Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living 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: March 27, 2018; Last Reviewed: October 17, 2017

Panel's Recommendations Regarding Initial Combination Regimens for the Antiretroviral-Naive Patient
Panel's Recommendations
  • An antiretroviral (ARV) regimen for a treatment-naive patient generally consists of two nucleoside reverse transcriptase inhibitors (NRTIs) 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 (booster) (cobicistat or ritonavir).
  • 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):
    • Dolutegravir/abacavir/lamivudineaonly for patients who are HLA-B*5701-negative (AI)
    • Dolutegravir plus tenofovir/emtricitabinea,b (AI)
    • Elvitegravir/cobicistat/tenofovir/emtricitabineb (AI)
    • Raltegravir plus tenofovir/emtricitabinea,b (AI for tenofovir disoproxil fumarate, AII for tenofovir alafenamide)a,b
  • To address individual patient characteristics and needs, the Panel also provides a list of Recommended Initial Regimens in Certain Clinical Situations (Table 6).
  • 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 testing results, comorbid conditions, access, and cost. Table 7 provides guidance on choosing an ARV regimen based on selected clinical case scenarios. Table 8 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 Lamivudine may substitute for emtricitabine or vice versa.
b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir 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 6. Recommended Antiretroviral Regimens for Initial Therapy

Selection of a regimen should be individualized based on virologic efficacy, potential adverse effects, 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 6. Recommended, Alternative, and Other Antiretroviral Regimen Options for Treatment-Naive Patients
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 + 2 NRTIs:
  • DTG/ABC/3TCa (AI)—if HLA-B*5701 negative
  • DTG + tenofovirb/FTCa (AI for both TAF/FTC and TDF/FTC)
  • EVG/c/tenofovirb/FTC (AI for both TAF/FTC and TDF/FTC)
  • RALc + tenofovirb/FTCa (AI for TDF/FTC, AII for TAF/FTC)
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).
Boosted PI + 2 NRTIs: (In general, boosted DRV is preferred over boosted ATV)
  • (DRV/c or DRV/r) + tenofovirb/FTCa (AI for DRV/r and AII for DRV/c)
  • (ATV/c or ATV/r) + tenofovirb/FTCa (BI)
  • (DRV/c or DRV/r) + ABC/3TCaif HLA-B*5701–negative (BII)
  • (ATV/c or ATV/r) + ABC/3TCaif HLA-B*5701–negative and HIV RNA <100,000 copies/mL (CI for ATV/r and CIII for ATV/c)

NNRTI + 2 NRTIs:
  • EFV + tenofovirb/FTCa (BI for EFV/TDF/FTC and BII for EFV + TAF/FTC)
  • RPV/tenofovirb/FTCa (BI)if HIV RNA <100,000 copies/mL and CD4 >200 cells/mm3

INSTI + 2 NRTIs:
  • RALc + ABC/3TCa (CII)if HLA-B*5701–negative and HIV RNA < 100,000 copies/mL

Regimens to Consider when ABC, TAF, and TDF Cannot be Used:d
  • DRV/r + RAL (BID) (CI)if HIV RNA <100,000 copies/mL and CD4 >200 cells/mm3
  • LPV/r + 3TCa (BID)e (CI)
a 3TC may be substituted for FTC, or vice versa, if a non–fixed-dose NRTI combination is desired.
b TAF and TDF are two forms of tenofovir approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.
c RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily.
d Several other NRTI-limiting treatment strategies are under investigation. See the section titled Selected Strategies That Are Under Evaluation and Not Yet Recommended below for discussion regarding these regimens.
e LPV/r plus 3TC is the only boosted PI plus 3TC regimen with published 48-week data in a randomized controlled trial in ART-naive patients. Limitations of LPV/r plus 3TC include twice-daily dosing, high pill burden, and greater rates of gastrointestinal side effects than other PIs.

Note: The following are available as coformulated drugs: ABC/3TC, ATV/c, DRV/c, DTG/ABC/3TC, EFV/TDF/FTC, EVG/c/TAF/FTC, EVG/c/TDF/FTC, LPV/r, RPV/TAF/FTC, RPV/TDF/FTC, TAF/FTC, and TDF/FTC.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BID = twice daily; CD4 = CD4 T lymphocyte; 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; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

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

This table is designed to guide 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 8 for additional information regarding the advantages and disadvantages of particular ARV medications.

Table 7. Antiretroviral Regimen Considerations as 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 + RAL
A higher rate of virologic failure has been observed in those with low pretreatment CD4 count.
HIV RNA >100,000 copies/mL Do Not Use the Following Regimens:
  • RPV-based regimens
  • ABC/3TC with EFV or ATV/r
  • DRV/r + RAL
Higher rates of virologic failure have been observed in those with high pretreatment HIV RNA.
HLA-B*5701–positive Do not use ABC-containing regimens. Abacavir hypersensitivity, a potentially fatal reaction, is highly associated with positivity for the HLA-B*5701 allele.
ARV must be started before HIV drug resistance results are available (e.g., in a person with acute HIV or when a rapid initiation of ART is warranted). See Initiation of Antiretroviral Therapy. Avoid NNRTI-based regimens.

Recommended ART Regimens:
  • (DRV/r or DRV/c) + tenofovira/FTC; or
  • DTG + tenofovira/FTC
Transmitted mutations conferring NNRTI resistance are more likely than mutations associated with PI or INSTI resistance.

Resistance to DRV and DTG emerges slowly; transmitted resistance to DRV is rare and transmitted resistance to DTG has not been reported to date.
ART-Specific Characteristics A one-pill, once-daily regimen is desired. STR Options Include:
  • DTG/ABC/3TC
  • EFV/TDF/FTC
  • EVG/c/TAF/FTC
  • EVG/c/TDF/FTC
  • RPV/TAF/FTC
  • RPV/TDF/FTC
Do not use RPV-based regimens if HIV RNA >100,000 copies/mL and CD4 count <200/mm3.

Since RPV-containing STRs are smaller in size than other STRs, they may be considered when a person has difficulty swallowing a larger pill.

Do not use DTG/ABC/3TC if patient is HLA-B*5701–positive.

See Appendix B, Table 7 for recommendations on ARV dose modification in the setting of renal impairment.
Food effects Regimens that Can be Taken Without Regard to Food:
  • RAL- or DTG-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 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. Use ABC or TAF.

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

TAF may be used if CrCl >30 mL/min.

Consider avoiding ATV.

Other Options When ABC or TAF Cannot be Used:
  • LPV/r + 3TC; or
  • RAL + DRV/r (if CD4 count >200 cells/mm3, HIV RNA <100,000 copies/mL)
  • See text for discussion of alternative NRTI-limiting regimens.
TDF has been associated with proximal renal tubulopathy. Higher rates of renal dysfunction reported in patients using TDF in conjunction with RTV-containing regimens.

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.

See Appendix B, Table 7 for recommendations on ARV dose modification in patients with renal insufficiency.
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 7 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 HLA-B*5701–negative. If HIV RNA >100,000 copies/mL, do not use ABC/3TC + (EFV or ATV/r).
TDF is associated with decreases in bone mineral density along with renal tubulopathy, urine phosphate wasting, and resultant osteomalacia. TAF and ABC are associated with smaller declines in bone mineral density than TDF.
Psychiatric illnesses Consider avoiding EFV- and RPV-based regimens.

Patients on INSTI-based regimens with pre-existing psychiatric conditions should be closely monitored.
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.
HIV-associated dementia (HAD) Avoid EFV-based regimens if possible. EFV-related neuropsychiatric effects may confound assessment of ART’s beneficial effects on improvement of HAD-related symptoms.
Favor DTG- or DRV-based regimens. There is a theoretical CNS penetration advantage of DTG- or DRV-based regimens.
Narcotic replacement therapy required If patient is receiving methadone, consider avoiding EFV-based regimens.

If EFV is used, an increase in methadone dose may be necessary.
EFV reduces methadone concentrations and may lead to withdrawal symptoms.
High cardiac risk DTG-, RAL- or RPV-based regimens may be advantageous in this setting.

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.
An increased CV risk 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, while this has not been seen with ATV (see text); further study is needed.
Cardiac QTc interval prolongation Consider avoiding EFV- or RPV-based regimens if 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 The Following ARV Drugs Have Been Associated with Dyslipidemia:
  • PI/r or PI/c
  • EFV
  • EVG/c
DTG, RAL, and RPV have fewer lipid effects.

TDF has been associated with lower lipid levels than ABC or TAF.
Patients with history of poor adherence to ARV or inconsistent engagement in care Consider boosted PI- or DTG-based regimens. These regimens have a high genetic barrier to resistance.
Pregnancy Refer to the Perinatal Guidelines for specific regimen recommendations.
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 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 is not recommended with any rifamycin-containing regimen.

If Rifampin is Used:
  • EFV can be used without dosage adjustment.
  • If RAL is used, increase RAL dose to 800 mg BID.
  • Use DTG at 50 mg BID dose only in patients without selected INSTI mutations (refer to product label).

If using a PI-based regimen, rifabutin should be used in place of rifampin in the TB regimen.
  • Rifamycins may significantly reduce TAF exposure.
  • Rifampin is a strong inducer of CYP3A4 and UGT1A1 enzymes, causing significant decrease in concentrations of PIs, INSTIs, and RPV.
  • Rifampin has a less significant effect on EFV concentration than on other NNRTIs, PIs, and INSTIs.
  • Rifabutin is a less potent inducer and is an option for patients receiving non-EFV-based regimens.

Refer to Tables 18a, b, d and e for dosing recommendations for rifamycins used with different ARV agents.
a TAF and TDF are two approved forms of tenofovir. TAF has less 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; BID = twice daily; c = cobicistat; CD4 = CD4 T lymphocyte; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FPV = fosamprenavir; FTC = emtricitabine; HBV = hepatitis B virus; HCV = hepatitis C virus; HLA = human leukocyte antigen; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PI/r = ritonavir-boosted protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV or r = ritonavir; STR = single-tablet regimen; TAF = tenofovir alafenamide; TB = tuberculosis; TDF = tenofovir disoproxil fumarate; UGT = uridine diphosphate glucuronosyltransferase

Table 8. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy

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

Table 8. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy
ARV Class ARV Agent(s) Advantage(s) Disadvantage(s)
Dual-NRTI ABC/3TC
  • Coformulated with DTG
  • May cause life-threatening HSRs in patients 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 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 after initiation of 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/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 with ABC/3TC in patients with baseline viral load ≥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
  • Osteomalacia has been reported as a consequence of proximal tubulopathy.
  • Decreases BMD more than other NRTI combinations
INSTI DTG
  • Higher barrier to resistance than EVG or RAL
  • Coformulated with ABC and 3TC
  • No food requirement
  • No CYP3A4 interactions
  • Favorable lipid profile
  • 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 18d.
  • Inhibits renal tubular secretion of Cr and can increase serum Cr without affecting glomerular function
  • UGT substrate; potential for drug interactions (see Table 18d)
  • 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 18d.
  • COBI inhibits active tubular secretion of Cr and can increase serum Cr, without affecting renal glomerular function.
  • Lower genetic barrier to resistance than boosted PI- 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
  • Lower genetic barrier to resistance than boosted PI- 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 fixed-dose combination 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 18d.
  • UGT substrate; potential for drug interactions (see Table 18d)
  • Depression and suicidal ideation (rare; usually in patients with pre-existing psychiatric conditions)
NNRTIs EFV
  • Coformulated with TDF/FTC
  • Long-term clinical experience
  • EFV-based regimens (except for EFV + 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
  • Teratogenic in nonhuman primates
  • Dyslipidemia
  • Rash
  • QTc interval prolongation; consider an alternative to EFV in patients taking medications with known risk of causing TdP, or in those at higher risk of TdP.
  • Transmitted resistance 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 18b and 19a)
  • 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 size 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 count <200 cells/mm3 because of higher rate of virologic failure in these patients
  • Depression and suicidality
  • QTc interval prolongation; consider an alternative to RPV in patients taking medications with known risk of causing TdP, or in those at higher risk of TdP.
  • Rash
  • Transmitted resistance more common than with PIs and INSTIs
  • More NNRTI-, TDF-, and 3TC-associated mutations at virologic failure than with regimen containing EFV and 2 NRTIs
  • Potential for CYP450 drug interactions (see Tables 18b and 19a)
  • Meal requirement (>390 kcal)
  • Requires acid for adequate absorption
    • Contraindicated with PPIs
    • Use with H2 antagonists or antacids with caution (see Table 18a for detailed dosing information).
PIs ATV/c
or
ATV/r
  • Higher genetic barrier to resistance than NNRTIs, EVG, and RAL
  • PI resistance at the time of treatment failure 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, while this has not been seen with ATV. Further study is needed. See text for discussion.
  • Commonly causes indirect hyperbilirubinemia, which may manifest as scleral icterus or jaundice
  • Food requirement
  • Absorption depends on food and low gastric pH (see Table 18a for interactions with H2 antagonists, antacids, and PPIs)
  • Nephrolithiasis, cholelithiasis, nephrotoxicity
  • GI adverse effects
  • CYP3A4 inhibitors and substrates: potential for drug interactions (see Table 18a)
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
  • Less long-term clinical experience than for ATV/r
  • COBI (like RTV) is a potent CYP3A4 inhibitor, which can result in significant interactions with CYP3A substrates.
DRV/c
or
DRV/r
  • Higher genetic barrier to resistance than NNRTIs, EVG, and RAL
  • PI resistance at the time of treatment failure uncommon with PK-enhanced PIs
  • Skin rash
  • Food requirement
  • GI adverse effects
  • CYP3A4 inhibitors and substrates: potential for drug interactions (see Table18a)
  • Increased CV risk in one observational cohort study
DRV/c

(Specific considerations)
  • Coformulated tablet
  • Less long-term clinical experience than for DRV/r
  • 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
  • Approval primarily based on PK data comparable to that for DRV/r rather than on trials comparing the efficacy of DRV/c and DRV/r
  • 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 200 mg per day of RTV
  • 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 effect.
  • Possible nephrotoxicity
  • CYP3A4 inhibitors and substrates: potential for drug interactions (see Table 18a)
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; BMD = bone mineral density; Ca = calcium; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI or c = cobicistat; Cr = creatinine; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DRV = darunavir; DTG = dolutegravir; eGFR = estimated glomerular filtration rate; EFV = efavirenz; EVG = elvitegravir; 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; Mg = magnesium; MI = myocardial infarction; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PK = pharmacokinetic; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV or r = ritonavir; SJS = Stevens-Johnson syndrome; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TdP = torsades de pointes; TEN = toxic epidermal necrosis; UGT = uridine diphosphate glucuronosyltransferase

Table 9. 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 + TDF
As quadruple-NRTI combination regimen
  • Inferior virologic efficacy
d4T + 3TC
  • Significant toxicities (including lipoatrophy, peripheral neuropathy) and hyperlactatemia (including symptomatic and life-threatening lactic acidosis, hepatic steatosis, and pancreatitis)
ddI + 3TC (or FTC)
  • Inferior virologic efficacy
  • Limited clinical trial experience in ART-naive patients
  • ddI toxicities such as pancreatitis and peripheral neuropathy
ddI + 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 (three 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 + 2 NRTIs
  • Higher pill burden than other PI-based regimens
  • Higher ritonavir 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
CCR5 Antagonist
MVC
  • 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 or c = cobicistat; d4T = stavudine; ddI = didanosine; DLV = delavirdine; DRV = darunavir; ECG = electrocardiogram; EFV = efavirenz; ETR = etravirine; FPV = fosamprenavir; FTC = emtricitabine; GI = gastrointestinal; IDV = indinavir; LPV = lopinavir; MVC = maraviroc; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RTV or r = ritonavir; SJS = Stevens Johnson Syndrome; SQV = saquinavir; TDF = tenofovir disoproxil fumarate; TEN = toxic epidermal necrolysis; TPV = tipranavir; ZDV = zidovudine

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