Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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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
Key Considerations and Recommendations
  • 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-B*5701 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.

Table 6a. 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. 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.

Table 6a. Recommended Antiretroviral Regimens for Initial Therapy
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 Table 6b before prescribing one of these regimens.
  • BIC/TAF/FTC (AI)
  • DTG/ABC/3TC (AI)—if HLA-B*5701 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 Table 7 for examples).
INSTI plus 2 NRTIs:
Note: For individuals of childbearing potential, see Table 6b 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-B*5701 negative (BII)
NNRTI plus 2 NRTIs:
  • DOR/TDFa/3TC (BI) or DOR plus TAFa/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 3TCa (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

Table 6b. Considerations Before Initiating Dolutegravir and Other Integrase Strand Transfer Inhibitors as Initial Therapy for Persons of Childbearing Potential
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  

Table 7. Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios

This table guides 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. Before initiating an INSTI-based regimen in a person of childbearing potential, review Table 6b for considerations in choosing the regimen.

Table 7. Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios
Patient or Regimen Characteristics Clinical Scenario Consideration(s) Rationale/Comments
Pre-ART Characteristics
CD4 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 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
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
  • DTG/3TC
For DTG/3TC, limited data are available in patients above this viral load threshold.
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 ART is being initiated rapidly. Avoid NNRTI-based regimens and DTG/3TC.

Avoid ABC.

Recommended ART Regimens:
  • BIC/TAF/FTC
  • DTG plus (TAF or TDF)a plus (3TC or FTC)
  • (DRV/r or DRV/c) plus (TAF or TDF)a plus (3TC or FTC)
Transmitted mutations conferring NNRTI and NRTI 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, BIC, and DTG is rare, and these drugs have high barriers to resistance.
ART-Specific Characteristics A one-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
  • DTG/3TC
  • EFV/TDF/FTC
  • EFV/TDF/3TC
  • EVG/c/TAF/FTC
  • EVG/c/TDF/FTC
  • RPV/TAF/FTC
  • RPV/TDF/FTC
Do not use DTG/ABC/3TC if patient is HLA-B*5701 positive.

DTG/3TC is not recommended if HIV RNA is >500,000 copies/mL.

Do not use DTG/ABC/3TC or DTG/3TC in the setting of HBV coinfection or unknown HBV status.

Do not use RPV-based regimens if HIV RNA is >100,000 copies/mL and CD4 count is <200/mm3.

See Appendix B, Table 10 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.
Regimens that Should be Taken with Food:
  • ATV/r- or ATV/c-based regimens
  • DRV/r- or DRV/c-based regimens
  • EVG/c/TAF/FTCa
  • EVG/c/TDF/FTCa
  • RPV-based regimens
Food improves absorption of these regimens. RPV-containing regimens should be taken with ≥390 calories of food.
Regimens that Should be Taken on an Empty Stomach:
  • EFV-based regimen
Food increases EFV absorption and may increase CNS side effects.
Presence of Other Conditions Chronic kidney disease (defined as CrCl <60 mL/min) In general, avoid TDF.

ABC may be used if patient is HLA-B*5701 negative. If HIV RNA is >100,000 copies/mL, do not use ABC/3TC plus (EFV or ATV/r).

TAF may be used if CrCl >30 mL/min or if patient is on chronic hemodialysis (only studied with EVG/c/TAF/FTC).

Consider avoiding ATV.

ART Options When ABC, TAF, or TDF Cannot be Used:
  • DTG/3TC (if HIV RNA <500,000 copies/mL and without HBV coinfection)
  • DRV/r plus 3TC
  • DRV/r plus RAL (if CD4 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 10 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.
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 10 for specific dosing recommendations.

Patients with cirrhosis should be carefully evaluated by an expert in advanced liver disease.
Osteoporosis Avoid TDF.a 

ABC may be used if patient is HLA-B*5701 negative. If HIV RNA is >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. TAFa 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 21a, 21b, and 21d) for dosing recommendations when drugs used for psychiatric illnesses are used with certain ARVs.
HIV-associated dementia (HAD) Avoid EFV-based regimens if possible. The beneficial effects of ART on HAD-symptoms may be confounded by EFV-related neuropsychiatric effects.
Medication-assisted treatment for opioid use disorder 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 21a, 21b, and 21d) for dosing recommendations.
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.
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.

Refer to Hyperlipidemia below for regimens associated with more favorable lipid profiles.
An increased risk of CV events 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.

Certain ART regimens are associated with more favorable lipid profiles than other regimens, although evidence on whether this improves CV outcomes is lacking.
Hyperlipidemia 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 lowers lipids; therefore, switching from TDF to TAF is associated with increased lipids.
TDF has been associated with lower lipid levels than ABC or TAF.
Patients with history of poor adherence to non-ARV medications or inconsistent engagement in care Consider using regimens with a boosted PI or BIC or DTG. These regimens have a high genetic barrier to resistance.
Pregnancy 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 Refer to Table 6b for further guidance.
Presence of Coinfections

HBV infection Use TDF or TAF, with FTC or 3TC

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 rifamycin antibiotics (rifabutin, rifampin, and rifapentine) Recommended regimens may require dose adjustment. See the drug-drug interaction tables (Tables 21a-e) and TB/HIV Coinfection for information on ARV use with rifamycin antibiotics. Rifamycin antibiotics are inducers of CYP3A4 and UGT1A1 enzymes, causing significant decreases in concentrations of PIs, INSTIs, and RPV.
a TAF and TDF are two FDA-approved forms of TFV. 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: 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; FDA = Food and Drug Administration; 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; TFV = tenofovir; UGT = uridine diphosphate glucuronosyltransferase

Table 8b. Characteristics of Integrase Strand Transfer Inhibitors That Are Recommended for Antiretroviral Therapy-Naive Patients

Before starting an INSTI-based regimen in a person of childbearing potential, clinicians should refer to Table 6b for further guidance.

Table 8b. Characteristics of Integrase Strand Transfer Inhibitors That Are Recommended for Antiretroviral Therapy-Naive Patients
Characteristics 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 drug resistance mutations
Once daily; requires boosting with COBI
  • 400 mg twice daily, or
  • 1,200 mg (two 600-mg tablets) once daily
STR Available for ART-Naive Patients BIC/TAF/FTC
  • DTG/ABC/3TC
  • DTG/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 twice-daily dosing for patients with certain INSTI drug resistance mutations No, but sometimes used in combination with DRV and TAF/FTC as part of a simplification regimen in patients with resistance. Yes, for patients with drug resistance mutations to RTV-boosted PIs or NNRTIs, but not to INSTIs
Virologic Efficacy Against EVG- or RAL-Resistant HIV In vitro data indicate activity, but clinical trial data are not available. Yes, for some isolates; effective with DTG 50 mg twice-daily dose No No
Adverse Effects Nausea, diarrhea (GI disturbance greater with EVG/c), headache, insomnia. Among ARV-naive individuals, initiation of INSTI-containing regimens has been associated with greater weight gain than NNRTI or boosted-PI regimens (see text). Depression and suicidality are rare, occurring primarily in patients with pre-existing psychiatric conditions.
↑ 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 21d 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: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; BID = twice daily; COBI = cobicistat; CPK = creatine phosphokinase; CYP = cytochrome P; DRV = darunavir; 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 cation 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

Table 8c. Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors that are Recommended for Antiretroviral Therapy-Naive Patients
 Characteristics 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, insomnia, somnolence
  • Skin rash
  • QTc prolongation
  • Depression, headache
  • Skin rash
  • QTc 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: 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

Table 8d. Characteristics of Protease Inhibitor Options that are Recommended for Antiretroviral Therapy-Naive Patients
Characteristics 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 21a for ATV dosing recommendations when the drug is coadministered with acid-lowering agents. N/A
Key: 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; N/A = not applicable; PI = protease inhibitor; PK = pharmacokinetic; RTV = ritonavir; TAF = tenofovir alafenamide

Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy

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

Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy
ARV Class ARV Agent(s) Advantage(s) Disadvantage(s)
Dual-NRTI Regimens 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-B*5701 allele. As a result, HLA-B*5701 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 HBV/HIV coinfection
  • Smaller decline in renal function, less proteinuria, and smaller reductions in BMD than TDF/FTC
  • Approved for patients with eGFR ≥30 mL/min
  • Can be used in patients with eGFR <30 mL/min and on chronic hemodialysis
  • TDF is associated with lower lipid levels than TAF, perhaps because TDF results in higher plasma levels of tenofovir, which lowers lipids.
  • Not recommended in pregnancy.
TDF/3TC
  • Coformulated with DOR
  • Generic formulations are available for TDF, 3TC, TDF/3TC, and 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.
Single NRTI 3TC
  • Coformulated with DTG as STR
  • Avoids potential toxicities associated with TDF, TAF, ABC
  • DTG/3TC is not recommended 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.
INSTI BIC
  • Coformulated with TAF/FTC
  • Higher barrier to resistance than EVG and RAL
  • No food requirement
  • See Table 6b for considerations related to prescribing an INSTI-based regimen to people of childbearing potential.
  • 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 21d.
  • Inhibits tubular secretion of Cr without affecting glomerular function.
  • CYP3A4 and UGT1A1 substrate (but not a CYP3A4 inducer or inhibitor); potential for drug-drug interactions.
  • Should not be used in pregnancy because of lack of data and coformulation with TAF.
  • See discussion in text regarding weight gain related to INSTIs.
DTG
  • Higher barrier to resistance than EVG or RAL
  • Coformulated with ABC/3TC and 3TC
  • No food requirement
  • Minimal CYP3A4 interactions
  • Favorable lipid profile
  • Data from Botswana suggest that DTG exposure during conception may be associated with risk of NTDs in the infant (0.3% vs. 0.1% with non-DTG ARV drugs).
  • See Table 6b for considerations related to prescribing an INSTI-based regimen for a person of childbearing potential.
  • 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 21d.
  • Inhibits renal tubular secretion of Cr and can increase serum Cr without affecting glomerular function.
  • UGT1A1 substrate; potential for drug interactions (see Table 21d).
  • Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions).
  • See discussion in text regarding weight gain related to INSTIs.
EVG/c
  • Coformulated with TDF/FTC or TAF/FTC
  • Compared with ATV/r, EVG/c causes smaller increases in total and LDL cholesterol.
  • EVG/c/TAF/FTC can be used in patients on chronic hemodialysis.
  • See Table 6b for considerations related to prescribing an INSTI-based regimen for a person of childbearing potential.
  • 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 21d.
  • 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).
  • Should not be used in pregnancy because of low drug exposure.
  • See discussion in text regarding weight gain related to INSTIs.
RAL
  • Compared to other INSTIs, has longest post-marketing experience
  • No food requirement
  • No CYP3A4 interactions
  • Favorable lipid profile
  • See Table 6b for considerations related to prescribing an INSTI-based regimen for a person of childbearing potential.
  • 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 FDC 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 21d.
  • UGT1A1 substrate; potential for drug interactions (see Table 21d).
  • Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions).
  • See discussion in text regarding weight gain related to INSTIs.
NNRTI DOR
  • Coformulated with TDF/3TC
  • Compared to EFV, fewer CNS side effects
  • No food requirement
  • Favorable lipid profile
  • Shorter-term clinical experience than with EFV and RPV.
  • Potential for CYP450 drug interactions (see Tables 21b, 22a and 22b).
  • 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.
  • EFV 400 mg has fewer CNS side effects than EFV 600 mg.
  • EFV 600 mg can be given with rifamycin antibiotics (rifampin, rifabutin, or rifapentine).
  • Short- and long-term neuropsychiatric (CNS) side effects, including depression and, in some studies, suicidality and catatonia. Late onset ataxia and encephalopathy have also been reported.
  • Periodic screening for depression and suicidality is recommended in people with HIV who are taking a regimen that includes EFV.
  • 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 21b and 22a).
  • 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 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 21b and 22a).
  • Meal requirement (>390 kcal)
  • Requires acid for adequate absorption.
    • Contraindicated with PPIs.
    • Use with H2 antagonists or antacids with caution (see Table 21a for detailed dosing information).
PI 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 are 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 21a for interactions with H2 antagonists, antacids, and PPIs).
  • Nephrolithiasis, cholelithiasis, nephrotoxicity
  • GI adverse effects
  • CYP3A4 inhibitors and substrates: potential for drug interactions (see Table 21a).
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.
  • COBI is not recommended in pregnancy because of low drug levels.
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 21a).
  • Increased CV risk reported in one observational cohort study.
  • Hepatotoxicity has been reported, especially in those with pre-existing liver disease.
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.
  • COBI is not recommended in pregnancy because of low drug levels.
Key: 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; EFV = efavirenz; eGFR = estimated glomerular filtration rate; 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/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

Table 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy
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: 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

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