What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient

Last Updated: December 18, 2019; Last Reviewed: December 18, 2019

Key Considerations and Recommendations Regarding Initial Combination Regimens for the Antiretroviral-Naive Patient

Panel’s Recommendations Regarding Initial Combination Regimens for the Antiretroviral-Naive Patient

An antiretroviral (ARV) regimen for a treatment-naive patient generally consists of two nucleoside reverse transcriptase inhibitors (NRTIs) 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 (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic (PK) 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 plus lamivudine, for initial treatment. Before initiating antiretroviral therapy (ART) in a person of childbearing potential, a pregnancy test should be performed (AIII). Before prescribing ART to a person of childbearing potential, please refer to Table 6b for information about safety of different INSTI-based regimens taken around the time of conception. The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) classifies the following regimens as Recommended Initial Regimens for Most People with HIV (in alphabetical order): Bictegravir/tenofovir alafenamide/emtricitabine (AI) Dolutegravir/abacavir/lamivudine—only for individuals who are HLA-B5701 negative and without chronic hepatitis B virus (HBV) coinfection (AI)* Dolutegravir plus (emtricitabine or lamivudine) plus (tenofovir alafenamide or tenofovir disoproxil fumarate)^a (AI) Dolutegravir/lamivudine (AI)—except for individuals with HIV RNA >500,000 copies/mL, HBV co-infection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available. Raltegravir plus (emtricitabine or lamivudine) plus (tenofovir alafenamide [TAF] or tenofovir disoproxil fumarate [TDF])^a (BI for TDF, BII for TAF) To address individual patient characteristics and needs, the Panel also provides a list of Recommended Initial Regimens in Certain Clinical Situations (Table 6a). 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. Table 7 provides guidance on choosing an ARV regimen based on selected clinical case scenarios. Table 9 highlights the advantages and disadvantages of different components in a regimen.
Rating of Recommendations: A = Strong; B = Moderate; C = Optional 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 TAF and TDF are two forms of tenofovir that are approved by the 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.

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. Drug classes and regimens within each class are arranged first by evidence rating, and, when ratings are equal, in alphabetical order. Table 7 provides 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.
INSTI plus 2 NRTIs: Note: For individuals of childbearing potential, see Considerations Before Initiating Dolutegravir and Other Intergrase Strand Transfer Inhibitors as Initial Therapy for Persons of Childbearing Potential before prescribing one of these regimens. BIC/TAF/FTC (AI) DTG/ABC/3TC *(AI)—if HLA-B5701 negative DTG plus (TAF or TDF)^a plus (FTC or 3TC) (AI) RAL plus (TAF or TDF)^a plus (FTC or 3TC) (BI for TDF/[FTC or 3TC], BII for TAF/FTC) INSTI plus 1 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
Recommended Initial Regimens in Certain Clinical Situations
These regimens are effective and tolerable but have some disadvantages when compared with the regimens listed above or have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred (see Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios for examples).
INSTI plus 2 NRTIs: Note: For individuals of childbearing potential, see Before Initiating Dolutegravir and Other Intergrase Strand Transfer Inhibitors as Initial Therapy for Persons of Childbearing Potential before prescribing one of these regimens. EVG/c/(TAF or TDF)^a/FTC (BI) Boosted PI plus 2 NRTIs: In general, boosted DRV is preferred over boosted ATV (DRV/c or DRV/r) plus (TAF or TDF)^a plus (FTC or 3TC) (AI) (ATV/c or ATV/r) plus (TAF or TDF)^a plus (FTC or 3TC) (BI) (DRV/c or DRV/r) plus ABC/3TC—if HLA-B5701 negative (BII) NNRTI plus 2 NRTIs:* DOR/TDF^a/3TC (BI) or DOR plus TAF^a/FTC (BIII) EFV plus (TAF or TDF)^a 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)/FTC (BI)—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^a (CI)
Rating of Recommendations: A = Strong; B = Moderate; C = Optional 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 TAF and TDF are two forms of TFV approved by 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; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; 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 = Food and Drug Administration; FTC = emtricitabine; HLA = human leukocyte antigen; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; STR = single-tablet regimen; TAF = tenofovir alafenamide; TFV = tenofovir; TDF = tenofovir disoproxil fumarate

Background:

Preliminary data from a study in Botswana suggested that there is an increased risk of NTDs (0.9%) in infants born to women who were receiving DTG at the time of conception.^5,9 Updated results have shown that the prevalence of NTDs in infants who were exposed to DTG at the time of conception is lower (0.3%) than reported in the preliminary data, but still higher than in infants who were exposed to ART that did not contain DTG (0.1%).^6,7
It is not yet known whether use of other INSTIs around the time of conception also poses a risk of NTDs (i.e., a class effect).
There are insufficient data to determine whether use of BIC around the time of conception and during pregnancy is safe.
There is limited data on RAL use around the time of conception. Thus far, based on data collected from the Antiretroviral Pregnancy Registry, the drug manufacturer, and in a cohort study from the United States and other countries, no case of NTD has been reported.^10-12 Among those receiving RAL during pregnancy, the rate of fetal malformations is within the expected range for pregnancy outcomes in the United States.^10-12

Before Initiating an INSTI-Containing Regimen in a Person of Childbearing Potential:

- A pregnancy test should be performed (AIII).
- To enable individuals of childbearing potential to make informed decisions, providers should discuss the benefits and risks of using DTG around the time of conception, including the low risk of NTDs and the relative lack of information on the safety of using other commonly prescribed ARV drugs, including other INSTIs, around the time of conception (AIII).
- For individuals who are trying to conceive, the Panel recommends initiating one of the following regimens, which are designated as Preferred regimens during pregnancy in the Perinatal Guidelines: RAL, ATV/r or DRV/r plus TDF/FTC, TDF/3TC, or ABC/3TC. DTG would be an Alternative, rather than a Preferred, option (BII).
- For individuals who are not planning to conceive but who are sexually active and not using contraception, consider a regimen’s effectiveness and tolerability, the available data on potential teratogenicity, and the person’s preferences (e.g., low pill burden) when choosing among regimens recommended for initial therapy (Table 6a). In this situation, DTG would be an Alternative, rather than Preferred, option (BII). If the person becomes pregnant, changes to the ARV regimen may be warranted. Clinicians should refer to the Perinatal Guidelines for recommendations.
- For individuals who are using effective contraception, a DTG-based regimen is one of the recommended options; however, clinicians should discuss the risks and benefits of using DTG with patients to allow them to make an informed decision (AIII).
- An approach similar to that outlined for DTG should be considered for BIC-containing ART (AIII).
- EVG/c should not be used during pregnancy because of inadequate drug concentrations in the second and third trimesters (AII).
- Clinicians should refer to the Perinatal Guidelines when prescribing ART for a pregnant person with HIV.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional
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

Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ATV/r = atazanavir/ritonavir; BIC = bictegravir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; NTD = neural tube defect; RAL = raltegravir; TDF = tenofovir disoproxil fumarate

This table provides guidance to clinicians in choosing an initial ARV regimen according to various patient and regimen characteristics and specific clinical scenarios. When more than one scenario applies to a person with HIV, clinicians should review considerations for each relevant scenario and use their clinical judgment to select the most appropriate regimen. This table is intended to guide the initial choice of regimen. However, if a person is doing well on a particular regimen, it is not necessary to switch to another regimen based on the scenarios outlined in this table. Please see Table 9 for additional information regarding the advantages and disadvantages of particular ARV medications.

Note: Preliminary data suggest that there may be an increased risk of NTDs in infants born to those who were receiving DTG at the time of conception.^6,7 Until more information is available, clinicians should review Table 6b for further guidance before prescribing an INSTI to a person of childbearing potential.

Patient or Regimen Characteristics	Clinical Scenario	Consideration(s)	Rationale/Comments
Pre-ART Characteristics	CD4 cell count <200 cells/mm³	Do Not Use the Following Regimens: RPV-based regimens DRV/r plus RAL	A higher rate of virologic failure has been observed in those with low pretreatment CD4 cell counts.
	HIV RNA >100,000 copies/mL (also see next row if HIV RNA >500,000 copies/mL)	Do Not Use the Following Regimens: RPV-based regimens ABC/3TC with EFV or ATV/r DRV/r plus RAL	Higher rates of virologic failure have been observed in those with high pretreatment HIV RNA levels.
	HLA-B*5701 positive or result unknown	Do not use ABC-containing regimens.	ABC hypersensitivity, a potentially fatal reaction, is highly associated with the presence of the HLA-B*5701 allele.
	ARV should be started before HIV drug resistance results are available (e.g., in a person with acute HIV) or when rapid initiation of ART is warranted	Avoid NNRTI-based regimens. Avoid ABC. Recommended ART Regimens: (DRV/r or DRV/c) plus tenofovir^a/FTC DTG plus tenofovir^a/FTC	Transmitted mutations conferring NNRTI resistance are more likely than mutations associated with PI or INSTI resistance. HLA-B*5701 results may not be available rapidly. Transmitted resistance to DRV and DTG is rare, and these drugs have high barriers to resistance. Refer to Table 6b for further guidance before initiating DTG in persons of childbearing potential.
ART-Specific Characteristics	A 1-pill, once-daily regimen is desired	STR Options as Initial ART Include: BIC/TAF/FTC DOR/TDF/3TC DRV/c/TAF/FTC DTG/ABC/3TC EFV/TDF/FTC EFV/TDF/3TC EVG/c/TAF/FTC EVG/c/TDF/FTC RPV/TAF/FTC RPV/TDF/FTC	Do not use RPV-based regimens if HIV RNA is >100,000 copies/mL and CD4 cell count is <200/mm³. Do not use DTG/ABC/3TC if patient is HLA-B*5701 positive. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential. See Appendix B, Table 8 for ARV dose recommendations in the setting of renal impairment.
	Food effects	Regimens that Can be Taken Without Regard to Food: BIC-, DOR-, DTG-, or RAL-based regimens	Oral bioavailability of these regimens is not significantly affected by food. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential.
		Regimens that Should be Taken with Food: ATV/r- or ATV/c-based regimens DRV/r- or DRV/c-based regimens EVG/c/TAF/FTC^a EVG/c/TDF/FTC^a RPV-based regimens	Food improves absorption of these regimens. RPV-containing regimens should be taken with at least 390 calories of food.
		Regimens that Should be Taken on an Empty Stomach: EFV-based regimens	Food increases EFV absorption and may increase CNS side effects.
Presence of Other Conditions	Chronic kidney disease (defined as CrCl <60 mL/min)	Avoid TDF unless the patient has ESRD. Use ABC or TAF. ABC may be used if patient is HLA-B*5701 negative. If HIV RNA >100,000 copies/mL, do not use ABC/3TC plus (EFV or ATV/r). TAF may be used if CrCl >30 mL/min. Consider avoiding ATV. ART Options When ABC, TAF or TDF Cannot be Used: DTG plus 3TC DRV/r plus 3TC DRV/r plus RAL (if CD4 cell count >200 cells/mm³ and HIV RNA <100,000 copies/mL)	TDF has been associated with proximal renal tubulopathy. Higher rates of renal dysfunction have been reported in patients using TDF in conjunction with RTV-containing regimens. An adjusted dose of TDF can be used in patients with ESRD or in those who are on hemodialysis. Refer to Appendix B, Table 8 for specific dosing recommendations. TAF has less impact on renal function and lower rates of proteinuria than TDF. ATV has been associated with chronic kidney disease in some observational studies. ABC has not been associated with renal dysfunction. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential.
	Liver disease with cirrhosis	Some ARVs are contraindicated or may require dosage modification in patients with Child-Pugh class B or C disease.	Refer to Appendix B, Table 8 for specific dosing recommendations. Patients with cirrhosis should be carefully evaluated by an expert in advanced liver disease.
	Osteoporosis	Avoid TDF. Use ABC or TAF. ABC may be used if patient is HLA-B*5701 negative. If HIV RNA >100,000 copies/mL, do not use ABC/3TC plus (EFV or ATV/r).	TDF is associated with decreases in BMD along with renal tubulopathy, urine phosphate wasting, and resultant osteomalacia. TAF and ABC are associated with smaller declines in BMD than TDF.
	Psychiatric illnesses	Consider avoiding EFV- and RPV-based regimens. Patients on INSTI-based regimens who have pre-existing psychiatric conditions should be closely monitored. Some ARVs are contraindicated and some psychiatric medications need dose adjustments when coadministered with certain ARVs.	EFV and RPV can exacerbate psychiatric symptoms and may be associated with suicidality. INSTIs have been associated with adverse neuropsychiatric effects in some retrospective cohort studies and case series. See the drug-drug interaction tables (Tables 19a, 19b, and 19d) for dosing recommendations when drugs used for psychiatric illnesses are used with certain ARVs.
	HAD	Avoid EFV-based regimens if possible. Favor DTG- or DRV-based regimens.	EFV-related neuropsychiatric effects may confound assessment of ART’s beneficial effects on improvement of HAD-related symptoms. There is a theoretical CNS penetration advantage of DTG- or DRV-based regimens.
	Medication-assisted treatment for opioid dependence	Opioid withdrawal may occur when EFV is initiated in patients who are on a stable dose of methadone. Clinical monitoring is recommended, as medications used to treat opioid dependence may need to be adjusted in some patients.	EFV reduces methadone concentrations and may lead to withdrawal symptoms. See the drug-drug interaction tables (Tables 19a, 19b, and 19d) for dosing recommendations.
	High cardiac risk	Consider avoiding ABC- and LPV/r -based regimens. If a boosted PI is the desired option, an ATV-based regimen may have advantages over a DRV-based regimen. BIC-, DOR-, DTG-, RAL-, or RPV-based regimens may be considered for those with high cardiac risk.	An increased CV risk with ABC has been observed in some studies. Observational cohort studies reported an association between some PIs (DRV, IDV, FPV, and LPV/r) and an increased risk of CV events; this risk has not been seen with ATV (see text). Further study is needed. BIC-, DOR-, DTG-, RAL- or RPV-based regimens have more favorable lipid profiles than other regimens, although evidence on whether this improves CV outcomes is lacking. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential.
	Cardiac QTc interval prolongation	Consider avoiding EFV- or RPV-based regimens if patient is taking other medications with known risk of Torsades de Pointes, or in patients at higher risk of Torsades de Pointes.	High EFV or RPV concentrations may cause QT prolongation.
	Hyperlipidemia AU comment: Australian hyperlipidaemia management guidelines	The Following ARV Drugs Have Been Associated with Dyslipidemia: PI/r or PI/c EFV EVG/c BIC, DOR, DTG, RAL, and RPV have fewer lipid effects.	TDF has been associated with lower lipid levels than ABC or TAF. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential.
	Patients with history of poor adherence to non-ARV medications or inconsistent engagement in care	Consider using regimens with a boosted PI or DTG. BIC also has a high barrier to resistance, but there are currently no data on its efficacy in this population.	These regimens have a high genetic barrier to resistance. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential.
	Pregnancy	Until more information is available, do not initiate a DTG-based regimen for those who are pregnant and within 12 weeks post-conception, because preliminary data suggest that there is an increased risk of NTDs in infants born to those who were receiving DTG at the time of conception.^6,7 Refer to Table 6b and the Perinatal Guidelines for further guidance on ARV use during pregnancy.
	Patients of childbearing potential who are planning to become pregnant or who are sexually active and not using effective contraception	Until more information is available, do not initiate a DTG-based regimen in these patients, because preliminary data suggest that there is an increased risk of NTDs in infants born to those who were receiving DTG at the time of conception.^6,7 Refer to Table 6b for further guidance before initiating an INSTI.
Presence of Coinfections	HBV infection	Use TDF or TAF, with FTC or 3TC, whenever possible. If TDF and TAF Are Contraindicated: For treatment of HBV, use FTC or 3TC with entecavir and a suppressive ART regimen (see HBV/HIV Coinfection).	TDF, TAF, FTC, and 3TC are active against both HIV and HBV. 3TC- or FTC-associated HBV mutations can emerge rapidly when these drugs are used without another drug that is active against HBV.
	HCV treatment required	Refer to recommendations in HCV/HIV Coinfection, with special attention to potential interactions between ARV drugs and HCV drugs.
	Treating TB disease with rifamycins	TAF and BIC are not recommended with any rifamycin-containing regimen. If Rifampin is Used: The following are not recommended: PI/c or PI/r, BIC, EVG, DOR, RPV, or TAF. EFV can be used without dose adjustment. If RAL is used, increase RAL dose to 800 mg BID. Do not use once-daily RAL. Use DTG at 50 mg BID dose only in patients without selected INSTI mutations (refer to product label).	Rifamycins may significantly reduce TAF and BIC exposures. Rifampin is a strong inducer of CYP3A4 and UGT1A1 enzymes, causing significant decreases in concentrations of PIs, INSTIs, DOR, and RPV. Rifampin has a less significant effect on EFV concentration than on the concentrations of other NNRTIs, PIs, and INSTIs. Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential. See the drug-drug interaction tables (Tables 19a, 19b, 19c, 19d and 19e) and TB/HIV Coinfection for information on ARV use with rifamycins.
^a TAF and TDF are two approved forms of tenofovir. TAF has fewer bone and kidney toxicities than TDF, whereas TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC= bictegravir; BID = twice daily; BMD = bone mineral density; COBI = cobicistat; CD4 = CD4 T lymphocyte; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ESRD = end stage renal disease; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FTC = emtricitabine; HAD = HIV-associated dementia; HBV = hepatitis B virus; HCV = hepatitis C virus; HLA = human leukocyte antigen; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; PI/c = cobicistat-boosted protease inhibitor; PI/r = ritonavir-boosted protease inhibitor RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; STR = single-tablet regimen; TAF = tenofovir alafenamide; TB = tuberculosis; TDF = tenofovir disoproxil fumarate; UGT = uridine diphosphate glucuronosyltransferase

	ABC/3TC	TAF/FTC	TDF/FTC	TDF/3TC
Dosing Frequency	Once daily	Once daily	Once daily	Once daily
Available Coformulations for ART-Naive Patients	ABC/3TC DTG/ABC/3TC	TAF 25 mg/FTC BIC/TAF 25 mg/FTC DRV/c/TAF 10 mg/FTC EVG/c/TAF 10 mg/FTC RPV/TAF 25 mg/FTC	TDF/FTC EFV/TDF/FTC EVG/c/TDF/FTC RPV/TDF/FTC	TDF/3TC DOR/TDF/3TC EFV 600 mg/TDF/3TC EFV 400 mg/TDF/3TC
Adverse Effects	ABC: HSR to ABC is associated with the presence of HLA-B*5701 allele Increase in CV events is associated with ABC use in some, but not all, cohort studies	TAF: Renal insufficiency, proximal renal tubulopathy (less frequent than with TDF) Decrease in BMD (less than with TDF; similar to ABC)	TDF: Renal insufficiency, proximal renal tubulopathy Decrease in BMD Renal and bone toxicity are exacerbated by pharmacologic boosters	TDF: Renal insufficiency, proximal renal tubulopathy Decrease in BMD Renal and bone toxicity are exacerbated by pharmacologic boosters
Adverse Effects		FTC: Nail pigmentation		3TC: No significant adverse effects
Other Considerations	Perform HLA-B*5701 testing before initiating ABC; if result is positive, do not start ABC and add ABC to allergy list If HIV RNA >100,000 copies/mL, use only with DTG	Also used for HBV treatment. Discontinuation may precipitate flair of HBV. See Appendix B, Table 8 for dose recommendations in patients with renal insufficiency.
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; BIC= bictegravir; BMD = bone mineral density; CV = cardiovascular; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; HBV = hepatitis B virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RPV = rilpivirine; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

Note: Preliminary data suggest that there may be an increased risk of NTDs in infants born to those who were receiving DTG at the time of conception.^6,7 Until more information is available:

Pregnancy testing should be performed for those of childbearing potential prior to initiation of ART.
DTG is not recommended for ART-naive individuals:
- Who are pregnant and within 12 weeks post-conception, or
- Who are of childbearing potential and who are planning to become pregnant or who are sexually active and not using effective contraception.

Clinicians should refer to Table 6b for further guidance before initiating an INSTI.

	BIC	DTG	EVG	RAL
Dosing Frequency	Once daily	Once Daily: In ART-naive or INSTI-naive persons Twice Daily: If used with certain CYP3A4 and UGT1A1 inducers; or In INSTI-experienced persons with certain INSTI DRMs	Once daily; requires boosting with COBI	400 mg BID, or 1200 mg (two 600-mg tablets) once daily
STR Available for ART-Naive Patients	BIC/TAF/FTC	DTG/ABC/3TC	EVG/c/TAF/FTC EVG/c/TDF/FTC	No
Available as a Single-Drug Tablet	No	Yes	No	Yes
Approved for ART-Experienced Patients	No	Yes, with BID dosing for patients with some INSTI DRMs	No	Yes, for patients with DRM to PI/r or NNRTIs, but no DRM to INSTIs
Virologic Efficacy Against EVG- or RAL-Resistant HIV	In vitro data indicate activity, but no clinical trial data are available	Yes, for some isolates; effective with 50 mg BID dose	No	No
Adverse Effects	Nausea, diarrhea (GI disturbance greater with EVG/c), headache, insomnia. Depression and suicidality are rare, occurring primarily in patients with pre-existing psychiatric conditions.
Adverse Effects	↑ CPK (4%)	Hypersensitivity, hepatotoxicity, ↑ CPK, myositis	↑ TG, ↑ LDL	↑ CPK, myopathy, hypersensitivity, SJS/TEN
CYP3A4 Drug-Drug Interactions	CYP3A4 substrate	CYP3A4 substrate (minor)	EVG is a CYP3A4 substrate; COBI is a CYP3A4 inhibitor	No
Chelation with Polyvalent Cation Supplements and Antacids	Oral absorption of all INSTIs may be reduced by polyvalent cations. See Table 19d for recommendations regarding dosing separation of INSTIs and these drugs.
Other Key Potential Drug Interactions	UGT1A1 substrate, OCT2 and MATE1 inhibitor	p-gp substrate, UGT1A1 substrate	EVG is a UGT1A1 substrate; COBI is a p-gp inhibitor	UGT1A1 substrate
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; BIC = bictegravir; BID = twice daily; COBI = cobicistat; CPK = creatine phosphokinase; CYP = cytochrome P; DRM = drug resistance mutation; DTG = dolutegravir; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; GI = gastrointestinal; INSTI = integrase strand transfer inhibitor; LDL = low density lipoprotein; MATE = multidrug and toxic compound extrusion; NNRTI = non-nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; OAT = organic anionic transporter; p-gp = p-glycoprotein; PI = protease inhibitor; PI/r = ritonavir-boosted protease inhibitor; RAL = raltegravir; SJS/TEN = Stevens Johnson Syndrome/toxic epidermal necrolysis; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TG = triglyceride; UGT = uridine diphosphate glucuronosyltransferase

	DOR	EFV	RPV
Dosing Frequency	Once daily	Once daily	Once daily
Food Requirement	With or without food	On an empty stomach	With a meal
STR Available for ART-Naive Patients	DOR/TDF/3TC	EFV 600 mg/TDF/FTC EFV 600 mg/TDF/3TC EFV 400 mg/TDF/3TC	RPV/TAF/FTC RPV/TDF/FTC
Available as a Single-Drug Tablet	Yes	Yes	Yes
Adverse Effects	Generally well tolerated	CNS side effects, including dizziness, abnormal dreams, headache, depression, suicidality, somnolence, and insomnia Skin rash	Depression, headache Skin rash QT prolongation
CYP3A4 Drug-Drug Interactions	CYP3A4 substrate	CYP3A4 substrate, mixed inducer/inhibitor	CYP3A4 substrate
Other Significant Drug Interactions	None	CYP2B6 and 2C19 inducer	RPV oral absorption is reduced with increased gastric pH. Use of RPV with PPIs is not recommended; see Drug-Drug Interactions for dosing recommendations when RPV is coadministered with H2 blocker or antacids.
Key to Acronyms: 3TC = lamivudine; CNS = central nervous system; CYP = cytochrome P; DOR = doravirine; EFV = efavirenz; FTC = emtricitabine; H2 = histamine 2; PPI = proton pump inhibitor; RPV = rilpivirine; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

	ATV	DRV
Dosing Frequency	Once daily	Once daily for PI-naive patients Twice daily for PI-experienced patients with certain PI mutations
PK Boosting	PK-boosting with RTV or COBI is generally recommended. Unboosted ATV is also FDA-approved for ART-naive patients.	DRV should only be used with a PK booster (i.e., RTV or COBI).
Fixed-Dose Formulation	ATV/c	DRV/c DRV/c/TAF/FTC
Available as a Single-Drug Tablet	Yes	Yes
Adverse Effects	Jaundice Indirect hyperbilirubinemia Cholelithiasis Nephrolithiasis PR prolongation	Skin rash Increase in serum transaminases Hyperlipidemia A higher cardiovascular risk was reported in participants taking DRV-based regimens than in those taking ATV-based regimens in an observational cohort study.
CYP3A4 Drug-Drug Interactions	CYP3A4 substrate, inhibitor	CYP34A substrate, inhibitor
Other Significant Drug Interactions	ATV absorption is reduced when ATV is given with acid-lowering therapies. See Table 19a for ATV dosing recommendations when the drug is coadministered with acid-lowering agents.	N/A
Key to Acronyms: ART = antiretroviral therapy; ATV = atazanavir; ATV/c = atazanavir/cobicistat; COBI = cobicistat; CYP = cytochrome P; DRV = darunavir; DRV/c = darunavir/cobicistat; FDA = Food and Drug Administration; FTC = emtricitabine; PI = protease inhibitor; PK = pharmacokinetic; RTV = ritonavir; TAF = tenofovir alafenamide

Note: All drugs within an ARV class are listed in alphabetical order.

ARV Class	ARV Agent(s)	Advantage(s)	Disadvantage(s)
Dual-NRTI	ABC/3TC	Coformulated with DTG Generic formulations are available for ABC/3TC, ABC, and 3TC.	May cause life-threatening HSRs in patients who test positive for the HLA-B5701 allele. As a result, HLA-B5701 testing is required before use. In the ACTG 5202 study, patients with baseline HIV RNA ≥100,000 copies/mL showed inferior virologic responses when ABC/3TC was given with EFV or ATV/r as opposed to TDF/FTC. This difference was not seen when ABC/3TC was used in combination with DTG. ABC use has been associated with CV disease and cardiac events in some, but not all, observational studies.
	TAF/FTC	Coformulated with BIC, DRV/c, EVG/c, or RPV Active against HBV; a recommended dual-NRTI option for patients with HIV/HBV coinfection Smaller decline in renal function, less proteinuria, and smaller reductions in BMD than TDF/FTC Approved for patients with eGFR ≥30 mL/min	TDF is associated with lower lipid levels than TAF, perhaps because TDF results in higher plasma levels of tenofovir, which lowers lipids.
	TDF/3TC	Coformulated with DOR and EFV Available as the following generic formulations: TDF 3TC TDF/3TC EFV/TDF/3TC Long-term clinical experience Active against HBV	Renal toxicity, including proximal tubulopathy and acute or chronic renal insufficiency, especially when combined with pharmacologic boosters. Osteomalacia has been reported as a consequence of proximal tubulopathy. Decreased BMD has been associated with use of TDF, especially when combined with pharmacologic boosters.
	TDF/FTC	Coformulated with EFV, EVG/c, and RPV as STRs Active against HBV; a recommended dual-NRTI option for patients with HIV/HBV coinfection Better virologic responses than ABC/3TC in patients with baseline viral loads ≥100,000 copies/mL when combined with ATV/r or EFV Associated with lower lipid levels than ABC or TAF	Renal toxicity, including proximal tubulopathy and acute or chronic renal insufficiency, especially when combined with pharmacologic boosters. Osteomalacia has been reported as a consequence of proximal tubulopathy. Decreased BMD has been associated with use of TDF, especially when combined with pharmacologic boosters.
INSTI	BIC	Coformulated with TAF/FTC In trials in ART-naive participants, BIC resistance was not detected No food requirement	Compared to other INSTIs, BIC has the shortest post-marketing experience. Oral absorption of BIC can be reduced by simultaneous administration with drugs or supplements containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 19d. Inhibits tubular secretion of creatinine without affecting glomerular function. CYP3A4 and UGT1A1 substrate (but not a CYP3A4 inducer or inhibitor); potential for drug interactions.
	DTG	Higher barrier to resistance than EVG or RAL Coformulated with ABC and 3TC No food requirement No CYP3A4 interactions Favorable lipid profile	Preliminary data suggests that DTG use before pregnancy and through conception may be associated with an increased risk of NTDs in the infant. See text and Table 6b for recommendations. Oral absorption of DTG can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 19d. Inhibits renal tubular secretion of Cr and can increase serum Cr without affecting glomerular function. UGT1A1 substrate; potential for drug interactions (see Table 19d). Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions).
	EVG/c	Coformulated with TDF/FTC or TAF/FTC Compared with ATV/r, causes smaller increases in total and LDL cholesterol	EVG/c/TDF/FTC is only recommended for patients with baseline CrCl ≥70 mL/min; this regimen should be discontinued if CrCl decreases to <50 mL/min. COBI is a potent CYP3A4 inhibitor, which can result in significant interactions with CYP3A substrates. Oral absorption of EVG can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 19d. COBI inhibits active tubular secretion of Cr and can increase serum Cr without affecting renal glomerular function. Has a lower barrier to resistance than boosted PI-, BIC-, or DTG-based regimens. Food requirement. Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions).
	RAL	Compared to other INSTIs, has longest post-marketing experience No food requirement No CYP3A4 interactions Favorable lipid profile	Has a lower barrier to resistance than boosted PI-, BIC-, or DTG-based regimens. Increases in creatine kinase, myopathy, and rhabdomyolysis have been reported. Rare cases of severe HSRs (including SJS and TEN) have been reported. Higher pill burden than other INSTI-based regimens. No STR formulation. Oral absorption of RAL can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 19d. UGT1A1 substrate; potential for drug interactions (see Table 19d). Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions).
NNRTI	DOR	Coformulated with TDF/3TC Compared to EFV, CNS side effects are less frequent No food requirement Favorable lipid profile	Shorter-term clinical experience than with EFV and RPV. Potential for CYP450 drug interactions (see Tables 19b, 20a and 20b). Treatment-emergent DOR resistance mutations may confer resistance to certain NNRTIs.
	EFV	EFV 600 mg is coformulated with TDF/FTC and TDF/3TC EFV 400 mg is coformulated with TDF/3TC EFV 600-mg dose has long-term clinical experience and EFV-based regimens (except for EFV plus ABC/3TC) have well-documented efficacy in patients with high HIV RNA	Short-and long-term neuropsychiatric (CNS) side effects, including depression and, in some studies, suicidality and catatonia. Screening for depression and suicidality is recommended in people with HIV who are taking a regimen that includes EFV. Teratogenic in nonhuman primates, although no rate increase has been seen in humans. Dyslipidemia Rash QTc interval prolongation; consider using an alternative to EFV in patients taking medications with known risk of causing Torsades de Pointes or in those at higher risk of Torsades de Pointes. Transmitted resistance is more common than with PIs and INSTIs. Greater risk of resistance at the time of treatment failure than with PIs. Potential for CYP450 drug interactions (see Tables 19b and 20a). Should be taken on an empty stomach (food increases drug absorption and CNS toxicities).
	RPV	Coformulated with TDF/FTC and TAF/FTC RPV/TDF/FTC and RPV/TAF/FTC have smaller pill sizes than other coformulated ARV drugs Compared with EFV: Fewer CNS adverse effects Fewer lipid effects Fewer rashes	Not recommended in patients with pre-ART HIV RNA >100,000 copies/mL or CD4 cell counts <200 cells/mm³ because of higher rate of virologic failure in these patients. Depression and suicidality QTc interval prolongation; consider using an alternative to RPV in patients taking medications with known risk of causing Torsades de Pointes or in those at higher risk of Torsades de Pointes. Rash Transmitted resistance is more common than with PIs and INSTIs. More NNRTI-, TDF-, and 3TC-associated mutations at virologic failure than with regimens that contain EFV and 2 NRTIs. Potential for CYP450 drug interactions (see Tables 19b and 20a). Meal requirement (>390 kcal) Requires acid for adequate absorption. Contraindicated with PPIs. Use with H2 antagonists or antacids with caution (see Table 19a for detailed dosing information).
PIs	ATV/c or ATV/r	Higher barrier to resistance than NNRTIs, EVG, and RAL PI resistance at the time of treatment failure is uncommon with PK-enhanced PIs ATV/c and ATV/r have similar virologic activity and toxicity profiles Observational cohort studies have found an association between some PIs (DRV, LPV/r, FPV, IDV) and an increased risk of CV events; this risk has not been seen with ATV. Further study is needed. See text for discussion. Individual ATV and RTV components available as generics	Commonly causes indirect hyperbilirubinemia, which may manifest as scleral icterus or jaundice. Food requirement Absorption depends on food and low gastric pH (see Table 19a for interactions with H2 antagonists, antacids, and PPIs). Nephrolithiasis, cholelithiasis, nephrotoxicity GI adverse effects CYP3A4 inhibitors and substrates: potential for drug interactions (see Table 19a).
	ATV/c (Specific considerations)	Coformulated tablet	COBI inhibits active tubular secretion of Cr and can increase serum Cr without affecting renal glomerular function. Coadministration with TDF is not recommended in patients with CrCl <70 mL/min. COBI (like RTV) is a potent CYP3A4 inhibitor, which can result in significant interactions with CYP3A substrates.
	DRV/c or DRV/r	Higher barrier to resistance than NNRTIs, EVG, and RAL PI resistance at the time of treatment failure is uncommon with PK-enhanced PIs	Skin rash Food requirement GI adverse effects CYP3A4 inhibitors and substrates: potential for drug interactions (see Table 19a). Increased CV risk reported in one observational cohort study.
	DRV/c (Specific considerations)	Coformulated as DRV/c and DRV/c/TAF/FTC	COBI inhibits active tubular secretion of Cr and can increase serum Cr without affecting renal glomerular function. Coadministration with TDF is not recommended in patients with CrCl <70 mL/min. COBI (like RTV) is a potent CYP3A4 inhibitor, which can result in significant interactions with CYP3A substrates.
	LPV/r	Only RTV-coformulated PI No food requirement	Requires RTV 200 mg per day. Possible higher risk of MI associated with cumulative use of LPV/r. PR and QT interval prolongation have been reported. Use with caution in patients at risk of cardiac conduction abnormalities or in patients receiving other drugs with similar effects. Possible nephrotoxicity CYP3A4 inhibitors and substrates: potential for drug interactions (see Table 19a).
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC= bictegravir; BMD = bone mineral density; Ca = calcium; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI = cobicistat; Cr = creatinine; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; eGFR = estimated glomerular filtration rate; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FDC = fixed=dose combination; FPV = fosamprenavir; FTC = emtricitabine; GI = gastrointestinal; HBV = hepatitis B virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; LPV = lopinavir; LPV/r = lopinavir/ritonavir; Mg = magnesium; MI = myocardial infarction; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; PK = pharmacokinetic; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SJS = Stevens-Johnson syndrome; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TEN = toxic epidermal necrosis; UGT = uridine diphosphate glucuronosyltransferase

ARV Components or Regimens	Reasons for Not Recommending as Initial Therapy
NRTIs
ABC/3TC/ZDV (Coformulated) As triple-NRTI combination regimen	Inferior virologic efficacy
ABC/3TC/ZDV plus TDF As quadruple-NRTI combination regimen	Inferior virologic efficacy
d4T plus 3TC	Significant toxicities (including lipoatrophy, peripheral neuropathy) and hyperlactatemia (including symptomatic and life-threatening lactic acidosis, hepatic steatosis, and pancreatitis)
ddI plus 3TC (or FTC)	Inferior virologic efficacy Limited clinical trial experience in ART-naive patients ddI toxicities, such as pancreatitis and peripheral neuropathy
ddI plus TDF	High rate of early virologic failure Rapid selection of resistance mutations Potential for immunologic nonresponse/CD4 cell decline Increased ddI drug exposure and toxicities
ZDV/3TC	Greater toxicities (including bone marrow suppression, GI toxicities, skeletal muscle myopathy, cardiomyopathy, and mitochondrial toxicities such as lipoatrophy, lactic acidosis, and hepatic steatosis) than recommended NRTIs
NNRTIs
DLV	Inferior virologic efficacy Inconvenient (three times daily) dosing
ETR	Insufficient data in ART-naive patients
NVP	Associated with serious and potentially fatal toxicity (hepatic events and severe rash, including SJS and TEN) When compared to EFV, NVP did not meet noninferiority criteria
PIs
ATV (Unboosted)	Less potent than boosted ATV
DRV (Unboosted)	Use without RTV or COBI has not been studied
FPV (Unboosted) or FPV/r	Virologic failure with unboosted FPV-based regimen may result in selection of mutations that confer resistance to FPV and DRV Less clinical trial data for FPV/r than for other RTV-boosted PIs
IDV (Unboosted)	Inconvenient dosing (3 times daily with meal restrictions) Fluid requirement IDV toxicities, such as nephrolithiasis and crystalluria
IDV/r	Fluid requirement IDV toxicities, such as nephrolithiasis and crystalluria
LPV/r	Higher pill burden than other PI-based regimens Higher RTV dose than other PI-based regimens GI intolerance
NFV	Inferior virologic efficacy Diarrhea
RTV as sole PI	High pill burden GI intolerance Metabolic toxicity
SQV (Unboosted)	Inadequate bioavailability Inferior virologic efficacy
SQV/r	High pill burden Can cause QT and PR prolongation; requires pretreatment and follow-up ECG
TPV/r	Inferior virologic efficacy Higher rate of adverse events than other RTV-boosted PIs Higher dose of RTV required for boosting than other RTV-boosted PIs
Entry Inhibitors
T20 Fusion Inhibitor	Only studied in patients with virologic failure Twice-daily subcutaneous injections High rate of injection site reactions
IBA CD4 Post-Attachment Inhibitor	Only studied in a very small number of patients with virologic failure Requires IV therapy High cost
MVC CCR5 Antagonist	Requires testing for CCR5 tropism before initiation of therapy No virologic benefit when compared with other recommended regimens Requires twice-daily dosing
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; CD4 = CD4 T lymphocyte; COBI = cobicistat; d4T = stavudine; ddI = didanosine; DLV = delavirdine; DRV = darunavir; ECG = electrocardiogram; EFV = efavirenz; ETR = etravirine; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; GI = gastrointestinal; IBA = ibalizumab; IDV = indinavir; IDV/r = indinavir/ritonavir; IV = intravenous; LPV = lopinavir; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RTV = ritonavir; SJS = Stevens Johnson Syndrome; SQV = saquinavir; SQV/r = saquinavir/ritonavir; T20 = enfuvirtide; TDF = tenofovir disoproxil fumarate; TEN = toxic epidermal necrolysis; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine