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Key Principles and Recommended Regimens for First-line Antiretroviral Therapy

Joseph J. Eron, Jr., MD
Program Director
Daniel R. Kuritzkes, MD
Program Director
Paul E. Sax, MD
Released: June 11, 2020

Antiretroviral Treatment Guidelines for First-line Therapy in Adult Patients

In the United States, HIV treatment guidelines are periodically issued by both the IAS-USA[2] and the DHHS.[1] The DHHS reissues recommendations in response to new data that are compelling; the IAS-USA issues new guidelines biennially at each International AIDS Conference. The current versions of these guidelines are similar in that INSTI-based regimens are the recommended options for first-line regimens. In addition, the DHHS panel gives the provider a choice between tenofovir disoproxil fumarate (DF) or tenofovir alafenamide (AF) for those regimens including tenofovir, and the 2-drug regimen dolutegravir/lamivudine with exceptions as described below.[1] However, the IAS-USA panel excludes tenofovir DF from the generally recommended initial regimens, albeit with a note stating that tenofovir DF is a generally well tolerated and effective option when tenofovir AF is unavailable, but tenofovir DF is not recommended for patients with or at high risk for osteopenia/osteoporosis or renal impairment. In addition, the IAS-USA panel includes only 2 of the 4 currently available INSTIs in the generally recommended regimen list, whereas 3 of the 4 INSTIs are included among regimens recommended for most patients with HIV in the DHHS guidelines. The IAS-USA guidelines have not yet been updated regarding the use of dolutegravir/lamivudine. The regimens most recently recommended as initial ART for most people with HIV by the DHHS are as follows[1]:

  • Abacavir/dolutegravir/lamivudine (only if HLA-B*5701 negative)
  • Dolutegravir plus either emtricitabine/tenofovir DF or emtricitabine/tenofovir AF
  • Raltegravir plus either emtricitabine/tenofovir DF or emtricitabine/tenofovir AF
  • Bictegravir/emtricitabine/tenofovir AF
  • Dolutegravir/lamivudine (only if HIV-1 RNA < 500,000 copies/mL, HBV negative, and resistance and HBV test results are available)

The initial regimens generally recommended by the IAS-USA panel are as follows:

  • Abacavir/dolutegravir/lamivudine (only if HLA-B*5701 negative)
  • Dolutegravir plus emtricitabine/tenofovir AF
  • Bictegravir/emtricitabine/tenofovir AF

Table 1. DHHS and IAS-USA: Recommended ART Regimens for Treatment-Naive Patients[1,2]


Guideline Recommendations Regarding INSTI Use in Individuals With HIV Who Are of Childbearing Potential
Initial results from Tsepamo, an ongoing National Institutes of Health–funded birth surveillance study in Botswana, reported an increased risk of neural tube defects (NTD) in infants whose mothers became pregnant while receiving dolutegravir-based ART (0.94% of 426 births in women receiving dolutegravir-based ART vs 0.12% of 11,300 births in women receiving non-dolutegravir–based ART).[3] However, an updated analysis reported at the 2019 IAS Conference on HIV Science and published in the New England Journal of Medicine showed that as of March 2019, there has been 1 additional NTD case among 1257 additional births with dolutegravir exposure at conception, providing an updated NTD prevalence rate of 0.30% (5/1683; 95% CI: 0.13% to 0.69%) (Capsule Summary).[4,5] This updated risk of NTD with dolutegravir remains higher than that reported for infants who were exposed to non-dolutegravir–based ART at the time of conception.[4,5] Based on these latest findings, the DHHS revised their recommendations regarding dolutegravir-based ART to include the following for persons of childbearing potential[1]:

  • A pregnancy test should be performed before initiating dolutegravir-based ART
  • Providers should discuss the benefits and risks of dolutegravir around the time of conception, including the risk of NTDs
  • Dolutegravir is recommended as an alternative rather than a preferred option for women trying to conceive or who are sexually active and not using effective contraception
  • For women not planning to conceive and using effective contraception, dolutegravir-based ART is recommended

It is important to note that in the Tsepamo study, there has been no evidence of increased NTDs among infants born to mothers who initiated dolutegravir-based ART during pregnancy. (Capsule Summary).[4,5] Therefore, dolutegravir is a recommended regimen in pregnancy, regardless of trimester.[6]

DHHS guidelines also stress that it is not yet known whether other INSTIs taken at the time of conception also pose a risk of NTDs, and there are insufficient or limited data regarding the risks of bictegravir or raltegravir at the time of conception.[1] Therefore, patients of childbearing potential should be made aware of the lack of information on these drugs at the time of conception during the informed decision-making process.[1]

Based on the latest NTD incidence data, the WHO also reconfirmed the use of dolutegravir-based ART as preferred first-line and second-line therapy for all individuals living with HIV.[7] The updated WHO guidelines state that for women of childbearing potential initiating ART, the benefits of dolutegravir—including better viral suppression, fewer maternal deaths, and fewer sexual and mother-to-child transmissions—likely outweigh the potential small increase in NTD risk associated with dolutegravir. The guidelines stress a woman-centered and rights-based approached, in which women are counseled on the benefits and risks to make an informed decision regarding dolutegravir use.

Regimens Recommended in Certain Clinical Situations
In addition to the initial ART regimens recommended for most people with HIV, the DHHS guidelines also list regimens “to be used in certain clinical situations” (Table 2). The IAS-USA guidelines provide a list of regimens that are recommended only for patients for whom “generally recommended regimens are not available or not an option” (Table 2).[2] Of note, the guidelines stress that choices should be “individualized based on virologic efficacy, potential adverse events, childbearing potential and use of effective contraception, pill burden, dosing frequency, drug–drug interaction potential, comorbid conditions, cost, access, and resistance testing results” and should “address individual patient characteristics and needs.”[1] Therefore, for some patients, these regimens may provide the optimal choice. The subsequent sections of this module will address the treatment decisions facing clinicians when selecting from among these choices.

Table 2. DHHS First-line Regimens to be Used in Certain Clinical Situations[1] and IAS-USA Initial Therapy Regimens Recommended for Patients When Generally Recommended Regimens Not Available or Not an Option[2]


The European AIDS Clinical Society (EACS) also regularly updates their guidelines for the treatment of adults with HIV.[8] In these guidelines, the EACS recommends a regimen consisting of 2 NRTIs plus an INSTI for persons starting ART. However, they acknowledge that an ART regimen must be tailored to the individual and therefore also include additional regimens in the recommended category, which consist of 1 NRTI plus an INSTI, 2 NRTIs plus an NNRTI, and 2 NRTIs plus a boosted PI (Table 3). These guidelines note that generic drugs may be substituted if they replace the same drug and do not break recommended fixed-dose coformulations.

Table 3. EACS: Recommended Initial Regimens for Treatment-Naive Patients[8]


In addition to the recommended regimens, the EACS guidelines also list several alternative regimens (Table 4).

Table 4. EACS Alternative Initial Regimens for Treatment-Naive Patients[8]


Of note, the 2-drug regimen dolutegravir/lamivudine is now included as a recommended regimen by both the DHHS and EACS guidelines.[1,8] Additional NRTI-sparing regimens—that is, regimens containing no NTRIs or only lamivudine—are also included as alternative regimen options under “other combinations” in the EACS guidelines (Table 4),[8] and as regimens to be used “when abacavir, tenofovir DF, or tenofovir AF cannot be used” in the alternative regimens tables of the DHHS and IAS-USA guidelines (Table 2).[1,2] These recommendations acknowledge the potency and potential cost savings of 2-drug regimens, as well as the potential toxicity of abacavir and/or tenofovir as components of 3-drug regimens.

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