do not use in people with HBV coinfection unless an HBV- active drug, such as entecavir, TAF, or TDF is also used.

Do not use following exposure to CAB-LA unless INSTI genotype shows sensitivity.
Boosted PI Plus Two NRTIs(DRV/ca or DRV/r) plus


(TAFor TDFb) plus (FTC or 3TC) (BI)		To avoid an INSTI-based regimen (e.g., documented INSTI resistance).Assess for potential RTV- or COBI-related DDIs.
(DRV/ca or DRV/r) plus ABC/3TC (BII)
(if HLA-B*5701-negative)
To avoid an INSTI-based regimen (e.g., with suspected or documented INSTI resistance), and

When concern about renal or bone-associated AEs precludes the use of TDF or TAF		Test for HLA-B*5701 before prescribing ABC; do not prescribe if HLA-B*5701- positive.

Consider avoiding ABC for people with multiple CV risk factors or known CV disease.

Do not use in people with HBV coinfection unless used with an HBV-active drug other than 3TC.

Assess for potential RTV- or COBI-related DDIs.
INSTI Plus Two NRTIsDOR/TDF/3TCb (BI) or DOR

plus TAF/FTCb (BIII)

To avoid an INSTI-based regimen (e.g., with suspected or documented INSTI resistance), and

To avoid a PI-based regimen (e.g., with significant DDIs with concomitant medications)
RPV/TAF/FTC (BII)

Only if HIV RNA
<100,000 copies/mL and CD4 count >200 cells/mm3		To avoid an INSTI-based regimen (e.g., with suspected or documented INSTI resistance), and

To avoid a PI-based regimen (e.g., with significant DDIs with concomitant medications), and

When a single-tablet regimen containing an NNRTI and TAF is desired		Cannot take with PPI; space apart from H2 antagonist.

Needs to be taken with a meal.
Rating of Recommendations: A = Strong; B = Moderate; C = Weak


Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion

aCOBI should be avoided in pregnancy because lower concentrations of COBI and DRV have been observed during the second and third trimesters. For further information, refer to the Perinatal Guidelines.

b TAF and TDF are two forms of TFV approved by the U.S. Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Note: The following are available as coformulated drugs: ABC/3TC, DOR/TDF/3TC, DRV/c, DRV/c/TAF/FTC, DTG/ABC/3TC, RPV/TAF/FTC, TAF/FTC, TDF/3TC, and TDF/FTC.

Key: 3TC = lamivudine; ABC = abacavir; AE = adverse event; ARV = antiretroviral; CD4 = CD4 T lymphocyte; COBI = cobicistat; CV = cardiovascular; DDI = drug–drug interaction; DOR = doravirine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; FTC = emtricitabine; H2 = histamine type 2; HBV = hepatitis B virus; HLA = human leukocyte antigen; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PPI = proton pump inhibitor; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir

Supporting Evidence and Rationale Used for the Panel’s Recommendations

The Panel’s recommendations are primarily based on clinical trial data published in peer-reviewed journals and on data prepared by drug manufacturers for FDA review. In select cases, the Panel considers data from abstracts presented at major scientific meetings. The Panel considers published information from randomized prospective clinical trials with adequate sample size that demonstrate that an ARV regimen produces high rates of viral suppression, increases CD4 count, and has a favorable safety profile to be the strongest evidence on which to base recommendations.

Comparative clinical trials of initial treatments generally are not designed to show significant differences in HIV-related clinical endpoints (such as progression to AIDS-defining conditions) or survival. Thus, the assessment of regimen efficacy and safety is primarily based on surrogate marker endpoints (i.e., rates of HIV RNA suppression) and the incidence and severity of adverse events.

In some instances, the Panel recommends regimens that include ARV drugs approved by the FDA based on bioequivalence or relative bioavailability studies that demonstrate that the exposure of the drug(s) in the new formulation or combination is comparable to the exposure of a reference drug(s) that has demonstrated safety and efficacy in randomized clinical trials. When developing recommendations, the Panel may also consider data from randomized switch studies in which a drug in an ARV initial regimen that suppressed patients’ viral loads is replaced by a new drug from the same class. Switch trials do not evaluate the ability of a drug or regimen to induce viral suppression; they only examine the drug or regimen’s ability to maintain suppression. Therefore, results from switch trials may not be directly applicable to the selection of an initial regimen and should be considered in conjunction with other data, including data from bioavailability/bioequivalence studies and from trials conducted in people taking their first ARV treatment regimen. In this section of the guidelines, the definition of an evidence rating of II is expanded to include supporting data from bioavailability/bioequivalence studies or randomized switch studies.

When developing recommendations, the Panel also considers tolerability and toxicity profiles, pill burden and dosing frequency, drug interaction potential, cost and access, postmarketing safety data, observational cohort data published in peer-reviewed publications, the experience of clinicians who are actively engaged in patient care, and the views of community members.

The Panel reviewed the available data to arrive at two classifications for initial ARV treatment regimens: (1) Recommended Initial Regimens for Most People With HIV (Table 6a) and (2) Other Initial Antiretroviral Regimens for Certain Clinical Scenarios (Table 6b). Recommended Initial Regimens for Most People With HIV are those regimens with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. The Panel also recognizes that in certain clinical situations, other regimens may be preferred; these options are included in Table 6b. See Table 7 for examples of clinical scenarios in which certain drugs in these regimens may be particularly advantageous.

Many other ARV regimens are effective for initial therapy but have disadvantages when compared with the regimens listed in Tables 6a and 6b. These disadvantages include greater toxicity, higher pill burden, less supporting data from large comparative clinical trials, and limitations for use in certain populations. These regimens are no longer included in Tables 6a and 6b. For people with HIV who have a suppressed viral load and are not experiencing any adverse effects while on a regimen that is not listed, changing to a regimen listed in Table 6a or 6b is not necessary. Clinicians should refer to Optimizing Antiretroviral Therapy in the Setting of Viral Suppression for further guidance if switching to a new regimen is desired.

Several tables in these guidelines provide clinicians with guidance on selecting and prescribing an optimal regimen for a person with HIV. Table 7 provides information on considerations based on specific clinical scenarios and ARV drug characteristics. Table 9 lists the potential advantages and disadvantages of the different ARV drug components. Appendix B, Tables 3–11, lists characteristics of individual ARV agents for initial therapy (e.g., formulations, dosing recommendations, PK, common adverse effects). Appendix B, Table 12 provides ARV dosing recommendations for people who have renal or hepatic insufficiency.

Changes Since the Last Revision of the Guidelines

Since the last revision of these guidelines, the Panel has made several important changes to the recommendations for initial therapy in people with HIV. Among these changes, the following deserve emphasis:

Changes in the Panel’s Recommendations for Initial Regimens in Most People With HIV:
  • The single-tablet regimen (STR) DTG/abacavir (ABC)/3TC has moved from Recommended Initial Regimens for Most People With HIV (Table 6a) to Other Initial Antiretroviral Regimens for Certain Clinical Scenarios (Table 6b) due to the necessity of obtaining an HLA-B*5701 assay to avoid ABC-associated hypersensitivity, data suggesting increased risk for cardiovascular events associated with ABC, and the availability of several other options for initial therapy (see the Nucleoside Reverse Transcriptase Inhibitor Options as Part of Initial Therapy section for more information).
  • Because of the current low rates of transmitted INSTI resistance in the United States, even when there is suspicion that HIV was acquired from a partner with virologic failure while on an INSTI, an INSTI-based regimen can be started pending the results of the INSTI genotype test.
No Longer Recommended as Initial Antiretroviral Regimens:
  • Raltegravir (RAL)-, elvitegravir/cobicistat (EVG/c)-, boosted atazanavir (ATV)-, and efavirenz (EFV)-based regimens and rilpivirine (RPV)/TDF/FTC are no longer recommended as initial therapy due to the following disadvantages compared with other regimens:
    • RAL: Low genetic barrier to resistance and higher pill burden
    • EVG/c: Drug–drug interactions with COBI and low genetic barrier to resistance of EVG
    • Boosted ATV: Toxicities, including hyperbilirubinemia, and drug–drug interactions
    • EFV: Toxicities, including neuropsychiatric effects and suicidality; low barrier to resistance; and drug–drug interactions
    • RPV/TDF/FTC: Availability of doravirine (DOR)/TDF/3TC as an STR, more drug–drug interactions than DOR, food restrictions, and HIV RNA and CD4 restrictions. RPV/TAF/3TC remains an option for those who wish to use an STR containing RPV and TAF
  • The two-drug regimens darunavir/ritonavir (DRV/r) plus RAL and DRV/r plus 3TC are no longer recommended for initial therapy.
    • DRV/r plus RAL is not recommended due to the higher rate of virologic failure in people with HIV RNA >100,000 copies/mL, the low genetic barrier to resistance, and the high pill burden of RAL.1-3

    • DRV/r plus 3TC is not recommended because it requires a PK booster with accompanying drug interactions, and published clinical trial data are lacking.4 For further information, see Other Antiretroviral Regimens for Initial Therapy.

Selecting an Initial Antiretroviral Regimen

The goal of ART is to improve health and prolong life for people with HIV and to prevent the transmission of HIV to others by maximizing virologic suppression. This is achieved by initiating therapy with a potent, safe, tolerable, and easy-to-adhere-to ARV regimen as soon as possible after diagnosis. Table 6a provides a list of Panel-recommended ARV regimens for most people with HIV. Some factors listed below may influence the selection of a regimen. See Table 6b and Table 7 for additional regimen recommendations to use in specific clinical scenarios.

Initial Characteristics to Consider in All People with HIV

  • Pre-treatment HIV RNA level (viral load)
  • Pre-treatment CD4 count
  • History of prior exposure to CAB-LA or oral TDF/FTC or TAF/FTC as PrEP, or use of INSTI- based post-exposure prophylaxis (PEP)
  • HIV genotypic drug resistance test results
    • Genotypic drug resistance testing in people without prior ARV exposure should focus on testing for mutations in the reverse transcriptase and protease genes.
    • If transmitted INSTI resistance is a concern, providers should also test for resistance mutations to this class of drugs.
  • Individual preferences
  • Anticipated adherence to the regimen

Presence of Specific Conditions

  • Comorbid conditions: Cardiovascular disease; hyperlipidemia; renal disease; liver disease; osteopenia, osteoporosis, or other conditions associated with bone mineral density loss; psychiatric illness; neurologic disease; substance use disorder requiring narcotic replacement therapy
  • Coinfections: Hepatitis B virus (HBV), hepatitis C virus, tuberculosis
  • Pregnancy and potential for pregnancy: See below in General Considerations for Persons of Childbearing Potential Initiating Antiretroviral Therapy

Regimen-Specific Considerations

  • Regimen’s barrier to resistance
  • HLA-B*5701 status (only for those considering initiation of ABC). Those who are HLA-B*5701 positive should not receive ABC. See Table 7 for regimens to initiate.
  • Potential adverse effects and drug toxicities, including risk for the development of comorbid diseases
  • Known or potential drug interactions with other medications (see Drug–Drug Interactions)
  • Convenience (e.g., pill burden, dosing frequency, availability of a fixed-dose combination or of STR formulations, food requirements)
  • Cost and access (see Cost Considerations and Antiretroviral Therapy)

Considerations for People With Prior Use of Pre- or Post-Exposure Prophylaxis

  • For people who acquired HIV after taking oral PrEP with TAF/FTC or TDF/FTC, there is concern for transmitted resistance, especially related to FTC or 3TC with the M184V/I mutation. In a cohort of people in New York City with newly diagnosed HIV, 2% had the M184V/I mutation. People who had used prior oral PrEP were four to seven times more likely to harbor resistance than people who had never used oral PrEP.5 This reinforces the Panel’s recommendation not to initiate DTG/3TC without the results of genotypic resistance testing.
  • For people who acquired HIV after exposure to CAB-LA as PrEP, there is concern for INSTI resistance. CAB-LA may remain detectable after treatment discontinuation for up to 3 years in men and 4 years in women.6 This long PK tail may contribute to the selection of drug-resistant variants in the setting of incident infection. In the HPTN 083 trial of CAB-LA as PrEP in cisgender men and transgender women, 10 of 32 people who acquired HIV after exposure to CAB-LA were found to harbor major INSTI resistance mutations.7 This is the basis for the Panel’s recommendation to obtain INSTI genotypic drug resistance testing in people with prior CAB-LA exposure and not to initiate INSTIs before these results are available and show INSTI sensitivity. If therapy is initiated before INSTI sensitivity is confirmed, the Panel recommends initiating a boosted DRV regimen with TAF/FTC or TDF/FTC while awaiting INSTI genotype results; once INSTI sensitivity is confirmed by genotypic resistance testing, a switch to an INSTI-based regimen can occur (AIII).
  • For people with no history of using CAB-LA for PrEP and who acquire HIV despite INSTI- based PEP use, an INSTI genotype should be obtained prior to beginning an INSTI-based regimen. However, because selection of INSTI-resistant virus is likely to be uncommon in this setting, an INSTI-based regimen could be started prior to the return of genotype results (CIII). This recommendation is based largely on theoretical concerns that INSTI resistance could occur in the setting of INSTI-based PEP failure, but it is likely to be uncommon. In addition, transmitted INSTI resistance remains low in the United States. For these reasons, the Panel supports using INSTI-based regimens in this setting.

General Considerations for Persons of Childbearing Potential Initiating Antiretroviral Therapy

  • A pregnancy test should be performed before initiating ART.
  • Clinicians should discuss intentions regarding pregnancy with all persons of childbearing potential.
  • People with HIV should attain maximum viral suppression before attempting conception in order to protect their own health, prevent sexual HIV transmission to partners without HIV, and minimize the risk of perinatal HIV transmission to the infant.
  • For individuals who are trying to conceive, the Panel recommends initiating a regimen designated as a Preferred regimen during pregnancy, as detailed in the Perinatal Guidelines.

General Considerations for INSTI-, PI-, or NNRTI-Based Regimens

Except when HIV is acquired after exposure to CAB-LA as PrEP and results from INSTI genotypic resistance testing are not available, INSTIs (specifically BIC and DTG) are recommended for initial therapy in most people because of their demonstrated efficacy, high barrier to resistance, tolerability, low potential for drug–drug interactions, convenience, and better adverse effects profile compared with NNRTIs and boosted PIs (see Tables 7 and 9).

INSTI-Based Regimens

The Panel’s Recommended Initial Regimens for Most People With HIV, as listed in Table 6a, include one of two INSTIs: BIC coformulated with TAF/FTC (AI); or DTG plus TAF or TDF plus FTC or 3TC (AI); or coformulated DTG/3TC (AI) for people who have not had exposure to CAB-LA as PrEP. In those with prior exposure to CAB-LA as PrEP, these regimens should not be initiated unless a recent genotype test result showing no INSTI resistance mutations is available. If an INSTI-based regimen is initiated and viral suppression is not achieved in 8 to 12 weeks, genotypic resistance testing should be repeated, including for INSTIs.

For most people, these INSTI-containing regimens will be highly effective and have relatively infrequent treatment-limiting adverse effects and few drug interactions. In several head-to-head comparisons between boosted PI- and INSTI-containing regimens, the INSTI-based regimens were better tolerated and caused fewer treatment discontinuations.8-10

The Panel recommends a two-drug regimen of DTG/3TC for initial therapy if certain criteria are met. Data from two randomized trials showed that, in terms of virologic efficacy, DTG plus 3TC was non- inferior to a three-drug regimen of DTG plus TDF/FTC. No treatment-emergent resistance was seen in either the two-drug or the three-drug group.11 Based on these data, DTG/3TC is not currently recommended for rapid ARV initiation as initial therapy before the availability of HBV serology, HIV RNA level, and an HIV genotypic test demonstrating sensitivity to 3TC.

Among the INSTI-based regimens, BIC- and DTG-containing regimens have a higher barrier to resistance than the first-generation INSTI-based regimens containing EVG or RAL and do not require a PK booster. Transmitted resistance to BIC or DTG is rare. Treatment-emergent resistance has been reported in individuals who failed three-drug DTG-based therapy12-15 and BIC-based regimens.16-19 Because of this high barrier to resistance and tolerability, BIC- and DTG-containing regimens may be used in people who have not previously used CAB-LA for PrEP and plan to start ART before resistance testing results are available (e.g., with rapid initiation of ART after diagnosis).

BIC-based regimens have been shown to be non-inferior to DTG-based regimens in clinical trials.20-22

There are data suggesting greater weight gain after initiating therapy with certain INSTI-based regimens and TAF than with other ARV drugs. The reasons for differences in weight gain are unclear and should not be a reason to withhold an INSTI- or TAF-based regimen.23-30

EVG- and RAL-based regimens have the disadvantage of having lower barriers to resistance than DTG- or BIC-containing regimens and therefore are no longer recommended as initial therapy.

Additionally, the pill burden with RAL is higher than for other INSTI-based regimens whereas EVG- based regimens have a greater potential for drug interactions because EVG is combined with COBI, a strong cytochrome P3A4 inhibitor (see Table 7).

PI-Based Regimens

In the setting of HIV acquisition following CAB-LA exposure, an RTV- or COBI-boosted DRV regimen containing TAF or TDF plus FTC or 3TC is recommended as initial therapy if a genotypic drug resistance test indicating INSTI sensitivity is not available at the time of ART initiation (AIII), if resistance to INSTI is confirmed (BI), or in certain clinical situations, such as when INSTIs must be avoided (BI). DRV/c/TAF/FTC is available as an STR. Large observational cohorts found an association between some PIs, including DRV/r, and an increased risk of cardiovascular events; however, further study is needed.31-36 COBI-boosted regimens should not be initiated during pregnancy because of inadequate drug levels. Boosted ATV is no longer recommended as initial therapy due to frequent adverse events (e.g., hyperbilirubinemia) and high rates of drug–drug interactions, including with tenofovir and acid-suppressive therapy.

Boosted ATV is no longer recommended as initial therapy due to frequent adverse events, such as hyperbilirubinemia and higher rates of drug–drug interactions (including with tenofovir and acid- suppressive therapy) compared to boosted DRV.

NNRTI-Based Regimens

NNRTI-based regimens are not recommended for initial therapy in most people with HIV, but selected regimens may be useful in some circumstances. The NNRTI-based regimens that are currently recommended by the Panel to be used in certain clinical scenarios include DOR/TDF/3TC (BI), DOR plus TAF/FTC (BIII), and RPV/TAF/FTC (BII). The emergence of drug resistance at the time of virologic failure has been reported with all NNRTIs, which generally have a lower barrier to resistance than INSTIs or boosted PIs.

DOR is available both as a single-drug tablet to be used with two NRTIs and as part of an STR with TDF/3TC. In randomized trials, DOR was non-inferior to both EFV and DRV/r when either of these drugs was taken in combination with two NRTIs,37,38 but DOR has not yet been compared against INSTIs. DOR has fewer central nervous system (CNS) side effects than EFV and more favorable lipid effects than both DRV/r and EFV. DOR also has fewer potential drug interactions than EFV or RPV, and unlike RPV, the virologic efficacy of DOR is not compromised in people with high HIV RNA levels and low CD4 counts.

RPV has fewer adverse effects than EFV, and RPV/TAF/FTC is available as one of the smallest tablet sizes among STRs. However, RPV has lower virologic efficacy in people with baseline HIV RNA levels >100,000 copies/mL and CD4 counts <200 cells/mm3 and is subject to numerous drug–drug interactions.39 EFV is no longer recommended for initial therapy due to a relatively high rate of CNS-related side effects, reported suicidality, high rates of drug discontinuation, and numerous drug–drug interactions.

Regimens When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used or Are Not Optimal

In people in whom ABC, TDF, or TAF cannot be used or are not optimal, only DTG/3TC is recommended by the Panel (AI). Several other NRTI-sparing/limiting two-drug regimens have been evaluated in clinical trials but are not currently recommended for initial therapy due to insufficient data. For more information on these regimens, see Other Antiretroviral Regimens for Initial Therapy. Two-drug ARV options should not be used in pregnancy due to insufficient data, or in those with known pre-existing resistance to any of the ARVs in the combination. Tenofovir-sparing regimens should not be used in individuals with HBV coinfection unless a drug with HBV activity (i.e., entecavir) is also used.

References

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  16. Lozano AB, Chueca N, de Salazar A, et al. Failure to bictegravir and development of resistance mutations in an antiretroviral-experienced patient. Antiviral Res. 2020;179:104717. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31982483.
  17. DeKoven S, Naccarato M, Brumme CJ, Tan DHS. Treatment-emergent reverse transcriptase resistance during antiretroviral therapy with bictegravir, tenofovir alafenamide, and emtricitabine: a case series. HIV Med. 2023;24(11):1137-1143. Available at: https://pubmed.ncbi.nlm.nih.gov/37317505.
  18. Nasreddine R, Florence E, Yombi JC, et al. Efficacy, durability, and tolerability of bictegravir/emtricitabine/tenofovir alafenamide for the treatment of HIV in a real-world setting in Belgium. HIV Med. 2023;24(8):914-924. Available at: https://pubmed.ncbi.nlm.nih.gov/37038245.
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  20. Stellbrink HJ, Arribas JR, Stephens JL, et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e364-e372. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31068272.
  21. Wohl DA, Yazdanpanah Y, Baumgarten A, et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e355-e363. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31068270.
  22. Sax PE, Arribas JR, Orkin C, et al. Bictegravir/emtricitabine/tenofovir alafenamide as initial treatment for HIV-1: five-year follow-up from two randomized trials. eClinicalMedicine. 2023;59:101991. Available at: https://pubmed.ncbi.nlm.nih.gov/37200995.
  23. Bhagwat P, Ofotokun I, McComsey GA, et al. Changes in waist circumference in HIV- infected individuals initiating a raltegravir or protease inhibitor regimen: effects of sex and race. Open Forum Infect Dis. 2018;5(11):ofy201. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30465010.

  24. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis.2020;71(6):1379-1389. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31606734.

  25. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N Engl J Med. 2019;381(9):803-815. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31339677.

  26. Bourgi K, Rebeiro PF, Turner M, et al. Greater weight gain in treatment naive persons starting dolutegravir-based antiretroviral therapy. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31100116.

  27. Venter WDF, Sokhela S, Simmons B, et al. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV. 2020;7(10):e666-e676. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33010240.

  28. Calmy A, Tovar Sanchez T, Kouanfack C, et al. Dolutegravir-based and low-dose efavirenz- based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon. Lancet HIV. 2020;7(10):e677-e687. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33010241.

  29. Aldredge A, Lahiri CD, Summers NA, et al. 980. Effects of integrase strand-transfer inhibitor use on lipids, glycemic control, and insulin resistance in the Women’s Interagency HIV Study (WIHS). Open Forum Infect Dis. 2019;6. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808914.

  30. Chandiwana NC, Siedner MJ, Marconi VC, et al. Weight gain after HIV therapy initiation: pathophysiology and implications. J Clin Endocrinol Metab. 2024;109(2):e478-e487. Available at: https://pubmed.ncbi.nlm.nih.gov/37437159.

  31. Lang S, Mary-Krause M, Cotte L, et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS Cohort CO4. Arch Intern Med. 2010;170(14):1228-1238. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20660842.

  32. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318-330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20039804.

  33. Monforte AD, Reiss P, Ryom L, et al. Atazanavir is not associated with an increased risk of cardio or cerebrovascular disease events. AIDS. 2013;27(3):407-415. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23291539.

  34. Ryom L, Mocroft A, Kirk O, et al. Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study. J Infect Dis. 2013;207(9):1359-1369. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23382571.

  35. LaFleur J, Bress AP, Rosenblatt L, et al. Cardiovascular outcomes among HIV-infected veterans receiving atazanavir. AIDS. 2017;31(15):2095-2106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28692532.

  36. Ryom L, Lundgren JD, El-Sadr W, et al. Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV. 2018;5(6):e291-e300. Available at: https://pubmed.ncbi.nlm.nih.gov/29731407.

  37. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE- AHEAD trial. Clin Infect Dis. 2019;68(4):535-544. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30184165.

  38. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-e220. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29592840.

  39. Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27(6):939- 950. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23211772.

Long-acting cabotegravir (CAB-LA) for PrEP was TGA approved in 2022 but as of June 2024 the process for listing this medication on the PBS has ceased. However, some patients may have accessed CAB-LA as PrEP while overseas. Clinicians should ensure that integrase genotypic resistance testing is requested to exclude integrase strand transfer inhibitor (INSTI) resistance. If initiating therapy before the result is available, please refer to the latest DHHS recommendations.

Australian clinicians should note that neither Atazanavir co–formulated with Ritonavir nor Doravirine are listed on the PBS.

Key Considerations and Recommendations
  • An initial antiretroviral (ARV) regimen for a person with HIV generally consists of two nucleoside reverse transcriptase inhibitors administered in combination with a third active ARV drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer (also known as a booster; the two drugs used for this purpose are cobicistat and ritonavir).
  • Data also support the use of the two-drug regimen, dolutegravir (DTG) plus lamivudine (3TC), for initial treatment.
  • Before initiating antiretroviral therapy (ART) in a person of childbearing potential, clinicians should discuss the person’s intentions regarding pregnancy and a pregnancy test should be performed (AIII). Clinicians should refer to the Perinatal Guidelines for recommendations on initial ARV treatment around the time of conception and during pregnancy.
  • The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) classifies the regimens below (in alphabetical order) as Recommended Initial Regimens for Most People with HIV.

    For people with HIV who do not have a history of using long-acting cabotegravir (CAB-LA) as pre-exposure prophylaxis (PrEP), the following regimens are recommended:

    • Bictegravir/tenofovir alafenamide (TAF)/emtricitabine (FTC) (AI)a
    • DTG/abacavir/3TC—only for individuals who are HLA-B*5701 negative and without chronic hepatitis B virus (HBV) coinfection (AI)
    • DTG plus (TAF or tenofovir disoproxil fumarate [TDF])b plus (FTC or 3TC) (AI)
    • DTG/3TC (AI)—except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or when ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available

For people with HIV and a history of using CAB-LA as PrEP, INSTI genotypic resistance testing should be done before the start of ART. If treatment is begun prior to results of genotypic testing, the following regimen is recommended:

    • Boosted darunavir plus (TAF or TDF)b plus (FTC or 3TC)—pending the results of the genotype test (AIII).
  • To address individual patient characteristics and needs, the Panel also provides a list of Recommended Initial Regimens in Certain Clinical Situations (see Table 6 below).
  • Given the many excellent options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug–drug interaction potential, resistance-test results, comorbid conditions, access, and cost. For guidance on choosing an ARV regimen based on selected clinical case scenarios, see Table 7. Also see Table 9 for the advantages and disadvantages of different components in an ARV regimen.
  • Patients without prior ART use who wish to begin long-acting intramuscular CAB and rilpivirine (RPV) should first achieve viral suppression on another regimen before switching to CAB and RPV (see Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression).
Rating of Recommendations: A = Strong; B = Moderate; C = Weak

Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion

a Bictegravir should not be initiated in pregnant people due to insufficient data in pregnancy.

b TAF and TDF are two forms of tenofovir that are approved by the U.S. Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Introduction

More than 30 antiretroviral (ARV) drugs in eight mechanistic classes are U.S. Food and Drug Administration (FDA)-approved for treatment of HIV infection. These eight classes are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), a fusion inhibitor, a CCR5 antagonist, a CD4 T lymphocyte (CD4) post-attachment inhibitor, and a gp120 attachment inhibitor. In addition, two drugs, ritonavir (RTV) and cobicistat (COBI) are used as pharmacokinetic (PK) enhancers (or boosters) to improve the PK profiles of PIs and the INSTI elvitegravir (EVG).

The initial ARV treatment regimen for a person with HIV generally consists of two NRTIs, usually abacavir/lamivudine (ABC/3TC) or either tenofovir alafenamide/emtricitabine (TAF/FTC) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), plus a drug from one of three drug classes: an INSTI, an NNRTI, or a boosted PI. As shown in clinical trials and by retrospective evaluation of cohorts of patients in clinical care, this strategy for initial treatment has resulted in suppression of HIV replication and CD4 count increases in most people with HIV.1-3 Additional data now support the use of the two-drug regimen dolutegravir/lamivudine (DTG/3TC) for initial treatment of some people with HIV.4

Supporting Evidence and Rationale Used for the Panel’s Recommendations

The Panel on Antiretroviral Guidelines for Adults and Adolescents’ (the Panel) recommendations are primarily based on clinical trial data published in peer-reviewed journals and on data prepared by drug manufacturers for FDA review. In select cases, the Panel considers data from abstracts presented at major scientific meetings. The Panel considers published information from randomized, prospective clinical trials with adequate sample size that demonstrate that an ARV regimen produces high rates of viral suppression, increases CD4 count, and has a favorable safety profile to be the strongest evidence on which to base recommendations. Comparative clinical trials of initial treatments generally show no significant differences in HIV-related clinical endpoints (such as progression to AIDS-defining conditions) or survival. Thus, assessment of regimen efficacy and safety are primarily based on surrogate marker endpoints (i.e., rates of HIV RNA suppression) and the incidence and severity of adverse events.

In some instances, the Panel recommends regimens that include ARV drugs approved by the FDA based on bioequivalence or relative bioavailability studies that demonstrate that the exposure of the drug(s) in the new formulation or combination is comparable to the exposure of a reference drug(s) that has demonstrated safety and efficacy in randomized clinical trials. When developing recommendations, the Panel may also consider data from randomized switch studies in which a drug in an ARV initial regimen that suppressed patients’ viral loads is replaced by a new drug from the same class. Switch trials do not evaluate the ability of a drug or regimen to induce viral suppression; they only examine the drug or regimen’s ability to maintain suppression. Therefore, results from switch trials may not be directly applicable to the selection of an initial regimen and should be considered in conjunction with other data, including data from bioavailability/bioequivalence studies and from trials conducted in people taking their first ARV treatment regimen. In this section of the guidelines, the definition of an evidence rating of II is expanded to include supporting data from bioavailability/bioequivalence studies or randomized switch studies.

When developing recommendations, the Panel also considers tolerability and toxicity profiles, pill burden and dosing frequency, drug interaction potential, cost and access, post-marketing safety data, observational cohort data published in peer-reviewed publications, the experience of clinicians who are actively engaged in patient care, and the views of community members.

The Panel reviewed the available data to arrive at two classifications for initial ARV treatment regimens: (1) Recommended Initial Regimens for Most People with HIV and (2) Recommended Initial Regimens in Certain Clinical Situations (see Table 6 below). Recommended Initial Regimens for Most People with HIV are those regimens with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. The Panel also recognizes that, in certain clinical situations, other regimens may be preferred; these options are included in Table 6 in the category of Recommended Initial Regimens in Certain Clinical Situations. See Table 7 for examples of clinical scenarios in which certain drugs in these regimens may be particularly advantageous.

There are many other ARV regimens that are effective for initial therapy but have disadvantages when compared with the regimens listed in Table 6. These disadvantages include greater toxicity, higher pill burden, less supporting data from large comparative clinical trials, or limitations for use in certain patient populations. These regimens are no longer included in Table 6. A person with HIV who has a suppressed viral load and is not experiencing any adverse effects while on a regimen that is not listed in Table 6 need not necessarily change to one that is listed in the table. Clinicians should refer to Optimizing Antiretroviral Therapy in the Setting of Viral Suppression for further guidance if switching to a new regimen is desired.

The ARV drugs and regimens listed in Table 10 are not recommended as initial therapy. In most instances, a clinician is urged to consider switching a patient who is on one of the regimens listed in Table 10 to a recommended regimen.

In addition to these tables, several tables in these guidelines provide clinicians with guidance on selecting and prescribing an optimal regimen for an individual patient. Table 9 lists the potential advantages and disadvantages of the different ARV drug components. Appendix B, Tables 3–9 list characteristics of individual ARV agents (e.g., formulations, dosing recommendations, PKs, common adverse effects). Appendix B, Table 11 provides ARV dosing recommendations for patients who have renal or hepatic insufficiency.

Changes Since the Last Revision of the Guidelines

Since the last revision of these guidelines, the Panel has made several important changes to the recommendations for initial therapy in people with HIV. Among these changes, the following deserve emphasis:

  • Long-acting injectable cabotegravir (CAB-LA) was approved by the FDA for HIV pre-exposure prophylaxis (PrEP). Because of the long half-life of CAB-LA, drug levels may be present in some individuals for up to 4 years. This persistent drug exposure at levels suboptimal to prevent infection may select for INSTI-resistant virus. Therefore, in this setting, the Panel recommends that results of an INSTI genotypic resistance test be available before initiating an INSTI-based regimen, because the presence of cabotegravir (CAB)-resistant mutations may have cross-resistance to other INSTIs, including bictegravir (BIC) and dolutegravir (DTG). When antiretroviral therapy (ART) is initiated before an INSTI genotype result is available, a non-INSTI regimen containing boosted darunavir (DRV) plus (tenofovir alafenamide [TAF] or tenofovir disoproxil fumarate [TDF]) plus (emtricitabine [FTC] or lamivudine [3TC]) should be initiated, pending genotype results. If an INSTI-based regimen is initiated and viral suppression is not achieved, genotypic resistance testing (including for INSTIs) should be repeated.

Table 6. Recommended Antiretroviral Regimens for Initial Therapy

Selection of a regimen should be individualized based on virologic efficacy, potential adverse effects, childbearing potential and use of effective contraception, pill burden, dosing frequency, drug–drug interaction potential, comorbid conditions, cost, access, and resistance-test results. A pregnancy test should be performed in persons of childbearing potential, and choice of ART for pregnant individuals should be guided by recommendations from the Perinatal Guidelines. Drug classes and regimens within each class are arranged first by evidence rating and, when ratings are equal, in alphabetical order. See Table 7 for ARV recommendations based on specific clinical scenarios.

Recommended Initial Regimens for Most People with HIV
Recommended regimens are those with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. Choice of ART during pregnancy should be guided by recommendations from the Perinatal Guidelines.
For people who do not have a history of CAB-LA use as PrEP, the following regimens are recommended:


INSTI plus Two NRTIs

  • BIC/TAF/FTC (AI)a

  • DTG/ABC/3TC (AI)—if HLA-B*5701 negative

  • DTG plus (TAF or TDF)c plus (FTC or 3TC) (AI)



INSTI plus One NRTI

  • DTG/3TC (AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available



For people with HIV and a history of CAB-LA use as PrEP, INSTI genotypic resistance testing should be performed before the start of ART. If treatment is begun prior to results of genotypic testing, the following regimen is recommended:


  • DRV/cb or DRV/r with (TAF or TDF)c plus (FTC or 3TC)—pending the results of the genotype test (AIII)
These regimens are effective and tolerable but have some disadvantages when compared with the regimens listed above or have fewer supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred (see Table 7 for examples).
INSTI plus Two NRTIs

  • EVG/c/(TAF or TDF)c FTC (BI)b

  • RAL plus (TAF or TDF)c plus (FTC or 3TC) (BI for TDF/[FTC or 3TC], BII for TAF/FTC)



Boosted PI plus Two NRTIs

  • In general, boosted DRV is preferred over boosted ATV

  • (DRV/cb or DRV/r) plus (TAF or TDF)c plus (FTC or 3TC) (AI) b

  • (ATV/cb or ATV/r) plus (TAF or TDF)c plus (FTC or 3TC) (BI) b

  • (DRV/cb or DRV/r) plus (TAF or TDF)c ABC/3TC— if HLA-B*5701 negative (BII) b



NNRTI plus Two NRTIs

  • DOR/TDFc/3TC (BI) or DOR plus TAFc/FTC (BIII)

  • EFV plus (TAF or TDF)c plus (FTC or 3TC)

    • EFV 600 mg plus TDF plus (FTC or 3TC) (BI)

    • EFV 400 mg/TDF/3TC (BI)

    • EFV 600 mg plus TAF/FTC (BII)



  • RPV/(TAF or TDF)c/FTC (BII for TAF and BI for TDF)—if HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3



Regimens to Consider When ABC, TAF, and TDF Cannot Be Used or Are Not Optimal

  • DTG/3TC (AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available

  • DRV/r plus RAL twice a day (CI)—if HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3

  • DRV/r once daily plus 3TC (CI)
Rating of Recommendations: A = Strong; B = Moderate; C = Weak
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion

a BIC should not be initiated in pregnant people due to insufficient data.

b COBI should be avoided in pregnancy because lower concentrations of COBI and its boosted drugs—EVG, DRV, and ATV—have been observed during the second and third trimesters. For individuals with viral suppression who become pregnant while on a COBI-containing regimen and wish to remain on that regimen after counseling regarding lower drug concentration, frequent viral load monitoring is recommended. For further information, refer to the Perinatal Guidelines.

c TAF and TDF are two forms of TFV approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Note: The following are available as coformulated drugs: ABC/3TC, ATV/c, BIC/TAF/FTC, DOR/TDF/3TC, DRV/c, DRV/c/TAF/FTC, DTG/3TC, DTG/ABC/3TC, EFV (400 mg or 600 mg)/TDF/3TC, EFV/TDF/FTC, EVG/c/TAF/FTC, EVG/c/TDF/FTC, RPV/TAF/FTC, RPV/TDF/FTC, TAF/FTC, TDF/3TC, and TDF/FTC.

Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; CAB-LA = cabotegravir long-acting; CD4 = CD4 T lymphocyte; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FDA = U.S. Food and Drug Administration; FTC = emtricitabine; HBV = hepatitis B virus; HLA = human leukocyte antigen; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PrEP = pre-exposure prophylaxis; RAL = raltegravir; RPV = rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir

Selecting an Initial Antiretroviral Regimen

The goal of ART is to provide a potent, safe, tolerable, and easy-to-adhere-to regimen in order to achieve sustained virologic control. Initial therapy should be with two NRTIs combined with an INSTI, the combination of DTG/3TC or, in some individuals, a combination including two NRTIs plus an NNRTI or an RTV- or COBI-boosted PI. When selecting a regimen for a person with HIV, a number of patient- and regimen-specific characteristics should be considered. Some of the factors can be grouped into the categories listed below, and these factors may influence the selection of a regimen. See Table 7 for additional regimen recommendations to use in specific clinical scenarios. Individuals without prior ART treatment who wish to use long-acting injectable CAB and rilpivirine (RPV) should first achieve viral suppression on another regimen before shifting to oral, and then injectable, CAB and RPV (see Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression).

Initial Characteristics to Consider in All People with HIV

  • Pre-treatment HIV RNA level (viral load)
  • Pre-treatment CD4 count
  • History of prior exposure to CAB-LA as PrEP
  • HIV genotypic drug resistance test results. Based on current rates of transmitted drug resistance to different ARV drugs, standard genotypic drug resistance testing in ARV-naive persons should focus on testing for mutations in the reverse transcriptase and protease genes. If transmitted INSTI resistance is a concern, providers should consider also testing for resistance mutations to this class of drugs. People who acquired HIV after a history of taking CAB-LA as PrEP should have a blood specimen collected for INSTI genotypic resistance testing prior to ART initiation, but they may initiate non–INSTI-based ART prior to receipt of results.
  • HLA-B*5701 status. Those who are HLA-B*5701 positive should not receive ABC. Regimens that do not include ABC can be initiated if HLA-B*5701 test results are not yet available; see Table 7 for regimens to initiate.
  • Individual preferences
  • Anticipated adherence to the regimen
  • Whether ART initiation occurs prior to availability of baseline laboratory results
  • It should be noted that results of pre-treatment HIV RNA, CD4 count, and resistance testing do not need to be available before starting ART, unless the individual is planning to begin an INSTI-containing regimen and has had prior exposure to CAB-LA as PrEP. See Table 7 for regimens to initiate if these results are not available.

Presence of Specific Conditions

  • Comorbid conditions: Cardiovascular disease; hyperlipidemia; renal disease; liver disease; osteopenia, osteoporosis, or other conditions associated with bone mineral density loss; psychiatric illness; neurologic disease; substance use disorder requiring narcotic replacement therapy
  • Coinfections: Hepatitis B virus (HBV), hepatitis C virus, tuberculosis (TB)
  • Pregnancy and potential for pregnancy: See below, General Considerations for Persons of Childbearing Potential Initiating Antiretroviral Therapy

Regimen-Specific Considerations

  • Regimen’s barrier to resistance
  • Potential adverse effects and drug toxicities, including risk for development of comorbid diseases
  • Known or potential drug interactions with other medications (see Drug–Drug Interactions)
  • Convenience (e.g., pill burden, dosing frequency, availability of a fixed-dose combination or single-tablet regimen [STR] formulations, food requirements)
  • Cost and access (see Cost Considerations and Antiretroviral Therapy)

General Considerations for Persons of Childbearing Potential Initiating Antiretroviral Therapy

  • A pregnancy test should be performed before initiating ART.
  • Clinicians should discuss intentions regarding pregnancy with all persons of childbearing potential.
  • People with HIV should attain maximum viral suppression before attempting conception in order to protect their own health, prevent sexual HIV transmission to partners without HIV, and minimize the risk of perinatal HIV transmission to the infant.
  • A DTG-based regimen is one of the recommended options for persons of childbearing potential initiating ART. Before initiating a DTG-based regimen, clinicians should discuss the risks and benefits of using DTG with persons of childbearing potential to allow them to make an informed decision. Please refer to the Women with HIV section and INSTI-Based Regimens below for additional details.
  • For individuals who are trying to conceive, the Panel recommends initiating a regimen designated as a Preferred regimen during pregnancy as detailed in the Perinatal Guidelines.

General Considerations for INSTI-, PI-, or NNRTI-Based Regimens

The choice between an INSTI, PI, or NNRTI in an initial ARV regimen should be guided by the ARV drug’s efficacy, barrier to resistance, and adverse effects profile; convenience; the patient’s comorbidities and concomitant medications; the potential for drug–drug interactions (see Tables 7 and 9); and whether the individual has been exposed to CAB-LA as PrEP prior to HIV acquisition.

Due to concerns about INSTI resistance in the setting of past use of CAB-LA as PrEP, the Panel recommends initiating a boosted PI regimen of darunavir/ritonavir (DRV/r) or darunavir/cobicistat (DRV/c) plus (TAF or TDF) plus (FTC or 3TC) while awaiting availability of INSTI genotype results. In HPTN 083, a study of CAB-LA as PrEP in cisgender men and transgender women, CAB-resistant mutations were reported in one of four cases of persons who received CAB-LA but had undetected HIV infection at baseline and in four of nine cases of incident HIV infection. In this study, there were no cases of infection during the tail phase of CAB decay following the last dose.5 One additional HIV acquisition with INSTI-resistant mutations occurred during the oral CAB lead-in phase.6 In HPTN 084, a study of CAB-LA as PrEP in cisgender women, four HIV infections occurred in the CAB-LA arm (one baseline, three incident) and no CAB-resistant mutations were detected. All individuals had low or unquantifiable CAB levels. Two of the three persons with incident infection never received injectable CAB.7 HPTN 077, a PK study of CAB-LA, suggested that suboptimal CAB levels could persist for as long as 3 years in men and 4 years in women, suggesting that HIV acquisition following even distant CAB-LA exposure may confer risk of INSTI resistance.8

INSTI-Based Regimens

The Panel’s Recommended Initial Regimens for Most People with HIV as listed in Table 6 include one of two INSTIs (BIC or DTG) plus two NRTIs or DTG/3TC for persons who have not had exposure to CAB-LA as PrEP. In those with prior exposure to CAB-LA as PrEP, these regimens should not be initiated unless a genotype test result showing no INSTI-resistance mutations is available. If an INSTI-based regimen is initiated and viral suppression is not achieved in 8 to 12 weeks, genotypic resistance testing should be repeated, including for INSTIs.

For most patients, these INSTI-containing regimens will be highly effective and have relatively infrequent treatment-limiting adverse effects and few drug interactions. In several head-to-head comparisons between boosted PI- and INSTI-containing regimens, the INSTI-based regimens were better tolerated and caused fewer treatment discontinuations.9-11 The Panel recommends a two-drug regimen of DTG/3TC for initial therapy if certain criteria are met. Data from two randomized trials showed that, in terms of virologic efficacy, DTG plus 3TC was noninferior to a three-drug regimen of DTG plus TDF/FTC. No treatment-emergent resistance was seen in either the two-drug or the three-drug group. The study inclusion criteria limited enrollment to participants with HIV RNA levels <500,000 copies/mL; no known major NRTI, PI, or NNRTI resistance; and without active HBV.4,12

Among the INSTI-based regimens, BIC- and DTG-containing regimens have a higher barrier to resistance and lower pill burden than the first-generation INSTI-based regimens that contain EVG or raltegravir (RAL). Treatment-emergent resistance has been reported very rarely in individuals receiving three-drug DTG-based therapy13-15 and rarely has been reported in those receiving BIC-based regimens.16 In addition, transmitted resistance to BIC and DTG is rare. Because of this high barrier to resistance and tolerability, BIC- and DTG-containing regimens may be considered for patients who plan to start ART before resistance-test results are available (e.g., with rapid initiation of ART after diagnosis). BIC-based regimens have been shown to be noninferior to DTG-based regimens in clinical trials.17,18

Preliminary data from a birth outcomes surveillance study in Botswana suggested an increased risk of neural tube defects (NTDs) (0.9%) in infants born to women who were receiving DTG at the time of conception.19 Updated data from the same study showed that the prevalence of NTDs in infants born to women on DTG at the time of conception is not significantly different from those on non-DTG regimens at the time of conception.20 For persons of childbearing potential who are trying to conceive, DTG-based regimens are among the recommended options for most individuals initiating ART, but clinicians should discuss the risks and benefits of using DTG in persons of childbearing potential to allow them to make an informed decision. BIC/TAF/FTC should not be used in pregnant people due to insufficient data in pregnancy. Because of inadequate drug levels in the second and third trimesters of pregnancy, COBI-boosted EVG should be avoided in a pregnant person. People with suppressed virus on a COBI-boosted regimen who wish to continue the regimen should be followed with frequent viral load monitoring. TAF is now recommended by the Perinatal Guidelines as an alternate drug in pregnancy due to insufficient data on teratogenicity in humans but reassuring data from the Antiretroviral Pregnancy Registry. Clinicians should refer to the Perinatal Guidelines before prescribing ART to a pregnant person or a person of childbearing potential.

There are now data suggesting greater weight gain with certain INSTI-based regimens and TAF than with other ARV drugs. The clinical significance of these findings is still unknown.21-27

EVG- and RAL-based regimens have the disadvantage of having lower barriers to resistance than DTG- or BIC-containing regimens and, therefore, are not recommended regimens for most people with HIV. Also of importance is that EVG-based regimens have a greater potential for drug interactions, because EVG is combined with COBI (EVG/c), a strong cytochrome P 3A4 inhibitor (see Table 7).

PI-Based Regimens

PK-enhanced PI-based regimens also are recommended in certain clinical situations. Similar to EVG/c, they have the disadvantage of greater drug interaction potential than other ARV drugs. For those individuals in whom ART needs to begin urgently before resistance-test results are available, boosted DRV may be an appropriate choice because the rate of transmitted PI resistance is low, and boosted DRV has a high barrier to resistance and a low rate of treatment-emergent resistance. DRV/c/TAF/FTC is available as an STR. Boosted atazanavir (ATV), like boosted DRV, has relatively few metabolic adverse effects in comparison to older boosted-PI regimens; however, atazanavir/ritonavir (ATV/r) had a higher rate of adverse effect-associated drug discontinuation than DRV/r or RAL in a randomized clinical trial.9 In a substudy of this trial, and in a separate cohort study, ATV/r use was associated with slower progression of atherosclerosis, as measured by carotid artery intima medial thickness.28,29 Large observational cohorts found an association between some PIs (DRV/r, fosamprenavir, indinavir, and RTV-boosted lopinavir) and an increased risk of cardiovascular events; however, this association was not seen with ATV.30-35 Further study is needed. DRV/c and COBI-boosted ATV should be avoided during pregnancy because of inadequate drug levels.

NNRTI-Based Regimens

NNRTI-based regimens (which include doravirine [DOR], efavirenz [EFV], or RPV plus 2-NRTIs) may be options for some patients, although these drugs, especially EFV and RPV, have low barriers to resistance. The emergence of resistance at the time of virologic failure also has been reported with DOR. EFV has a long track record of widespread use, is considered safe in persons of childbearing potential, and has minimal PK interaction with rifamycins, making it an attractive option for patients who require TB treatment. EFV-based regimens (using either 400-mg or 600-mg dosing) have excellent virologic efficacy,36 including in patients with high HIV RNA (except when EFV is used with ABC/3TC). However, the relatively high rate of central nervous system (CNS)-related side effects reduces the tolerability of EFV-based regimens. As an STR, EFV 600 mg is available with TDF/FTC or TDF/3TC; EFV 400 mg is available with TDF/3TC. RPV has fewer adverse effects than EFV, is available as one of the smallest tablet sizes among STRs that also include TAF/FTC or TDF/FTC, and has a favorable lipid profile. However, RPV has lower virologic efficacy in patients with baseline HIV RNA levels >100,000 copies/mL and CD4 counts <200 cells/mm3. DOR is available both as a single-drug tablet to be used with two NRTIs and as part of an STR with TDF/3TC. In randomized trials, DOR was noninferior to both EFV and DRV/r when either of these drugs were taken in combination with two NRTIs.37,38 DOR has CNS tolerability advantages over EFV and more favorable lipid effects than DRV/r and EFV. DOR also has fewer potential drug interactions than EFV or RPV, and unlike RPV, the virologic efficacy of DOR is not compromised in patients with high HIV RNA levels and low CD4 counts. In a cross-trial analysis, DOR was not associated with weight gain compared with EFV 600 mg or boosted DRV.39

Regimens When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used or Are Not Optimal

In those patients in whom ABC, TDF, or TAF cannot be used or are not optimal, there are several two-drug options that do not contain these agents. Two-drug ARV options should not be used in individuals with HBV coinfection (unless separate HBV treatment is also used) or in those with known pre-existing resistance to any of the ARVs in the combination. Among the two-drug regimens, DTG/3TC is preferred because there are substantial data for this combination in initial therapy, with the caveat that people with HIV RNA >500,000 copies/mL were excluded from the largest trial.4,12 Another two-drug treatment option that can be considered is the combination of DRV/r (once daily) plus RAL (twice daily), but this combination should only be used in those with baseline CD4 counts >200 cells/mm3 and HIV RNA levels <100,000 copies/mL.40 A small randomized trial indicated that once-daily DRV/r plus 3TC had similar efficacy to once-daily DRV/r plus TDF/3TC, although this study has yet to be published.41

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The ARV Guidelines with Australian commentary is administered by ASHM

The Australian Government Department of Health

While the Australian Department of Health provides financial support for the ARV Guidelines, the material contained in this resource should not be taken to represent the views of the Australian Department of Health.

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