Selecting an Initial ART Regimen

Selecting an Initial ART Regimen

Purpose of This Guideline

Reviewed and updated: Antonio E. Urbina, MD; October 2021
Writing group: Joseph P. McGowan, MD, FACP, FIDSA; Steven M. Fine, MD, PhD; Rona Vail, MD; Samuel T. Merrick, MD; Asa Radix, MD, MPH, PhD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee: Medical Care Criteria Committee
Date of original publication: January 2019

This guideline was developed by the New York State Department of Health (NYSDOH) AIDS Institute (AI) for primary care providers and other practitioners who are initiating therapy in nonpregnant, antiretroviral therapy (ART)-naive adults with HIV. The guideline aims to achieve the following goals:

  • Provide a clear and concise roadmap for clinicians to follow in choosing from among several equally efficacious ART regimens based on individual patient characteristics and preferences.
  • Provide a list of ART regimens to avoid.
  • Provide dosing considerations for individuals with renal or hepatic impairment and important drug-drug and food interactions.
  • Encourage clinicians to seek the assistance of an experienced HIV care provider when treating patients with extensive comorbidities.
  • Integrate current evidence-based clinical recommendations into the healthcare-related implementation strategies of the New York State Ending the Epidemic initiative.

The NYSDOH AI is publishing this guideline at a critical time: 1) prompt initiation of ART is now recommended for all individuals diagnosed with HIV; 2) identifying and linking individuals with HIV to care and treatment that achieves optimal virologic suppression are crucial to the success of New York State’s Ending the Epidemic initiative; and 3) the ability of primary care providers and other clinicians in NYS to properly select initial ART is key to the successful treatment of individuals with HIV.

Introduction: The NYSDOH AI Medical Care Criteria Committee recommendations for prescribing ART regimens for treatment-naive, nonpregnant adults (age ≥18 years) with HIV-1 and without acquired resistance are based on a comprehensive review of available clinical trial data. (For guidelines specific to treatment of adolescents with HIV, please consult the U.S. Department of Health and Human Services [DHHS] Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV). In formulating its recommendations for NYS, this Committee balanced the strength of published evidence regarding efficacy of treatment regimens with factors that influence adherence, including pill burden, tolerability, and dosing schedule. Preferred regimens are supported by evidence and have favorable adherence profiles, with lower pill burdens, fewer adverse effects, and dosing schedules that may be easier for individuals to manage. Ranking of regimens in this manner is designed to inform discussion and decision-making with patients.

How to use this guideline: Tables presenting preferred and alternative regimens appear first (see the Available ART Regimens section of this guideline: Tables 2 and 3). To help guide the choice among regimens of similar efficacy, each table includes comments that address selected pertinent issues regarding each regimen, such as limitations based on a patient’s kidney function and drug-drug interactions.

Other sections of the guideline include a review of relevant issues, patient considerations, essential laboratory assessments, and the rationale for the recommendations. Reference to the expanded information is crucial for addressing factors that may be of particular importance when individualizing a patient’s treatment, such as loss of bone mineral density with a regimen that includes tenofovir disoproxil fumarate and the conflicting data on cardiac risk with abacavir; see the Specific Factors to Consider and Discuss With Patients section of this guideline. In addition, a review of psychosocial factors and individual patient preferences may help in the selection of an initial ART regimen. Importantly, a patient-centered approach that incorporates both clinical and nonclinical issues should be prioritized.

Scope: This guideline addresses initial treatment of HIV-1 infection with ART in nonpregnant adults. For information regarding ART in individuals who are or who may become pregnant, please refer to the DHHS guideline Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States [DHHS 2021b]. Please refer to the NYSDOH AI guideline Diagnosis and Management of HIV-2 in Adults for recommendations regarding treatment of HIV-2 infection. For recommendations regarding second-line regimens, please refer to the DHHS guideline on management of the treatment-experienced patient [DHHS 2021a].

For the NYSDOH definition of “experienced HIV care provider,” see HIV Care Provider Definitions.

References

DHHS. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. 2021a Aug 16. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelines [accessed 2018 May 1]

DHHS. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. 2021b Feb 10. https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines [accessed 2018 May 1]

Available ART Regimens

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

Note: The recommendations in this guideline pertain to initial antiretroviral therapy (ART) regimens for adults with HIV who are not pregnant.

RECOMMENDATIONS
Regimen Selection
  • When selecting an initial ART regimen for treatment naive-patients, clinicians should:
    • Perform genotypic HIV resistance testing results for protease (A2), reverse transcriptase (A2), and integrase (B2) genotypic resistance if the testing has not already been performed or results are not otherwise available.
    • Inform patients of the regimen options and engage in shared decision-making to optimize the likelihood of adherence. (A3)
    • Assess for comorbidities and chronic coadministered medications that may affect the choice of regimen for a patient’s initial ART. (A3)
    • Choose a preferred ART regimen unless one of the alternative regimens is a better choice based on individual patient factors. (A1)
    • Recommend a single-tablet regimen or a regimen with once-daily dosing unless those regimens are contraindicated by HIV resistance, drug-drug interactions, intolerance, allergy, or access. (A2)
    • Ask patients about their reproductive plans [a] and discuss the use of contraception. (A3)
  • With the exception of dolutegravir/lamivudine (DTG/3TC), clinicians should not prescribe 2-drug regimens as initial ART. (A3) Clinicians should prescribe DTG/3TC only after:
    • HIV resistance and hepatitis B virus (HBV) status are known. (A1)
    • Genotypic resistance testing results have confirmed that a patient does not have a major reverse transcriptase mutation, including the M184V/I resistance mutation. DTG/3TC is contraindicated in patients with these resistance-associated mutations. (A1)
Expert Consultation
  • Clinicians should consult with an experienced HIV care provider when selecting an initial ART regimen for a patient who has:
    • Baseline genotypic testing results indicating the need for an ART regimen other than the available preferred or alternative regimens. (A3)
    • Extensive comorbidities, including metabolic complications and obesity; comedications; impaired renal function; HBV or hepatitis C virus coinfection; or active opportunistic infections. (B3)
      • The NYSDOH Clinical Education Initiative (CEI) provides access to HIV specialists through their toll-free CEI Line: 1-866-637-2342.
Follow-up
  • Clinicians or clinical support staff should follow up by telephone or other methods, preferably within 2 weeks after treatment initiation, to assess tolerance and adherence; adherence should be reinforced at regular intervals. (A3)
  • Clinicians should obtain a viral load test within 4 weeks after ART initiation to assess initial response to therapy. (A3)

——–

[a] Refer to the DHHS guideline in choosing an initial ART regimen for a patient who is pregnant or planning a pregnancy: Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.

Available Antiretroviral Agents and Regimens

Abbreviations used in this section:
Drug names: Other:
  • 3TC: lamivudine
  • ABC: abacavir
  • BIC: bictegravir
  • COBI: cobicistat
  • DTG: dolutegravir
  • EFV: efavirenz
  • EVG: elvitegravir
  • FTC: emtricitabine
  • LPV: lopinavir
  • RAL: raltegravir
  • RAL HD: RAL high-dose
  • RPV: rilpivirine
  • RTV: ritonavir
  • TAF: tenofovir alafenamide
  • TDF: tenofovir disoproxil fumarate
  • ART: antiretroviral therapy
  • CrCl: creatinine clearance
  • CYP3A4: cytochrome P450 3A4
  • DHHS: U.S. Department of Health and Human Services
  • INSTI: integrase strand transfer inhibitor
  • MTR: multi-tablet regimen
  • NNRTI: non-nucleoside reverse transcriptase inhibitor
  • PI: protease inhibitor
  • PPI: proton pump inhibitor
  • STR: single-tablet regimen

An initial ART regimen should be selected on the basis of patient preferences and clinical characteristics, and a preferred regimen should be used whenever possible (Table 2, below). Each of the preferred, alternative, and other initial ART regimens for nonpregnant adults is expected to produce full viral suppression; however, the regimens differ in tolerability, possible toxicities, convenience, and the potential for drug-drug interactions, all of which can affect overall adherence and, therefore, suppression rates.

Preferred backbone: This Committee recommends that either formulation of tenofovir (TAF or TDF) can be used as part of the backbone in preferred regimens. A recent meta-analysis of 14 clinical trials [Pilkington, et al. 2020], comparing the efficacy and safety of TAF versus TDF in boosted and unboosted subgroups, found comparable efficacy and safety profiles with the use of unboosted TDF compared with TAF (see Table 1: Important Clinical Considerations With TDF/FTC or TAF/FTC as Initial Antiretroviral Therapy, below). Studies have shown that TDF-related renal toxicity is more common when using TDF in a regimen containing COBI or RTV [Pilkington, et al. 2020; Hill, et al. 2018; Cuzin, et al. 2017; Ryom, et al. 2013; Goicoechea, et al. 2008]. Therefore, this Committee does not recommend TDF use with boosted regimens when initiating therapy.

In a study of ART-naive individuals, RAL HD 1200 mg once daily was noninferior to 400 mg tablets dosed twice daily and is thus preferred [Cahn, et al. 2017].

Greater weight gain has also been observed after initiation of TAF or with a switch from TDF to TAF, especially in conjunction with INSTIs [Łomiak, et al. 2021; Surial, et al. 2021; Bourgi, et al. 2020a; Bourgi, et al. 2020b; Calmy, et al. 2020; Lake, et al. 2020; Sax, et al. 2020; Venter, et al. 2020; Venter, et al. 2019]. However, the predictors, mechanisms of actions, and clinical significance of these findings is unknown.

Third drug: An INSTI as the third drug is preferred over PIs and NNRTIs based on tolerability and a lower incidence of drug-drug interactions. RPV is not appropriate for patients with a viral load >100,000 copies/mL or CD4 count ≤200 cells/mm3 and is contraindicated with PPIs. TAF/FTC/RPV is included as an alternative regimen.

EFV-containing regimens, although efficacious, have been shown to be less well tolerated than the preferred or alternative regimens in Tables 2 and 3, below.

LPV/RTV-containing regimens are no longer included among the options for initial treatment because of pill burden and reduced tolerability in comparison with other boosted PIs.

When initiating ART at the time of HIV diagnosis (i.e., “rapid start” or “test and treat”), avoid regimens containing ABC unless the result of HLA-B*5701 testing is known to be negative.

Single-Tablet Regimens Versus Multi-Tablet Regimens

The advantages of STRs compared with MTRs include simplicity, convenience, and lower risk of selective nonadherence [Gardner, et al. 2008]. A recent meta-analysis demonstrated that STRs had better adherence rates when compared with MTRs of any frequency (once daily or twice daily) and had higher 48-week viral suppression rates with comparable adverse effects [Clay, et al. 2015].

In another retrospective study, INSTI-based regimens generally had greater rates of suppression and a lower probability of viral rebound after suppression in comparison to NNRTI-based regimens, regardless of whether an STR or MTR was used, but STR INSTI-based therapy was more durable [Mills, et al. 2016b]. In the same study, STR NNRTI-based therapy led to greater rates of suppression than MTR NNRTI-based therapy [Mills, et al. 2016b].

Table 1: Important Clinical Considerations With Either TDF/FTC or TAF/FTC as Initial Antiretroviral Therapy [a]
Download PDF

If the patient is at risk of chronic kidney disease (e.g., age >40 years, with hypertension, diabetes, or preexisting mild kidney disease): The greater possibility of kidney disease among individuals who have risk factors is an essential component of the risk-benefit discussion and shared decision-making regarding initiation of tenofovir-containing regimens.

  • Higher rates of renal dysfunction have been reported in individuals taking TDF in conjunction with RTV- and COBI-containing regimens [Pilkington, et al. 2020; Hill, et al. 2018; Cuzin, et al. 2017; Ryom, et al. 2013; Goicoechea, et al. 2008].
  • For people at low risk for kidney disease, TDF, when not combined with a regimen that contains a pharmacokinetic booster (RTV or COBI), appears to have similar renal safety to TAF [Pilkington, et al. 2020; Hill, et al. 2018].
  • TAF has fewer adverse effects on renal function and is associated with lower rates of proteinuria than TDF [Mills, et al. 2016a; Pozniak, et al. 2016; Sax, et al. 2015].
  • TDF/FTC should be initiated only in individuals with CrCl ≥50 mL/min.
  • TAF/FTC should be initiated only in individuals with CrCl ≥30 mL/min.

If the patient has osteopenia, osteomalacia, or osteoporosis:

  • The risk of bone loss in individuals with preexisting risk factors or documented osteopenia, osteomalacia, or osteoporosis is an important component of the risk-benefit discussion and shared decision-making regarding initiation of TDF/FTC or TAF/FTC.
  • TDF is associated with osteomalacia and decreases in bone mineral density [McComsey, et al. 2011; Stellbrink, et al. 2010; Perrot, et al. 2009].
  • TAF/FTC is preferred for people with osteoporosis.

If the patient has concerns about weight gain, hyperlipidemia, or metabolic disorders:

  • Greater weight gain has been observed with initiation of TAF than TDF and with a switch from TDF to TAF, especially in conjunction with INSTIs [Łomiak, et al. 2021; Surial, et al. 2021; Bourgi, et al. 2020a; Bourgi, et al. 2020b; Calmy, et al. 2020; Lake, et al. 2020; Sax, et al. 2020; Venter, et al. 2020; Venter, et al. 2019].
  • TDF is associated with lower lipid levels than TAF [Souza, et al. 2013].

If the patient is an adolescent or youth:

  • There is limited data on bone safety in adolescents taking TAF/FTC. However, given the more favorable bone biomarkers of TAF versus TDF, TAF may have an advantage in adolescents who have not achieved bone maturation. Because this advantage is theoretical and not currently supported with clinical data, a clear recommendation cannot be made at this time.

If the patient is pregnant or attempting to conceive:

  • Information about the potential benefits and risks of taking tenofovir-containing regimens during pregnancy is an essential component of shared decision-making regarding risk reduction.
  • Due to the greater experience with TDF in this population, TDF/FTC is the preferred dual NRTI backbone for use as HIV treatment during pregnancy [b].
  • Prospectively report information regarding use of ART medications during pregnancy to the Antiretroviral Pregnancy Registry.

If the patient has active chronic HBV:

  • TDF, TAF, and FTC are active against HBV. TDF and TAF are considered equally effective against HBV [c].
  • Discontinuation of TDF/FTC or TAF/FTC in patients with chronic HBV requires close monitoring for rebound HBV viremia.

 Abbreviations: 3TC, lamivudine; ART, antiretroviral therapy; COBI, cobicistat; CrCl, creatinine clearance; DHHS, U.S. Department of Health and Human Services; FDA, U.S. Food and Drug Administration; FTC, emtricitabine; HBV, hepatitis B virus; INSTI, integrase strand transfer inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; RTV, ritonavir; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate.

Notes:

  1. Consider safety, cost, and access when choosing between use of TDF/FTC or TAF/FTC.
  2. Refer to DHHS Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.
  3. TDF and TAF are approved by the FDA as treatment for HBV. FTC is also active against HBV but is not FDA-approved for HBV treatment. TDF or TAF in combination with FTC or 3TC, which is FDA-approved for HBV treatment and is molecularly similar to FTC, is commonly used in patients with HIV/HBV coinfection as part of an antiretroviral regimen to treat both infections.

Other studies have demonstrated better efficacy and adherence, lower cost to patients, and fewer hospital admissions associated with STRs than with MTRs [Griffith, et al. 2016; Mills, et al. 2016b; Armstrong, et al. 2015; Maggiolo, et al. 2015; Hanna, et al. 2014; Nachega, et al. 2014; Sweet, et al. 2014; Cohen, et al. 2013; Colombo, et al. 2013; Raboud, et al. 2011; Bangalore, et al. 2007].

There are 3 STRs listed below as preferred regimens. It is possible that these regimens may contain 1 or more components that are not appropriate for an individual patient, do not allow for adjustment of individual components for renal function, have significant drug-drug interactions, are poorly tolerated, or may be more expensive than the individual components prescribed separately, particularly if available as generic formulations. With full adherence, any of the preferred or alternative regimens should lead to full suppression. This includes MTRs, which can be used when an STR is not possible or not tolerated. Cost and access may also be determinative factors.

For patients with impaired baseline renal function, separating the drugs into individual components and adjusting each may be appropriate (see Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment).

Table 2 includes initial ART regimens preferred by this Committee; Table 3 lists alternative initial regimens. Table 4 lists other available ART regimens that this Committee considers neither preferred nor alternative. Within each table, regimens are listed alphabetically. For specific details on choosing a regimen, see the discussions in other sections of this guideline and/or the package inserts for the drugs listed below. 

Table 2: Preferred Initial Antiretroviral Therapy Regimens for Nonpregnant Adults [a]
(listed alphabetically; for specific details, see Specific Factors to Consider and Discuss With Patients and drug package inserts)
Download PDF
Regimen Comments Rating
Available as a Single-Tablet Formulation
Abacavir/lamivudine/dolutegravir [b,c]
(ABC/3TC/DTG; Triumeq)
  • Initiate only in patients confirmed to be negative for HLA-B*5701, including when a “rapid-start” or “test-and-treat” initiation of ART occurs before baseline laboratory test results are available.
  • Initiate only in patients with CrCl ≥30 mL/min [d].
  • Consider underlying risk of coronary heart disease.
  • Documented DTG resistance after initiation in treatment-naive patients is rare.
  • Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
A1
Lamivudine/dolutegravir [b,c]
(3TC/DTG; Dovato)
  • Initiate only in patients with CrCl ≥30 mL/min [d].
  • Do not use in patients with hepatitis B virus coinfection.
  • Do not initiate before HIV resistance tests results are available.
  • Do not initiate in patients with NRTI resistance, including the M184V/I mutation.
  • Do not initiate in patients with baseline HIV RNA levels >500,000 copies/mL until additional study data are available.
  • Documented DTG resistance after initiation in treatment-naive patients is rare.
  • Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
A1
Tenofovir alafenamide/
emtricitabine/bictegravir [c]
(TAF 25 mg/FTC/BIC; Biktarvy)
  • Initiate only in patients with CrCl ≥30 mL/min [d].
  • Contains 25 mg of TAF, unboosted [c].
  • Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after BIC; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
  • Documented DTG resistance after initiation in treatment-naive patients is rare.
A1
Available as a Multi-Tablet Regimen With Once-Daily Dosing
Tenofovir alafenamide/
emtricitabine or tenofovir disoproxil fumarate/emtricitabine and dolutegravir [b,c]
(TAF 25 mg/FTC or TDF 300 mg/FTC and DTG; Descovy or Truvada and Tivicay)
  • For TAF/FTC, initiate only in patients with CrCl ≥30 mL/min [d].
  • Contains 25 mg of TAF, unboosted [c].
  • For TDF/FTC, initiate only in patients with CrCl ≥50 mL/min [d].
  • For TDF/FTC, consider bone mineral density.
  • Magnesium- or aluminum-containing antacids may be taken 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
  • Documented DTG resistance after initiation in treatment-naive patients is rare.
A1
Tenofovir alafenamide/
emtricitabine or tenofovir disoproxil fumarate/emtricitabine and raltegravir HD [c]
(TAF 25 mg/FTC or TDF 300 mg/FTC and RAL HD; Descovy or Truvada and Isentress HD)
  • For TAF/FTC, initiate only in patients with CrCl ≥30 mL/min [d].
  • Contains 25 mg of TAF, unboosted [c].
  • For TDF/FTC, initiate only in patients with CrCl ≥50 mL/min [d].
  • For TDF/FTC, consider bone mineral density.
  • Administer as TAF/FTC or TDF/FTC once daily and RAL HD 1200 mg once daily, dosed as two 600 mg HD tablets.
  • To date, no clinical trials have been conducted with TAF and RAL; data are based on bioequivalence pharmacokinetic studies.
  • Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium-containing antacids is not recommended with RAL HD.
A2

Abbreviations: ART, antiretroviral therapy; CrCl, creatinine clearance; DHHS, U.S. Department of Health and Human Services; NRTI, nucleoside/nucleotide reverse transcriptase inhibitors.

Notes:

  1. Refer to DHHS for ART regimens for individuals of childbearing potential: Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.
  2. See Use of Dolutegravir in Individuals of Childbearing Capacity.
  3. Substitutions: 
    – In all cases, FTC and 3TC are interchangeable.
    – TAF 10 mg and TAF 25 mg are not interchangeable.
  4. For dose adjustments, refer to Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment.
Table 3: Alternative Initial Antiretroviral Therapy Regimens for Nonpregnant Adults [a]
(listed alphabetically; for specific details, see Specific Factors to Consider and Discuss With Patients and drug package inserts)
Download PDF
Regimen Comments Rating
Available as a Single-Tablet Formulation
Tenofovir alafenamide/
emtricitabine/darunavir/cobicistat [b]
(TAF 10 mg/FTC/DRV/COBI; Symtuza)
  • Initiate only in patients with CrCl ≥30 mL/min [c].
  • Carefully consider drug-drug interactions with COBI [Eron, et al. 2018].
  • Contains 10 mg TAF, boosted [b].
B2
Tenofovir alafenamide/
emtricitabine/elvitegravir/cobicistat [b]
(TAF 10 mg/FTC/EVG/COBI; Genvoya)
  • Initiate only in patients with CrCl ≥30 mL/min [c].
  • Carefully consider drug-drug interactions with COBI.
  • Contains 10 mg of TAF, boosted with COBI [b].
  • Separate dosing of cation-containing (Ca++, AL, Mg) antacids by 2 hours, either before or after dose of EVG.
B1

Tenofovir alafenamide/
emtricitabine/rilpivirine [b]
(TAF 25 mg/FTC/RPV; Odefsey)

  • Initiate only in patients confirmed to have a CD4 count ≥200 cells/mm3 and HIV RNA level <100,000 copies/mL. Avoid use of RPV in a rapid-start or test-and-treat regimen if a patient’s viral load and CD4 count results are not available.
  • Initiate only in patients with CrCl ≥30 mL/min [c].
  • Use with caution in patients with depression or a history of suicidality.
  • To date, no clinical trials have been conducted; data are based on bioequivalence pharmacokinetic studies of TAF compared with TDF.
  • Contraindicated with proton pump inhibitors.
  • Use H2-blockers with caution and separate dosing by 12 hours.
  • Must take with food.
  • Contains 25 mg of TAF, unboosted [b].
B3
Tenofovir disoproxil fumarate/ lamivudine/doravirine [b]
(TDF/3TC/DOR; Delstrigo)
  • Initiate only in patients with CrCl ≥50 mL/min [c].
  • Contraindicated when coadministered with drugs that are strong CYP3A enzyme inducers.
  • Consider bone mineral density.
B1
Available as a Multi-Tablet Regimen With Once-Daily Dosing
Abacavir/lamivudine and doravirine [b]
(ABC/3TC and DOR; Epzicom and Pifeltro)
[Molina, et al. 2018]
  • Initiate only in patients confirmed to be negative for HLA-B*5701.
  • When a “rapid-start” or “test-and-treat” initiation of ART occurs before baseline laboratory test results are available, avoid use of ABC until a patient’s HLA-B*5701 test is confirmed negative.
  • Consider underlying risk of coronary heart disease.
  • Contraindicated when coadministered with drugs that are strong CYP3A enzyme inducers.
B2
Tenofovir alafenamide/emtricitabine and doravirine [b]
(TAF 25 mg/FTC and DOR; Descovy and Pifeltro)
  • Initiate only in patients with CrCl ≥30 mL/min [c].
  • Contraindicated when coadministered with drugs that are strong CYP3A enzyme inducers.
B2
Available as a Multi-Tablet Regimen With Twice-Daily Dosing

Tenofovir alafenamide/emtricitabine or tenofovir disoproxil fumarate/emtricitabine and raltegravir [b]
(TAF 25 mg/FTC or TDF 300 mg/FTC and RAL; Descovy or Truvada and Isentress)

  • For TAF/FTC, initiate only in patients with CrCl ≥30 mL/min [c].
  • For TDF/FTC, initiate only in patients with CrCl ≥50 mL/min [c].
  • For TDF/FTC, consider bone mineral density.
  • Administer as TAF/FTC or TDF/FTC once daily and RAL 400 mg twice daily.
  • Magnesium- or aluminum-containing antacids are contraindicated; calcium-containing antacids are acceptable with RAL.
B3

Abbreviations: ART, antiretroviral therapy; CrCl, creatinine clearance; CYP, cytochrome P450; DHHS, U.S. Department of Health and Human Services.

Notes:

  1. Refer to DHHS for ART regimens for individuals of childbearing potential: Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.
  2. Substitutions: 
    – In all cases, FTC and 3TC are interchangeable.
    – TAF 10 mg and TAF 25 mg are not interchangeable.
    – COBI and RTV should not be considered interchangeable because of their drug-interaction profiles.
  3. For dose adjustments, refer to Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment.
Table 4: Other Antiretroviral Therapy Regimens Not Included as Preferred or Alternative for Nonpregnant Adults [a]
(listed alphabetically; for specific details, see Specific Factors to Consider and Discuss With Patients and drug package inserts)
Download PDF
Regimen Comments Rating
Available as a Single-Tablet Regimen
Tenofovir disoproxil fumarate/ emtricitabine/efavirenz [b]
(TDF/FTC/EFV; Atripla)
  • Initiate only in patients with CrCl ≥50 mL/min [c].
  • Use with caution in patients with depression or a history of suicidality.
  • Consider bone mineral density.
B1
Tenofovir disoproxil fumarate/ emtricitabine/rilpivirine [b]
(TDF/FTC/RPV; Complera)
  • Initiate only in patients confirmed to have a CD4 count ≥200 cells/mm3 and HIV RNA level <100,000 copies/mL [d].
  • Initiate only in patients with CrCl ≥50 mL/min [c].
  • Use with caution in patients with depression or a history of suicidality.
  • Contraindicated with PPIs.
  • Use H2-blockers with caution and separate dosing by 12 hours.
  • Must take with food.
  • Consider bone mineral density.
B1
Available as a Multi-Tablet Regimen With Once-Daily Dosing
Abacavir/lamivudine and atazanavir and ritonavir [b,e]
(ABC/3TC and ATV and RTV; Epzicom and Reyataz and Norvir)
  • Initiate only in patients confirmed to be negative for HLA-B*5701 [b,e].
  • Initiate only in patients with viral load <100,000 copies/mL.
  • Carefully consider drug-drug interactions with RTV.
  • Consider underlying risk of coronary heart disease.
  • In treatment-naive patients on boosted ATV, H2-blockers should be taken simultaneously with ATV/RTV and food. If simultaneous dosing with food is not possible, ATV/RTV should be taken at least 10 hours after the H2-blocker. H2-blocker doses should not exceed the equivalent of 40 mg famotidine twice daily for ART-naive patients or 20 mg famotidine twice daily for ART-experienced patients.
  • Use no more than the equivalent of 20 mg of omeprazole with ATV; administer PPIs at least 12 hours before ATV/RTV.
  • When combined with antacids, ATV should be given 2 hours before or 1 to 2 hours after antacids and buffered medications.
  • Scleral icterus from benign hyperbilirubinemia may be a concern.
C1
Abacavir/lamivudine and darunavir/cobicistat [b,e]
(ABC/3TC and DRV/COBI; Epzicom and Prezcobix)
  • Initiate only in patients confirmed to be negative for HLA-B*5701 [b,e].
  • Carefully consider drug-drug interactions with COBI.
  • Consider underlying risk of coronary heart disease.
B3
Abacavir/lamivudine and darunavir and ritonavir [b,e]
(ABC/3TC and DRV and RTV; Epzicom and Prezista and Norvir)
  • Initiate only in patients confirmed to be negative for HLA-B*5701 [b,e].
  • Carefully consider drug-drug interactions with RTV.
  • Consider underlying risk of coronary heart disease.
B2
Abacavir/lamivudine and efavirenz [b,e]
(ABC/3TC and EFV; Epzicom and Sustiva)
  • Initiate only in patients confirmed to be negative for HLA-B*5701 [b,e].
  • Initiate only in patients with viral load <100,000 copies/mL.
  • Use with caution in patients with depression or a history of suicidality.
  • Consider underlying risk of coronary heart disease.
C1
Tenofovir alafenamide/emtricitabine and efavirenz [b]
(TAF 25 mg/FTC and EFV; Descovy and Sustiva)
  • Initiate only in patients with CrCl ≥50 mL/min [c].
  • Use with caution in patients with depression or a history of suicidality.
  • Contains 25 mg of TAF, unboosted [b].
B3

Abacavir/lamivudine and raltegravir HD [b,e]
(ABC/3TC and RAL HD; Epzicom and Isentress HD)

  • Initiate only in patients confirmed to be negative for HLA-B*5701 [b,e].
  • Consider underlying risk of coronary heart disease.
  • Administer as ABC/3TC once daily and RAL HD 1200 mg once daily, dosed as two 600 mg HD tablets.
  • Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium-containing antacids is not recommended with RAL HD. 
B3
Available as a Multi-Tablet Regimen With Twice-Daily Dosing
Tenofovir disoproxil fumarate/emtricitabine and raltegravir [b]
(TDF/FTC and RAL; Truvada and Isentress)
  • Initiate only in patients with CrCl ≥50 mL/min [c].
  • Consider bone mineral density.
  • TDF/FTC once daily and RAL 400 mg twice daily.
  • Magnesium- or aluminum-containing antacids are contraindicated; calcium-containing antacids are acceptable with RAL.
B1
Abacavir/lamivudine and raltegravir [b,e]
(ABC/3TC and RAL; Epzicom and Isentress)
  • Initiate only in patients confirmed to be negative for HLA-B*5701 [b,e].
  • Consider underlying risk of coronary heart disease.
  • Administer as ABC/3TC once daily and RAL 400 mg twice daily.
  • Magnesium- or aluminum-containing antacids are contraindicated; calcium-containing antacids are acceptable with RAL.
B1

Abbreviations: ART, antiretroviral therapy; CrCl, creatinine clearance; DHHS, U.S. Department of Health and Human Services; PPI, proton pump inhibitor.

Notes:

  1. Refer to DHHS for ART regimens for individuals of childbearing potential: Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.
  2. Substitutions:
    – In all cases, FTC and 3TC are interchangeable.
    – TAF 10 mg and TAF 25 mg are not interchangeable.
    – COBI and RTV should not be considered interchangeable because of their drug-interaction profiles.
  3. For dose adjustments, refer to Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment.
  4. When a “rapid-start” or “test-and-treat” initiation of ART occurs before viral load and CD4 count are available, avoid use of RPV.
  5. When a “rapid-start” or “test-and-treat” initiation of ART occurs before baseline laboratory test results are available, avoid use of ABC until HLA-B*5701 is confirmed negative.
Use of Dolutegravir in Individuals of Childbearing Capacity 
Lead author: Geoffrey A. Weinberg, MD, with the MCCC, updated May 2021

Evidence from multiple studies indicates no difference in rates of total birth defects among infants exposed to antiretroviral (ARV) medications during the first trimester compared with infants exposed later in pregnancy. ARVs are generally considered safe and may be taken by pregnant patients with HIV without increasing the risk of infant birth defects. The MCCC is providing the following updated information for medical care providers concerning preliminary reports that previously had linked dolutegravir (DTG) to neural tube defects (NTDs) in infants exposed to dolutegravir during the periconception period [Zash, et al. 2018; Zash, et al. 2019; Reefhuis, et al. 2020]. Read the full statement.

References

Armstrong B, Chan DJ, Stewart MJ, et al. Single tablet regimen usage and efficacy in the treatment of HIV infection in Australia. AIDS Res Treat 2015;2015:570316. [PMID: 26550490

Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007;120(8):713-719. [PMID: 17679131

Bourgi K, Jenkins CA, Rebeiro PF, et al. Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada. J Int AIDS Soc 2020a;23(4):e25484. [PMID: 32294337

Bourgi K, Rebeiro PF, Turner M, et al. Greater weight gain in treatment-naive persons starting dolutegravir-based antiretroviral therapy. Clin Infect Dis 2020b;70(7):1267-1274. [PMID: 31100116

Cahn P, Kaplan R, Sax PE, et al. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet HIV 2017;4(11):e486-e494. [PMID: 28918877

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

Clay PG, Nag S, Graham CM, et al. Meta-analysis of studies comparing single and multi-tablet fixed dose combination HIV treatment regimens. Medicine (Baltimore) 2015;94(42):e1677. [PMID: 26496277

Cohen CJ, Meyers JL, Davis KL. Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US Medicaid population with HIV. BMJ Open 2013;3(8):e003028. [PMID: 23906955

Colombo GL, Di Matteo S, Maggiolo F. Antiretroviral therapy in HIV-infected patients: a proposal to assess the economic value of the single-tablet regimen. Clinicoecon Outcomes Res 2013;5:59-68. [PMID: 23430273

Cuzin L, Pugliese P, Allavena C, et al. Antiretroviral therapy as a risk factor for chronic kidney disease: Results from traditional regression modeling and causal approach in a large observational study. PLoS One 2017;12(12):e0187517. [PMID: 29216208

Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. Aids 2018;32(11):1431-1442. [PMID: 29683855

Gardner EM, Sharma S, Peng G, et al. Differential adherence to combination antiretroviral therapy is associated with virological failure with resistance. Aids 2008;22(1):75-82. [PMID: 18090394

Goicoechea M, Liu S, Best B, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis 2008;197(1):102-108. [PMID: 18171292

Griffith D, Farmer C, Rutstein R, et al. Uptake and virologic outcomes of one-pill versus multi-pill antiretroviral therapy among treatment-naïve non-perinatally HIV-infected youth (2006-2014). IDWeek; 2016 Oct 26-30; New Orleans, LA. https://idsa.confex.com/idsa/2016/webprogram/Paper58740.html

Hanna DB, Hessol NA, Golub ET, et al. Increase in single-tablet regimen use and associated improvements in adherence-related outcomes in HIV-infected women. J Acquir Immune Defic Syndr 2014;65(5):587-596. [PMID: 24326606

Hill A, Hughes SL, Gotham D, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad 2018;4(2):72-79. [PMID: 29682298

Lake JE, Wu K, Bares SH, et al. Risk factors for weight gain following switch to integrase inhibitor-based antiretroviral therapy. Clin Infect Dis 2020;71(9):e471-e477. [PMID: 32099991

Łomiak M, Stępnicki J, Mikuła T, et al. Weight and body mass index increase after switch from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate-containing treatment in an antiretroviral therapy-experienced group. Int J STD AIDS 2021;32(6):570-577. [PMID: 33612018

Maggiolo F, Colombo GL, Di Matteo S, et al. Cost-effectiveness analysis of antiretroviral therapy in a cohort of HIV-infected patients starting first-line highly active antiretroviral therapy during 6 years of observation. Patient Relat Outcome Meas 2015;6:53-60. [PMID: 25733942

McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203(12):1791-1801. [PMID: 21606537

Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis 2016a;16(1):43-52. [PMID: 26538525

Mills A, Fusco J, Schulman K, et al. The impact of antiretroviral tablet burden and polypharmacy on viral suppression in treatment naïve patients. Open Forum Infect Dis 2016b;3(suppl_1):1512. https://doi.org/10.1093/ofid/ofw172.1214

Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV 2018;5(5):e211-220. [PMID: 29592840

Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. Clin Infect Dis 2014;58(9):1297-1307. [PMID: 24457345

Perrot S, Aslangul E, Szwebel T, et al. Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. J Clin Rheumatol 2009;15(2):72-74. [PMID: 19265350

Pilkington V, Hughes SL, Pepperrell T, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate: an updated meta-analysis of 14 894 patients across 14 trials. AIDS 2020;34(15):2259-2268. [PMID: 33048869]

Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study. J Acquir Immune Defic Syndr 2016;71(5):530-537. [PMID: 26627107]

Raboud J, Li M, Walmsley S, et al. Once daily dosing improves adherence to antiretroviral therapy. AIDS Behav 2011;15(7):1397-1409. [PMID: 20878227

Ryom L, Mocroft A, Kirk O, et al. Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study. J Infect Dis 2013;207(9):1359-1369. [PMID: 23382571

Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: Risk factors in randomized comparative clinical trials. Clin Infect Dis 2020;71(6):1379-1389. [PMID: 31606734]

Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials. Lancet 2015;385(9987):2606-2615. [PMID: 25890673

Souza SJ, Luzia LA, Santos SS, et al. Lipid profile of HIV-infected patients in relation to antiretroviral therapy: A review. Rev Assoc Med Bras (1992) 2013;59(2):186-198. [PMID: 23582562

Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010;51(8):963-972. [PMID: 20828304

Surial B, Mugglin C, Calmy A, et al. Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV: A cohort study. Ann Intern Med 2021;174(6):758-767. [PMID: 33721521

Sweet D, Song J, Zhong Y, et al. Real-world medication persistence with single versus multiple tablet regimens for HIV-1 treatment. J Int AIDS Soc 2014;17(4 Suppl 3):19537. [PMID: 25394046

Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N Engl J Med 2019;381(9):803-815. [PMID: 31339677]

Venter WDF, Sokhela S, Simmons B, et al. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): Week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV 2020;7(10):e666-676. [PMID: 33010240

General Principles in Choosing an Initial ART Regimen

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

Abbreviations used in this section:
Drug names: Other:
  • 3TC: lamivudine
  • ABC: abacavir
  • ATV: atazanavir
  • BIC: bictegravir
  • COBI: cobicistat
  • DOR: doravirine
  • DRV: darunavir
  • DTG: dolutegravir
  • EFV: efavirenz
  • EVG: elvitegravir
  • FTC: emtricitabine
  • LPV: lopinavir
  • RAL: raltegravir
  • RAL HD: RAL high-dose
  • RPV: rilpivirine
  • RTV: ritonavir
  • TAF: tenofovir alafenamide
  • TDF: tenofovir disoproxil fumarate
  • ZDV: zidovudine
  • ART: antiretroviral therapy
  • CrCl: creatinine clearance
  • FDA: U.S. Food and Drug Administration
  • FDC: fixed-dose combination
  • HBV: hepatitis B virus
  • INSTI: integrase strand transfer inhibitor
  • NRTI: nucleoside/nucleotide reverse transcriptase inhibitor
  • NNRTI: non-nucleoside reverse transcriptase inhibitor
  • PI: protease inhibitor
  • PPI: proton pump inhibitor
  • STR: single-tablet regimen

Goals of ART: The issue of when to start ART was settled with the publication of the START and TEMPRANO studies early in 2015 [Danel, et al. 2015; Lundgren, et al. 2015]. Treatment is now recommended for all individuals with confirmed HIV regardless of CD4 cell count or viral load (see the NYSDOH guideline When to Initiate ART, With Protocol for Rapid Initiation).

The goal of ART is complete and durable suppression of plasma viremia while minimizing toxicity and maximizing quality of life. Properly selected ART may never require a change or adjustment once started. Treatment interruptions should be avoided [El-Sadr, et al. 2006].

Since the approval of ZDV on March 19, 1987, there have been 30 individual agents approved for the treatment of HIV and 1 pharmacokinetic enhancer or “booster,” COBI, which is currently used to enhance the pharmacokinetics of EVG, ATV, or DRV. RTV at treatment doses is poorly tolerated and is used only at lower doses for pharmacokinetic boosting of PIs. An additional 18 FDA-approved FDCs are also available. These FDCs include STRs, of which there are 9 currently available that provide a complete and effective treatment regimen for HIV that is combined into 1 pill for use in properly selected individuals. The goal of initial therapy is to start a regimen that suits an individual’s lifestyle and is appropriate given existing baseline medical comorbidities (see Table 5: Individual Antiretroviral Medications or Combinations to Avoid in Initial Therapy for Nonpregnant Adults, below).

Active drugs from 2 different classes: Although regimen options for treatment-naive, nonpregnant adults are constantly evolving, the same general principles that were established with the first effective and durable therapies are still true today [Gulick, et al. 2000]. The backbone of therapy has traditionally been 2 NRTIs paired with 1 of the following: an NNRTI, a boosted PI, or a boosted or unboosted INSTI. In a large meta-analysis, INSTIs were superior to other drug classes as a third drug [Lee, et al. 2014], and DTG may have specific advantages because of the lack, to date, of documented resistance developing in ART-naive patients who initiate DTG-containing regimens [Wainberg and Mesplede 2015]. The entry inhibitors and fusion inhibitors are not recommended for initial therapy (see Table 6, below), but they may have a role in ART for treatment-experienced patients with extensive drug resistance (see All FDA-Approved HIV Medications, including generic and trade names).

The only 2-drug regimen that this committee recommends for ART initiation is DTG/3TC, although other dual- and even monotherapy regimens have been and continue to be studied [Cahn, et al. 2020; Cahn, et al. 2019; Baril, et al. 2016; Cahn, et al. 2016; Maggiolo, et al. 2016; Bedimo, et al. 2014; Cahn, et al. 2014; Raffi, et al. 2014; Taiwo, et al. 2011]. Importantly, use of DTG/3TC is recommended only after the result of HIV resistance and HBV testing are known. Further, this committee recommends against the use of DTG/3TC in patients with major NRTI resistance, including the M184V/I mutation.

If DTG/3TC is started in a patient with HBV infection, a third antiviral agent with activity against HBV should be added. Because the Gemini 1 and 2 studies restricted entry to patients with HIV-1 RNA ≤500,000 copies/mL, this committee recommends against use of DTG/3TC in patients with HIV-1 RNA >500,000 copies/mL.

TAF, a prodrug formulation for tenofovir, was developed as an alternative to TDF and has been approved as part of the following STRs:

  • TAF 10 mg/FTC/COBI/EVG
  • TAF 25 mg/FTC/RPV
  • TAF 25 mg/FTC/BIC [FDA 2018a, 2016b, 2016c]
  • TAF 10 mg/FTC/COBI/DRV [FDA 2018b] and the FDC TAF 25 mg/FTC [FDA 2016a]

Oral administration of TAF results in lower circulating levels of tenofovir in plasma and affects markers of renal toxicity and bone mineral density less adversely than does TDF [Mills, et al. 2016; Pozniak, et al. 2016; Sax, et al. 2015]. Bioequivalence studies in healthy volunteers show that the TAF 10 mg dose administered with COBI 150 mg is equivalent to the TAF 25 mg dose without COBI [Zack, et al. 2016a; Zack, et al. 2016b].

A switch study showed good maintenance of viral suppression when changing from TDF/FTC to TAF 10 mg/FTC if the third drug was a boosted PI, or to TAF 25 mg/FTC if the third drug was an unboosted NNRTI or INSTI [Gallant, et al. 2016]. Note that TAF 10 mg alone and TAF 10 mg/FTC are not currently FDA-approved. 

Until further safety data are available, this Committee has not included TAF 25 mg/FTC in combination with COBI or RTV as recommended regimens and recommends caution when using TAF 25 mg/FTC with regimens that contain either COBI or RTV in the setting of CrCl <50 mL/min.

COBI-boosted DRV was approved based on bioavailability studies [FDA 2016d; Kakuda, et al. 2014]. DRV/COBI has demonstrated comparable efficacy to RTV-boosted DRV in a single-arm study [Tashima, et al. 2014]. However, because randomized clinical trials that compare COBI- versus RTV-boosted DRV are not yet available, it has a lower strength of evidence rating. COBI-boosted ATV showed noninferiority when compared with RTV-boosted ATV with a TDF/FTC backbone in a randomized, double-blind study [Gallant, et al. 2013].

KEY POINT
  • INSTI-based regimens are generally the best choice for most individuals because of tolerability and durability.

All of the currently recommended preferred regimens have similar virologic efficacy when measured by an “on-treatment” metric, but adherence, the potential for drug interactions, and tolerability under real-life conditions may inform the choice of preferred versus alternative versus other regimens.

The following general conclusions can be drawn based on currently available evidence from a number of pivotal studies:

  • When ABC/3TC is used as a backbone with EFV or boosted ATV, time to failure was shorter in the ≥100,000 copies/mL viral load stratum when compared with a backbone of TDF/FTC [Sax, et al. 2011; Post, et al. 2010; Sax, et al. 2009].
  • DTG is as efficacious as (i.e., noninferior to) RAL [Raffi, et al. 2013] and superior to both DRV/RTV [Molina, et al. 2014] and coformulated TDF/FTC/EFV [Walmsley S, et al. 2015]. DTG was superior at 48 weeks when combined with ABC/3TC as compared to TDF/FTC/EFV [Walmsley SL, et al. 2013].
  • RAL, although dosed twice daily, has a favorable tolerability profile, provides durable virologic control [Lennox, et al. 2014; DeJesus, et al. 2012; Young, et al. 2010], and was superior to both DRV/RTV and ATV/RTV based on the cumulative incidence of virologic failure and tolerability [Lennox, et al. 2014].
  • In a study of ART-naive individuals, RAL HD 1200 mg once daily was noninferior to RAL 400 mg tablets dosed twice daily [Cahn, et al. 2017].
  • TAF/FTC/COBI/EVG as an STR was noninferior to the STR TDF/FTC/COBI/EVG, with fewer adverse effects on kidney function and bone mineral density [Sax, et al. 2015].
  • In 2 separate trials of treatment-naive individuals, TAF/FTC/BIC was noninferior to both TAF/FTC and DTG [Sax, et al. 2017] and ABC/3TC/DTG [Gallant, et al. 2017].
  • RPV has equivalent efficacy relative to EFV when baseline viral load is <100,000 copies/mL and is better tolerated [van Lunzen, et al. 2016; Behrens, et al. 2014; Cohen C, et al. 2014; Cohen CJ, et al. 2013; Cohen CJ, et al. 2012]. But RPV should not be initiated in individuals with baseline viral load >100,000 copies/mL or CD4 counts <200 cells/mm3.
  • In 2 separate trials of treatment-naive individuals, TDF/3TC/DOR was noninferior to TDF/FTC/EFV, or DRV/RTV with either TDF/FTC or ABC/3TC [Orkin, et al. 2019; Molina, et al. 2018].
  • DRV/RTV once daily is better tolerated and noninferior to either ATV/RTV or LPV/RTV [Lennox, et al. 2014; Orkin, et al. 2013], although LPV/RTV shows excellent efficacy when combined with either commonly used NRTI backbone [Smith, et al. 2009] and when compared with ATV/RTV [Molina, et al. 2008]. One open-label study using ABC/3TC as the backbone combined with DRV/RTV showed good safety and efficacy [Trottier, et al. 2012].
Table 5: Individual Antiretroviral Medications (ARVs) or Combinations to Avoid in Initial Therapy for Nonpregnant Adults
ARV Comments
Nevirapine (NVP; Viramune) Life-threatening rash: Stevens-Johnson syndrome and toxic epidermal necrolysis are possible.
  • Stavudine (d4T; Zerit)
  • Didanosine (ddI; Videx)
Serious toxicities: Potentially fatal lactic acidosis, peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis are possible.
Delavirdine (DLV; Rescriptor) Thrice-daily dosing and inferior efficacy.
Etravirine (ETR; Intelence) ETR does not have an FDA indication in ART-naive patients.
  • Maraviroc (MVC; Selzentry)
  • NRTI-only regimens, either triple or quadruple
Inferior efficacy and durability.
Zidovudine (ZDV; Retrovir) Not well tolerated because of bone marrow suppression (notably anemia), headache, and myopathies.
Unboosted PIs Inferior efficacy relative to boosted PIs.
  • Fosamprenavir (FPV; Lexiva)
  • Indinavir (IDV; Crixivan)
  • Tipranavir (TPV; Aptivus)
  • Nelfinavir (NFV; Viracept)
Either not well-studied or limited by dosing and side effects relative to recommended PIs.
Abbreviations: FDA, U.S. Food and Drug Administration; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; PI, protease inhibitor.
References

Baril JG, Angel JB, Gill MJ, et al. Dual therapy treatment strategies for the management of patients infected with HIV: A systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients. PLoS One 2016;11(2):e0148231. [PMID: 26849060

Bedimo RJ, Drechsler H, Jain M, et al. The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health. PLoS One 2014;9(8):e106221. [PMID: 25170938

Behrens G, Rijnders B, Nelson M, et al. Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected patients with HIV-1 RNA </=100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis. AIDS Patient Care STDS 2014;28(4):168-175. [PMID: 24660840

Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis 2014;14(7):572-580. [PMID: 24783988

Cahn P, Kaplan R, Sax PE, et al. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet HIV 2017;4(11):e486-e494. [PMID: 28918877]

Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet 2019;393(10167):143-155. [PMID: 30420123

Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr 2020;83(3):310-318. [PMID: 31834000

Cahn P, Rolan MJ, Figueroa MI, et al. Dolutegravir-lamivudine as initial therapy in HIV-Infected, ARV naïve patients: 48 Week Results of the PADDLE trial. International AIDS Conference; 2016 Jul 18-22; Durban, South Africa. http://www.natap.org/2016/IAC/IAC_54.htm

Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. Aids 2014;28(7):989-997. [PMID: 24508782

Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE trials. J Acquir Immune Defic Syndr 2012;60(1):33-42. [PMID: 22343174]

Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS 2013;27(6):939-950. [PMID: 23211772

Danel C, Moh R, Gabillard D, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med 2015;373(9):808-822. [PMID: 26193126

DeJesus E, Rockstroh JK, Lennox JL, et al. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV Clin Trials 2012;13(4):228-232. [PMID: 22849964]

El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355(22):2283-2296. [PMID: 17135583

FDA. Descovy (emtricitabine and tenofovir alafenamide) tablets, for oral use. 2016a Apr. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208215s000lbl.pdf [accessed 2018 May 2]

FDA. Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use. 2016b Dec. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207561s002lbl.pdf [accessed 2018 May 2]

FDA. Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) tablets, for oral use. 2016c Mar. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208351s000lbl.pdf [accessed 2018 May 2]

FDA. Prezcobix (darunavir and cobicistat) tablets, for oral use. 2016d Mar. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205395s001lbl.pdf [accessed 2018 May 2]

FDA. Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. 2018a Feb. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf [accessed 2018 May 2]

FDA. Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use. 2018b Jul. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210455s000lbl.pdf [accessed 2018 Oct 30]

Gallant J, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV 2016;3(4):e158-165. [PMID: 27036991]

Gallant J, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis 2013;208(1):32-39. [PMID: 23532097

Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet 2017;390(10107):2063-2072. [PMID: 28867497

Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine. Ann Intern Med 2000;133(1):35-39. [PMID: 10877738

Kakuda TN, Opsomer M, Timmers M, et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers. J Clin Pharmacol 2014;54(8):949-957. [PMID: 24644095

Lee FJ, Amin J, Carr A. Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks’ follow-up. PLoS One 2014;9(5):e97482. [PMID: 24830290

Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med 2014;161(7):461-471. [PMID: 25285539

Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015;373(9):795-807. [PMID: 26192873

Maggiolo F, Di Filippo E, Valenti D, et al. NRTI sparing therapy in virologically controlled HIV-1 infected subjects: Results of a controlled, randomized trial (Probe). J Acquir Immune Defic Syndr 2016;72(1):46-51. [PMID: 26910503

Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis 2016;16(1):43-52. [PMID: 26538525

Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008;372(9639):646-655. [PMID: 18722869

Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naive HIV-1-positive individuals: 96 week results from FLAMINGO. J Int AIDS Soc 2014;17(4 Suppl 3):19490. [PMID: 25393999

Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV 2018;5(5):e211-220. [PMID: 29592840

Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial. HIV Med 2013;14(1):49-59. [PMID: 23088336

Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: Week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis 2019;68(4):535-544. [PMID: 30184165

Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr 2010;55(1):49-57. [PMID: 20431394

Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study. J Acquir Immune Defic Syndr 2016;71(5):530-537. [PMID: 26627107]

Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet 2014;384(9958):1942-1951. [PMID: 25103176

Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013;13(11):927-935. [PMID: 24074642

Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): A randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet 2017;390(10107):2073-2082. [PMID: 28867499

Sax PE, Tierney C, Collier AC, et al. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: Final results. J Infect Dis 2011;204(8):1191-1201. [PMID: 21917892

Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 2009;361(23):2230-2240. [PMID: 19952143

Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials. Lancet 2015;385(9987):2606-2615. [PMID: 25890673

Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS 2009;23(12):1547-1556. [PMID: 19542866

Taiwo B, Zheng L, Gallien S, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 2011;25(17):2113-2122. [PMID: 21857490

Tashima K, Crofoot G, Tomaka FL, et al. Cobicistat-boosted darunavir in HIV-1-infected adults: Week 48 results of a phase IIIb, open-label single-arm trial. AIDS Res Ther 2014;11:39. [PMID: 25926858

Trottier B, Machouf N, Thomas R, et al. Abacavir/lamivudine fixed-dose combination with ritonavir-boosted darunavir: A safe and efficacious regimen for HIV therapy. HIV Clin Trials 2012;13(6):335-342. [PMID: 23195671

van Lunzen J, Antinori A, Cohen CJ, et al. Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: Week 96 efficacy and safety from a randomized phase 3b study. AIDS 2016;30(2):251-259. [PMID: 26684822

Wainberg MA, Mesplede T. Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy. J Int AIDS Soc 2015;18(1):20824. [PMID: 26642452

Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: Week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr 2015;70(5):515-519. [PMID: 26262777

Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013;369(19):1807-1818. [PMID: 24195548

Young B, Vanig T, Dejesus E, et al. A pilot study of abacavir/lamivudine and raltegravir in antiretroviral-naive HIV-1-infected patients: 48-week results of the SHIELD trial. HIV Clin Trials 2010;11(5):260-269. [PMID: 21126956

Zack J, Chu H, Chuck S, et al. Bioequivalence of two co-formulations of emtricitabine/tenofovir alafenamide fixed-dose combinations with 200/10 mg and 200/25 mg. J Bioequiv Availab 2016a;8:68-73. https://www.longdom.org/open-access/bioequivalence-of-two-coformulations-of-emtricitabinetenofoviralafenamide-fixeddose-combinations-jbb-1000270.pdf

Zack J, Chuck S, Chu H, et al. Bioequivalence of the rilpivirine/emtricitabine/tenofovir alafenamide single-tablet regimen. J Bioequiv Availab 2016b;8:49-54. https://www.longdom.org/open-access/bioequivalence-of-the-rilpivirineemtricitabinetenofovir-alafenamidesingletablet-regimen-jbb-1000266.pdf

General Considerations With Initial ART Regimens

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

Abbreviations used in this section:
Drug names: Other:
  • 3TC: lamivudine
  • ABC: abacavir
  • COBI: cobicistat
  • DRV: darunavir
  • DTG: dolutegravir
  • EFV: efavirenz
  • EVG: elvitegravir
  • FTC: emtricitabine
  • IDV: indinavir
  • RPV: rilpivirine
  • RTV: ritonavir
  • TAF: tenofovir alafenamide
  • TDF: tenofovir disoproxil fumarate
  • ZDV: zidovudine
  • ART: antiretroviral therapy
  • FDC: fixed-dose combination
  • HBV: hepatitis B virus
  • HCV: hepatitis C virus
  • INSTI: integrase strand transfer inhibitor
  • NRTI: nucleoside/nucleotide reverse transcriptase inhibitor
  • NNRTI: non-nucleoside reverse transcriptase inhibitor
  • PI: protease inhibitor
  • STR: single-tablet regimen

The recommended ART regimens should work well for the majority of patients, but some circumstances may make 1 regimen more favorable than another for a given individual. In general, an INSTI-based regimen will be the best option for most patients [Mills, et al. 2016; Lee, et al. 2014]. To date, no resistance has been reported in ART-naive patients treated with DTG as part of a registrational trial of combination therapy, suggesting that this medication may be an excellent choice, particularly given its tolerability and lack of drug-drug interactions [Cevik, et al. 2020; Wainberg and Mesplede 2015]. Regimens containing a boosted PI or DTG may be more appropriate when adherence is a concern, given the higher barrier to resistance. For patients with acute symptomatic infection or advanced HIV with an opportunistic infection, some experts would use both DTG and boosted DRV together with the NRTI backbone given the possibility of transmitted NRTI resistance until genotypic information is available, at which time the regimen can be adjusted. Consultation with an experienced HIV care provider is recommended when choosing a regimen for patients with extensive comorbidities, impaired renal function, HBV or HCV coinfection, or very high viral loads.

Early clinical trials in HIV used surrogate markers, such as viral load and CD4 cell count, or clinical endpoints, such as morbidity and mortality, to demonstrate superiority of new therapies over the “gold standard” treatment of the era. One of the trials that led to the 1996 approval of IDV compared IDV alone versus ZDV/3TC versus ZDV/3TC/IDV in ZDV- treatment-experienced patients, given that, at the time, dual NRTI treatment was considered acceptable [Gulick, et al. 1997].

As treatment has evolved and become more effective, the use of clinical end points has become challenging; most trials in the current era of HIV therapy are powered to detect noninferiority when compared with standard of care. For a variety of reasons, including cost and complexity, it would be impractical to conduct head-to-head comparisons of all available regimens. Some STRs and FDCs have been approved primarily based on bioequivalence studies when compared with the individual components, such as TDF/FTC/EFV, ABC/3TC/DTG, TAF/FTC/RPV, TAF/FTC, and DRV/COBI.

Some of the cutoff values used for comparisons, such as viral load <100,000 copies/mL or CD4 count ≥200 cells/mm3, are somewhat arbitrary. For example, most studies including RPV show that its efficacy is diminished when initiated at viral loads ≥100,000 copies/mL, and 1 study showed that RPV worked less well than EFV-based therapy at a viral load of ≥500,000 copies/mL [Domingo and Ribera 2013].

Some agents have been approved based on noninferiority to the relatively less well-tolerated TDF/FTC/EFV regimen, which is, nevertheless, a potent and effective regimen for those who tolerate it well. The higher prevalence of NNRTI resistance mutations when transmitted drug resistance occurs has prompted most experts to avoid NNRTI-based regimens if treatment is indicated before genotypic resistance testing results are available [Panichsillapakit, et al. 2016; Rhee, et al. 2015; Stekler, et al. 2015]. Although coformulated TAF/FTC/COBI/EVG is approved for use at any starting viral load, reports of failure using TDF/FTC/COBI/EVG, with resistance, have been documented in individuals with very high baseline viral loads >1,000,000 copies/mL [Adams, et al. 2016; Rhee, et al. 2015].

A paucity of data is available demonstrating how different antiretroviral medications perform based on race and gender, although studies have suggested, for instance, that DRV/RTV is less well tolerated in women than in men and that discontinuation of DRV/RTV occurs at a higher rate among Black patients than among others [Smith, et al. 2012; Currier, et al. 2010].

References

Adams JL, Byrne D, Pepe R, et al. Virological failure in two patients with HIV-1 RNA viral loads >1,000,000 copies/ml initiated on elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate. Antivir Ther 2016;21(2):175-180. [PMID: 26308882

Cevik M, Orkin C, Sax PE. Emergent resistance to dolutegravir among INSTI-naive patients on first-line or second-line antiretroviral therapy: a review of published cases. Open Forum Infect Dis 2020;7(6):ofaa202. [PMID: 32587877

Currier J, Averitt Bridge D, Hagins D, et al. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med 2010;153(6):349-357. [PMID: 20855799

Domingo P, Ribera E. [Data on rilpivirine in treatment-naive patients. Lessons from ECHO, THRIVE and STaR]. Enferm Infecc Microbiol Clin 2013;31(Suppl 2):20-29. [PMID: 24252530

Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337(11):734-739. [PMID: 9287228

Lee FJ, Amin J, Carr A. Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks’ follow-up. PLoS One 2014;9(5):e97482. [PMID: 24830290

Mills A, Fusco J, Schulman K, et al. The impact of antiretroviral tablet burden and polypharmacy on viral suppression in treatment naïve patients. Open Forum Infect Dis 2016;3(suppl_1):1512. https://academic.oup.com/ofid/article/3/suppl_1/1512/2635860

Panichsillapakit T, Smith DM, Wertheim JO, et al. Prevalence of transmitted HIV drug resistance among recently infected persons in San Diego, CA 1996-2013. J Acquir Immune Defic Syndr 2016;71(2):228-236. [PMID: 26413846

Rhee SY, Blanco JL, Jordan MR, et al. Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: An individual-patient- and sequence-level meta-analysis. PLoS Med 2015;12(4):e1001810. [PMID: 25849352

Smith KY, Garcia F, Kumar P, et al. Assessing darunavir/ritonavir-based therapy in a racially diverse population: 48-week outcomes from GRACE. J Natl Med Assoc 2012;104(7-8):366-376. [PMID: 23092052

Stekler JD, McKernan J, Milne R, et al. Lack of resistance to integrase inhibitors among antiretroviral-naive subjects with primary HIV-1 infection, 2007-2013. Antivir Ther 2015;20(1):77-80. [PMID: 24831260

Wainberg MA, Mesplede T. Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy. J Int AIDS Soc 2015;18(1):20824. [PMID: 26642452

Specific Factors to Consider and Discuss With Patients

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

Abbreviations used in this section:
Drug names: Other:
  • 3TC: lamivudine
  • ABC: abacavir
  • ATV: atazanavir
  • BIC: bictegravir
  • COBI: cobicistat
  • DOR: doravirine
  • DRV: darunavir
  • DTG: dolutegravir
  • EFV: efavirenz
  • EVG: elvitegravir
  • FTC: emtricitabine
  • RAL: raltegravir
  • RAL HD: RAL high-dose
  • RPV: rilpivirine
  • RTV: ritonavir
  • TAF: tenofovir alafenamide
  • TDF: tenofovir disoproxil fumarate
  • ZDV: zidovudine
  • ART: antiretroviral therapy
  • ARV: antiretroviral
  • CrCl: creatinine clearance
  • DHHS: U.S. Department of Health and Human Services
  • FDC: fixed-dose combination
  • INSTI: integrase strand transfer inhibitor
  • PPI: proton pump inhibitor
  • PrEP: pre-exposure prophylaxis
  • STR: single-tablet regimen

Before initiating ART, the following factors are important to consider and discuss with patients.

Age: As individuals with HIV age, they have a higher prevalence of comorbidities than younger patients with HIV and are likely to be on more non–HIV-specific medications, particularly cardiovascular or gastrointestinal agents, posing a higher risk for adverse interactions [Marzolini, et al. 2011]. For individuals older than 50 years, careful regimen selection, with the use of INSTIs when possible rather than cytochrome P450 inhibitors, such as COBI or RTV, can help minimize interactions. And use of TAF rather than TDF can lower the risk of renal and bone toxicity.

Comorbidities: Assessment for existing cardiovascular risk, renal disease or risk factors for the development of renal disease, hepatic disease, bone health, mental health, and substance use should be performed. Additionally, the risk for greater weight gain and potential exacerbation of metabolic complications with TAF- versus TDF-containing regimens, especially when combined with certain INSTI-based regimens, should be discussed prior to initiation of ART.

Cost: STRs may be favorable because of the lower copays that could be associated with fewer prescriptions. Conversely, the individual components of these regimens may be available generically as separate pills.

Dosing requirements (daily vs. twice daily): Most patients express a preference for once-daily dosing, especially if they are not taking other medications or are taking other medications that are dosed once daily. If individuals are already taking other medications that are dosed twice daily and report no adherence issues, twice-daily dosing is an acceptable option.

Drug-drug interactions: Because of some key drug-drug interactions, coadministration of some medications is to be avoided (Table 6, below). For instance, PPIs should not be coadministered with oral RPV; however, injectable RPV can be used with PPIs. Given the availability of over-the-counter PPIs and the possibility that these drugs may be prescribed by a different care provider, this interaction is especially important to discuss with patients. In this case, to avoid unnecessary regimen changes once started, even patients who are not currently taking a PPIs should be asked whether they have needed PPIs in the past or may need them in the future. Dose limitations for metformin may also be required when combined with DTG and possibly BIC.

RTV and COBI have many significant and important interactions, including with cardiac medications. Methadone maintenance requirements may also change with some antiretroviral agents. A detailed review of all of a patient’s medications, including over-the-counter medications or supplements, is essential.

Before prescribing an ART regimen, using an automated interaction checker embedded in the electronic medical record or tools such as the following to check for potential drug-drug interactions with currently prescribed medications can help avoid serious problems:

Table 6: Selected Drug-Drug Interactions to Discuss Before Initiating ART in Treatment-Naive Patients
Drugs ARV(s): Comments
H2-blockers
  • ATV: In treatment-naive patients on boosted ATV, H2-blockers should be taken simultaneously with ATV/RTV with food. If simultaneous dosing with food is not possible, ATV/RTV should be taken at least 10 hours after the H2-blocker. H2-blocker doses should not exceed the equivalent of 40 mg famotidine twice daily for ART-naive patients or 20 mg famotidine twice daily for ART-experienced patients.
  • RPV: Use with caution; administer H2-blockers at least 12 hours before or at least 4 hours after RPV.
  • Inhaled steroids
  • Statins
  • COBI; RTV: Alternatives or dose adjustments may be needed.
  • Consult the package inserts for drug-drug interactions between specific statins and ARVs.
Polyvalent cations [a]
  • BIC; DTG: Take 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
  • RAL: Magnesium- or aluminum-containing antacids are contraindicated; calcium-containing antacids are acceptable.
  • RAL HD: Magnesium- or aluminum-containing antacids are contraindicated; coadministration of calcium-containing antacids is not recommended.
  • EVG: Separate dosing by 2 hours, either before or after dose of EVG.
PPIs
  • ATV: Contraindicated with ATV in treatment-experienced patients; in treatment-naive patients, use no more than equivalent of 20 mg of omeprazole with ATV, separated by 12 hours.
  • RPV: Contraindicated.
Metformin
  • DTG: Metformin levels are significantly raised when coadministered with DTG. If used concomitantly, total daily dose of metformin should not exceed 1,000 mg without clinical evaluation of efficacy and adverse events.
Ethinyl estradiol and norethindrone [b]
  • ATV/COBI; DRV/COBI; DRV/RTV; EFV: Use alternative or additional (e.g., barrier) contraceptive methods or choose alternative ART regimen.
  • ATV; ATV/RTV: Use with caution; see manufacturer’s package insert for specific dosing information.
Factor Xa inhibitors
  • COBI; RTV:
    • Apixaban: Reduce dose by 50% if patient is on 5 mg twice daily; avoid use if the indicated dose is 2.5 mg twice daily (based on age, weight, creatinine level).
    • Dabigatran: No adjustment needed if CrCl ≥50 mL/min; avoid if CrCl <50 mL/min.
    • Rivaroxaban: Avoid use.
Platelet inhibitors
  • COBI; RTV:
    • Clopidogrel: Avoid use.
    • Prasugrel: No adjustment needed.
    • Ticagrelor: Avoid use.

Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral medication; ATV, atazanavir; BIC, bictegravir; COBI, cobicistat; CrCl, creatinine clearance; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; PPI, proton pump inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir.

Notes:

  1. Aluminum, calcium, magnesium, or iron in some antacids or vitamin preparations.
  2. For emergency contraception, other oral combinations, and patch, ring, or injectable formulations, please refer to package insert for specific ARV for dosing instructions and safety information.

Food requirements: Because an individual may have a strong preference for taking medication with or without food, it is important to discuss which medications must be taken on an empty stomach, which must be taken with food, and which can be taken with or without food, as listed in Box 1, below.

Box 1: Antiretroviral Medications That Can be Taken With or Without Food, Must Be Taken With Food, or Must Be Taken on an Empty Stomach
Take With
or Without Food
Take With Food Take on Empty Stomach
  • 3TC
  • ABC
  • DOR
  • DTG
  • FTC
  • RAL
  • TAF
  • TDF
  • DTG/3TC
  • TAF/FTC/BIC
  • TAF/FTC/DOR
  • ATV/COBI
  • ATV/RTV
  • DRV/COBI
  • DRV/RTV
  • EVG
  • RPV
  • TAF/FTC/EVG/COBI
  • TAF/FTC/DRV/COBI
  • EFV
Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; BIC, bictegravir; COBI, cobicistat; DOR, doravirine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Known adverse effects and toxicities: Review known and potential adverse effects in advance.

Number of pills: Some patients feel strongly that the fewer the number of pills, the better. For others, the greatest concern may be the ability to take all pills (regardless of the number) together once daily. Sometimes using individual agents rather than a multi-agent FDC or STR may be attractive depending on pill size. In rare cases, individuals who either cannot or will not swallow pills may need liquid formulations or pill crushing. Table 7, below, presents an abbreviated summary of commonly used ARVs and their availability in liquid formulation and/or the acceptability of crushing or dissolving them prior to ingestion.

Table 7: Acceptable Alternative Formulations and Methods of Administration of Antiretroviral Medications

Drug Available as Liquid, Powder, or Chewable Tablet? Can Tablet Be Split/Crushed/Dissolved?
Single-Tablet Formulations
Abacavir/lamivudine/dolutegravir
(ABC/3TC/DTG; Triumeq)
No Probably acceptable to split/crush
Tenofovir alafenamide/
emtricitabine/bictegravir
(TAF/FTC/BIC; Biktarvy)
No No data; not recommended
Tenofovir alafenamide/
emtricitabine/cobicistat/darunavir
(TAF/FTC/COBI/DRV; Symtuza)
No No data; not recommended
Tenofovir alafenamide/
emtricitabine/elvitegravir/cobicistat
(TAF/FTC/COBI/EVG; Genvoya)
No No data; not recommended
Tenofovir alafenamide/
emtricitabine/rilpivirine
(TAF/FTC/RPV; Odefsey)
No No data; not recommended

Tenofovir disoproxil fumarate/
lamivudine/doravirine
(TDF/3TC/DOR); Delstrigo)

No No data; not recommended
Tenofovir disoproxil fumarate/
emtricitabine/efavirenz
(TDF/FTC/EFV; Atripla)
No No data; not recommended
Dolutegravir/lamivudine
(DTG/3TC; Dovato)
No No data; not recommended
Tenofovir disoproxil fumarate/
emtricitabine/rilpivirine 
(TDF/FTC/RPV; Complera)
No No data; not recommended
Fixed-Dose Combinations
Abacavir/lamivudine
(ABC/3TC; Epzicom)
See individual components below Probably acceptable to split/crush
Darunavir/cobicistat
(DRV/COBI; Prezcobix)
No No
Tenofovir alafenamide/emtricitabine
(TAF/FTC; Descovy)
No No
Tenofovir disoproxil fumarate/ emtricitabine
(TDF/FTC; Truvada)
See individual components below Acceptable to crush/dissolve
Zidovudine/lamivudine
(ZDV/3TC; Combivir)
See individual components below Probably acceptable to split/crush
Individual Drugs
Abacavir
(ABC; Ziagen)
Oral solution (20 mg/mL) No data
Atazanavir
(ATV; Reyataz)
Oral dispersible powder (50 mg/packet) Can open capsule and sprinkle contents
Darunavir
(DRV; Prezista)
Oral suspension (100 mg/mL) Probably acceptable to crush
Doravirine
(DOR; Pifeltro)
No No data
Dolutegravir
(DTG; Tivicay)
No Acceptable to crush
Efavirenz
(EFV; Sustiva)
No No
Elvitegravir
(EVG; Vitekta)
No No data
Emtricitabine
(FTC; Emtriva)
Oral solution (10 mg/mL) Acceptable to open and dissolve in water
Lamivudine
(3TC; Epivir)
Oral solution (10 mg/mL) Acceptable to crush or split
Raltegravir
(RAL; Isentress)
Chewable tablet (25 mg, 100 mg); oral powder for suspension (100 mg/packet); neither is bioequivalent to the 400 mg adult dose Not recommended
Raltegravir HD
(RAL HD; Isentress HD)
No No data, not recommended
Rilpivirine
(RPV; Edurant)
No No data, not recommended
Ritonavir
(RTV; Norvir)
Oral solution (80 mg/mL) No
Tenofovir alafenamide (TAF; Vemlidy) No Acceptable to crush
Tenofovir disoproxil fumarate
(TDF; Viread)
Oral powder mixed with soft food only (40 mg/1 g) Acceptable to dissolve in water

Pill size: Use images or real examples to give patients an idea of pill size before they fill the prescription. TAF/FTC/BIC and TAF/FTC/RPV are the smallest STR pills.

Pregnancy or conception planning: Individuals of childbearing potential should receive a pregnancy test and be assessed for use of contraception. When selecting an initial regimen for those who are not using effective contraception or who are contemplating pregnancy, clinicians should consult the DHHS guideline Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.

All patients should be assessed for conception plans, which also provides an opportunity to discuss PrEP for partners without HIV (see the NYSDOH AI guideline PrEP to Prevent HIV and Promote Sexual Health). Additionally, all individuals with HIV should be informed that maintaining a plasma HIV RNA level <200 copies/mL with ART prevents sexual transmission of HIV to their partners (see the NYSDOH AI guidance U=U Guidance for Implementation in Clinical Settings).

Reference

Marzolini C, Back D, Weber R, et al. Ageing with HIV: medication use and risk for potential drug-drug interactions. J Antimicrob Chemother 2011;66(9):2107-2111. [PMID: 21680580

Special Considerations for Comorbid Conditions

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

Abbreviations used in this section:
Drug names: Other:
  • 3TC: lamivudine
  • ABC: abacavir
  • ATZ: atazanavir
  • BIC: bictegravir
  • COBI: cobicistat
  • DRV: darunavir
  • DTG: dolutegravir
  • EVG: elvitegravir
  • FTC: emtricitabine
  • LPV: lopinavir
  • RAL: raltegravir
  • RPV: rilpivirine
  • RTV: ritonavir
  • TAF: tenofovir alafenamide
  • TDF: tenofovir disoproxil fumarate
  • ART: antiretroviral therapy
  • ARV: antiretroviral medication
  • CrCl: creatinine clearance
  • INSTI: integrase strand transfer inhibitor
  • NRTI: nucleoside/nucleotide reverse transcriptase inhibitor
  • NNRTI: non-nucleoside reverse transcriptase inhibitor
  • PI: protease inhibitor

Bone disease: TDF causes a decrease in bone mineral density in all patients after initiation of ART and should be used with caution in patients with preexisting severe osteoporosis [McComsey, et al. 2011; Stellbrink, et al. 2010; Perrot, et al. 2009]. Some experts recommend baseline bone densitometry screening for osteoporosis in postmenopausal women and in men and transgender women older than 50 years who have HIV [Aberg, et al. 2014]. The TAF formulation available currently in TAF/FTC, TAF/FTC/EVG/COBI, TAF/FTC/BIC, and TAF/FTC/RPV is an alternative, with lower markers of bone turnover in clinical trials [Bonora, et al. 2016; Pozniak, et al. 2016].

Cardiovascular risks: COBI- or RTV-containing regimens typically elevate lipids; TAF and certain INSTIs can cause greater weight gain than other ART regimens, with the potential for increased risk of metabolic complications [Łomiak, et al. 2021; Surial, et al. 2021; Bourgi, et al. 2020a; Bourgi, et al. 2020b; Calmy, et al. 2020; Lake, et al. 2020; Sax, et al. 2020; Venter, et al. 2020; Venter, et al. 2019]. TDF-containing regimens can have a beneficial effect on lipids [Souza, et al. 2013]. ABC has been associated with a higher risk of myocardial infarction in some studies [Marcus, et al. 2016; Choi, et al. 2011; Obel, et al. 2010; Sabin, et al. 2008; SMART/INSIGHT and D:A:D Study Groups 2008], whereas other studies have not confirmed this association [Ding, et al. 2012; Bedimo, et al. 2011; Ribaudo, et al. 2011; Brothers, et al. 2009]. Based on the available data, ABC should be used with caution in patients with multiple cardiac risk factors or known coronary heart disease; however, the absolute risk of myocardial infarction remains low, and no clear causality has been established. In the appropriate clinical circumstance, such as for a patient with impaired renal function, the use of ABC would be acceptable [Llibre and Hill 2016]. Clinicians should be made aware of the conflicting study data and share this information with patients.

Liver disease: In patients with existing liver disease of any etiology, dose adjustment of ARVs may be required depending on the severity of hepatic impairment (see Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment).

Mental health and substance use: Factors that may influence adherence should be addressed. There are also potential interactions between illicit (e.g., methamphetamine) and licit substances (e.g., methadone) and ARVs [Kumar, et al. 2015].

KEY POINT
  • Neither mental health nor substance use disorders are contraindications to initiating ART. In some special cases, delay of initiation (for as short a time as possible) may be appropriate while addressing adherence issues and possible interactions (see the NYSDOH AI guideline When to Initiate ART, With Protocol for Rapid Initiation).

Renal function: TDF can cause renal tubular dysfunction, such as acquired Fanconi syndrome [Zimmermann, et al. 2006; Karras, et al. 2003]. The risk of renal impairment has been shown to be elevated in patients with preexisting renal disease, longer treatment duration, low body weight, and when used in conjunction with RTV- or COBI-boosted regimens [Mocroft, et al. 2016; Gervasoni, et al. 2013]. In general, full-dose TDF should be used with caution in patients with baseline CrCl <70 mL/min and should be adjusted or changed to an alternative agent if CrCl decreases to <50 mL/min; TAF is a better choice in these patients. As noted above, TAF 25 mg/FTC should be used with caution in boosted regimens when CrCl is <50 mL/min.

Both ATV/RTV and LPV/RTV have also been independently associated with a greater decrease in renal function over time than NNRTI-based regimens [Quesada, et al. 2015; Goicoechea, et al. 2008]. COBI, and to a lesser extent DTG, can inhibit the excretion of creatinine, with expected elevations of creatinine at initiation of therapy. However, such increases are not clinically relevant and do not significantly affect glomerular filtration rate [Lepist, et al. 2014; Koteff, et al. 2013; German, et al. 2012].

Although DTG is highly bound to plasma proteins and is unlikely to be removed by dialysis, it has not been studied in this population [FDA 2013]; therefore, RAL or a boosted PI with renally adjusted 3TC and either ABC or once-weekly TDF are usually the regimens of choice in this population.

Additional information on prescribing agents for patients with reduced renal function is available in Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment.

Very high viral load (HIV RNA level >750,000 copies/mL): In some cases, experts will recommend use of both boosted DRV and DTG in addition to 2 NRTIs when a patient’s viral load is very high, with possible simplification once viral suppression is achieved. Numerous switch studies have demonstrated the safety of simplifying ARV regimens in virally suppressed individuals with no preexisting drug resistance [Cazanave, et al. 2015; Arribas, et al. 2014; Mills, et al. 2013; Fisher, et al. 2009]. Consultation with an experienced HIV care provider in these situations is helpful.

KEY POINTS
  • Both COBI and DTG can cause decreased tubular excretion of creatinine and may cause a slight increase in measured creatinine.
  • ABC has been associated with a higher risk of myocardial infarction in some studies, although not in others. No clear causal link has been established.
  • Boosted PIs and COBI-boosted EVG are associated with a higher incidence of hyperlipidemia than unboosted INSTIs.
  • Consultation with an experienced HIV care provider is advised when a patient’s baseline viral load is very high (HIV RNA level >750,000 copies/mL).
References

Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2014;58(1):1-10. [PMID: 24343580

Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis 2014;14(7):581-589. [PMID: 24908551

Bedimo RJ, Westfall AO, Drechsler H, et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis 2011;53(1):84-91. [PMID: 21653308

Bonora S, Calcagno A, Trentalange A, et al. Elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide for the treatment of HIV in adults. Expert Opin Pharmacother 2016;17(3):409-419. [PMID: 26642079

Bourgi K, Jenkins CA, Rebeiro PF, et al. Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada. J Int AIDS Soc 2020a;23(4):e25484. [PMID: 32294337]

Bourgi K, Rebeiro PF, Turner M, et al. Greater weight gain in treatment-naive persons starting dolutegravir-based antiretroviral therapy. Clin Infect Dis 2020b;70(7):1267-1274. [PMID: 31100116

Brothers CH, Hernandez JE, Cutrell AG, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr 2009;51(1):20-28. [PMID: 19282778

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

Cazanave C, Reigadas S, Mazubert C, et al. Switch to rilpivirine/emtricitabine/tenofovir single-tablet regimen of human immunodeficiency virus-1 RNA-suppressed patients, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales CO3 Aquitaine Cohort, 2012-2014. Open Forum Infect Dis 2015;2(1):ofv018. [PMID: 26034768

Choi AI, Vittinghoff E, Deeks SG, et al. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. Aids 2011;25(10):1289-1298. [PMID: 21516027

Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr 2012;61(4):441-447. [PMID: 22932321

FDA. Tivicay (dolutegravir) tablets for oral use. 2013 Aug. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf [accessed 2018 May 2]

Fisher M, Moyle GJ, Shahmanesh M, et al. A randomized comparative trial of continued zidovudine/lamivudine or replacement with tenofovir disoproxil fumarate/emtricitabine in efavirenz-treated HIV-1-infected individuals. J Acquir Immune Defic Syndr 2009;51(5):562-568. [PMID: 19561519

German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr 2012;61(1):32-40. [PMID: 22732469

Gervasoni C, Meraviglia P, Landonio S, et al. Low body weight in females is a risk factor for increased tenofovir exposure and drug-related adverse events. PLoS One 2013;8(12):e80242. [PMID: 24312465

Goicoechea M, Liu S, Best B, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis 2008;197(1):102-108. [PMID: 18171292

Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003;36(8):1070-1073. [PMID: 12684922

Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2013;75(4):990-996. [PMID: 22905856

Kumar S, Rao PS, Earla R, et al. Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems. Expert Opin Drug Metab Toxicol 2015;11(3):343-355. [PMID: 25539046

Lake JE, Wu K, Bares SH, et al. Risk factors for weight gain following switch to integrase inhibitor-based antiretroviral therapy. Clin Infect Dis 2020;71(9):e471-e477. [PMID: 32099991

Lepist EI, Zhang X, Hao J, et al. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int 2014;86(2):350-357. [PMID: 24646860

Llibre JM, Hill A. Abacavir and cardiovascular disease: A critical look at the data. Antiviral Res 2016;132:116-121. [PMID: 27260856

Łomiak M, Stępnicki J, Mikuła T, et al. Weight and body mass index increase after switch from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate-containing treatment in an antiretroviral therapy-experienced group. Int J STD AIDS 2021;32(6):570-577. [PMID: 33612018

Marcus JL, Neugebauer RS, Leyden WA, et al. Use of abacavir and risk of cardiovascular disease among HIV-infected individuals. J Acquir Immune Defic Syndr 2016;71(4):413-419. [PMID: 26536316

McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011;203(12):1791-1801. [PMID: 21606537

Mills A, Cohen C, Dejesus E, et al. Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens. HIV Clin Trials 2013;14(5):216-223. [PMID: 24144898

Mocroft A, Lundgren JD, Ross M, et al. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: A prospective international cohort study. Lancet HIV 2016;3(1):e23-32. [PMID: 26762990

Obel N, Farkas DK, Kronborg G, et al. Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: A population-based nationwide cohort study. HIV Med 2010;11(2):130-136. [PMID: 19682101

Perrot S, Aslangul E, Szwebel T, et al. Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. J Clin Rheumatol 2009;15(2):72-74. [PMID: 19265350

Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study. J Acquir Immune Defic Syndr 2016;71(5):530-537. [PMID: 26627107

Quesada PR, Esteban LL, Garcia JR, et al. Incidence and risk factors for tenofovir-associated renal toxicity in HIV-infected patients. Int J Clin Pharm 2015;37(5):865-872. [PMID: 26008219

Ribaudo HJ, Benson CA, Zheng Y, et al. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short and long-term results from ACTG A5001/ALLRT. Clin Infect Dis 2011;52(7):929-940. [PMID: 21427402

Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: A multi-cohort collaboration. Lancet 2008;371(9622):1417-1426. [PMID: 18387667

Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: Risk factors in randomized comparative clinical trials. Clin Infect Dis 2020;71(6):1379-1389. [PMID: 31606734

SMART/INSIGHT, D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008;22(14):f17-24. [PMID: 18753925]

Souza SJ, Luzia LA, Santos SS, et al. Lipid profile of HIV-infected patients in relation to antiretroviral therapy: A review. Rev Assoc Med Bras (1992) 2013;59(2):186-198. [PMID: 23582562

Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010;51(8):963-972. [PMID: 20828304

Surial B, Mugglin C, Calmy A, et al. Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV: A cohort study. Ann Intern Med 2021;174(6):758-767. [PMID: 33721521

Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N Engl J Med 2019;381(9):803-815. [PMID: 31339677

Venter WDF, Sokhela S, Simmons B, et al. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): Week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV 2020;7(10):e666-676. [PMID: 33010240

Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: A case of multiple drug interactions. Clin Infect Dis 2006;42(2):283-290. [PMID: 16355343

ART-Initiation Laboratory Testing

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

Abbreviations used in this section:
Drug names: Other:
  • 3TC: lamivudine
  • ABC: abacavir
  • ATV: atazanavir
  • BIC: bictegravir
  • COBI: cobicistat
  • DOR: doravirine
  • DRV: darunavir
  • DTG: dolutegravir
  • EFV: efavirenz
  • EVG: elvitegravir
  • FTC: emtricitabine
  • RPV: rilpivirine
  • RTV: ritonavir
  • TAF: tenofovir alafenamide
  • TDF: tenofovir disoproxil fumarate
  • TMP-SMX: trimethoprim-sulfamethoxazole
  • ART: antiretroviral therapy
  • ARV: antiretroviral medication
  • CDC: Centers for Disease Control and Prevention
  • CrCl: creatinine clearance
  • FDC: fixed-dose combination
  • HBV: hepatitis B virus
  • HCV: hepatitis C virus
  • INSTI: integrase strand transfer inhibitor
  • NRTI: nucleoside/nucleotide reverse transcriptase inhibitor
  • NNRTI: non-nucleoside reverse transcriptase inhibitor
  • PI: protease inhibitor
  • STR: single-tablet regimen
  • TB: tuberculosis

Baseline CD4 cell count: Some regimens should not be used when the CD4 count is <200 cells/mm3 because of an increased risk of treatment failure (see Table 8, below). When Pneumocystis jiroveci pneumonia prophylaxis is indicated, it may be prudent to defer ART for 7 to 10 days if 2 medications that may cause rash will be started, such as TMP-SMX and EFV.

Baseline HIV genotypic resistance profile: Genotypic resistance testing that includes the protease, reverse transcriptase, and integrase genes should be obtained at diagnosis (or initial visit if not done previously), but ART initiation should not be delayed pending the results [Kuritzkes, et al. 2008; Borroto-Esoda, et al. 2007].

Transmitted integrase resistance was identified in 0.7% of genotypic resistance tests obtained within 3 months of HIV diagnosis from 2013 to2017 in New York State [Wang, et al. 2019]. Similarly, 0.8% of baseline genotypic resistance tests across 23 U.S. jurisdictions of the CDC reported INSTI resistance, which had a higher prevalence (1.6%) in metropolitan areas (population 50,000 to 500,000) [McClung, et al. 2019]. Although INSTI resistance overall remains rare, most experts believe that transmission of INSTI resistance will increase over time, given that this class of ARV has become the preferred therapy for ART initiation (including rapid ART initiation) in all major guidelines.

Consultation with a care provider experienced in ART management is warranted when patients have baseline resistance that requires treatment with a regimen other than the listed preferred or alternative regimens. If treatment is indicated before genotypic resistance testing results are available, NNRTI-based regimens should be avoided because of the higher prevalence of transmitted resistance in NNRTIs than in PIs or INSTIs [Panichsillapakit, et al. 2016; Rhee, et al. 2015; Stekler, et al. 2015]. In the case of, for example, a patient with symptomatic acute HIV or advanced HIV with an opportunistic infection, some experts would include a second-generation INSTI (DTG or BIC or boosted DRV, or both together) with the NRTI backbone, given the possibility of transmitted NRTI resistance, with possible simplification once genotypic information is available.

Baseline viral load: Some regimens should not be used when the HIV RNA level is ≥100,000 copies/mL (see Table 8, below, and comments in the tables of preferred and alternative ART regimens).

Coinfections: Patients should be assessed for chronic HBV, HCV coinfection, and TB. The ART regimen for individuals with chronic HBV should treat both HIV and HBV when possible (see the NYSDOH AI guideline HBV-HIV Coinfection). For those planning concurrent HCV treatment or treatment for active TB, drug-drug interactions will play an important role in the selection of a regimen. The University of Liverpool HEP Drug Interactions Checker is a useful resource for identifying drug-drug interactions.

Creatinine clearance level: Some ARVs are contraindicated below a given CrCl level, and some may need adjustments that require the use of individual elements of an FDC or STR rather than the single-tablet version of the drug (see Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment for more information).

Hepatic profile: Some ARVs require dose adjustment in the presence of impaired liver function; patients with abnormal liver enzyme levels or evidence of decreased synthetic function should be assessed for underlying liver disease (see the Special Considerations for Comorbid Conditions section of this guideline and Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment).

KEY POINTS
  • When initiating ART at the time of HIV diagnosis (“rapid start”), it is not necessary to have the results of baseline laboratory tests immediately available. Laboratory tests, as indicated below, should be ordered at the time of initiation of ART, and any necessary adjustments to therapy should be made as soon as the results are available (such as for renal function or evidence of resistance).
  • ABC-containing regimens should not be used for rapid start without a documented negative HLA-B*5701 test result.

HLA-B*5701 testing: To avoid potentially serious or life-threatening hypersensitivity reactions, HLA-B*5701 testing is mandatory before initiating ART that includes ABC [Mallal, et al. 2008; Saag, et al. 2008].

Initiation of the regimens listed in Table 8, below, is contraindicated based on the listed baseline laboratory parameters.

Table 8: ART Regimens That Are Not Recommended Based on Routine Baseline Laboratory Parameters [a]
Laboratory Parameter ART Regimens That Are Not Recommended
HIV RNA level ≥100,000 copies/mL
  • ABC/3TC and ATV/COBI (Epzicom and Evotaz)
  • ABC/3TC and EFV (Epzicom and Sustiva)
  • ABC/3TC and ATV and RTV (Epzicom and Reyataz and Norvir)
  • TAF/FTC/RPV (Odefsey)
  • TDF/FTC/RPV (Complera)
CD4 count <200 cells/mm3
  • TAF/FTC/RPV (Odefsey)
  • TDF/FTC/RPV (Complera)
CrCl <50 mL/min
  • ABC/3TC (Epzicom)
  • ABC/3TC/DTG (Triumeq)
  • TDF/3TC/DOR (Delstrigo)
  • TDF/FTC/EFV (Atripla)
  • TDF/FTC/RPV (Complera)
CrCl <30 mL/min
  • TAF/FTC (Descovy)
  • TAF/FTC/BIC (Biktarvy)
  • TAF/FTC/DRV/COBI (Symtuza)
  • TAF/FTC/EVG/COBI (Genvoya) [b]
  • TAF/FTC/RPV (Odefsey)
  • TDF/FTC (Truvada)
  • DTG/3TC (Dovato)

Abbreviations: 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BIC, bictegravir; COBI, cobicistat; CrCl, creatinine clearance; DOR, doravirine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Notes:

  1. For renal adjustment of fixed-dose combinations and single-tablet regimens while on therapy, see Table 9: Recommended Dose Adjustments for Use of Selected Fixed-Dose Combination Antiretroviral Medications in Patients With Hepatic or Renal Impairment.
  2. Unless CrCl <15 mL/min and on chronic hemodialysis.
References

Borroto-Esoda K, Waters JM, Bae AS, et al. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses 2007;23(8):988-995. [PMID: 17725415

Kuritzkes DR, Lalama CM, Ribaudo HJ, et al. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis 2008;197(6):867-870. [PMID: 18269317

Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358(6):568-579. [PMID: 18256392]

McClung RP, Ocfemia CB, Saduvala N, et al. Integrase and other transmitted HIV drug resistance: 23 US jurisdictions, 2013-2016. CROI; 2019 Mar 4-7; Seattle, WA. http://www.croiconference.org/sessions/integrase-and-other-transmitted-hiv-drug-resistance-23-us-jurisdictions-2013-2016

Panichsillapakit T, Smith DM, Wertheim JO, et al. Prevalence of transmitted HIV drug resistance among recently infected persons in San Diego, CA 1996-2013. J Acquir Immune Defic Syndr 2016;71(2):228-236. [PMID: 26413846

Rhee SY, Blanco JL, Jordan MR, et al. Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: An individual-patient- and sequence-level meta-analysis. PLoS Med 2015;12(4):e1001810. [PMID: 25849352

Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 2008;46(7):1111-1118. [PMID: 18444831

Stekler JD, McKernan J, Milne R, et al. Lack of resistance to integrase inhibitors among antiretroviral-naive subjects with primary HIV-1 infection, 2007-2013. Antivir Ther 2015;20(1):77-80. [PMID: 24831260

Wang Z, Collura RV, Rosenthal M, et al. Integrase genotypic testing and drug resistance among new HIV diagnoses in New York. CROI; 2019 Mar 4-7; Seattle, WA. http://www.croiconference.org/sessions/integrase-genotypic-testing-and-drug-resistance-among-new-hiv-diagnoses-new-york

ARV Dose Adjustments for Hepatic or Renal Impairment

Lead authors: Nicole Bradley PharmD, BCPS, BCIDP; Yuman Lee, PharmD, BCIDP, AAHIVP; John M. Conry, PharmD, AAHIVP, FNAP; with the Medical Care Criteria Committee; May 2020

Download table PDF

DRUG MANUFACTURER PACKAGE INSERTS

Atripla: FDA. Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets for oral use. 2006. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021937s037lbl.pdf [accessed 2020 Mar 5].

Biktarvy: FDA. Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. 2018 Feb. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf [accessed 2020 Mar 5].

Complera: FDA. Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) tablets, for oral use. 2013 Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202123s003lbl.pdf [accessed 2020 May 14].

Descovy: FDA. Descovy (emtricitabine and tenofovir alafenamide) tablets, for oral use. 2016 Apr. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208215s000lbl.pdf [accessed 2020 Mar 5].

Delstrigo: FDA. Delstrigo (doravirine, lamivudine, and tenofovir disoproxil fumarate) tablets, for oral use. 2018 Aug. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210807s000lbl.pdf [accessed 2020 Mar 5].

Dovato: FDA. Dovato (dolutegravir and lamivudine) tablets, for oral use. 2019 Apr. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211994s000lbl.pdf [accessed 2020 Mar 5].

Epzicom: FDA. Epzicom (abacavir sulfate and lamivudine) tablets for oral use. 2012 Mar. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021652s015lbl.pdf [accessed 2020 Mar 5].

Evotaz: FDA. Evotaz (atazanavir and cobicistat) tablets, for oral use. 2015 Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206353s000lbl.pdf [accessed 2020 May 14].

Genvoya: FDA. Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use. 2015 Nov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207561s000lbl.pdf [accessed 2020 Mar 5].

Isentress: FDA. Isentress (raltegravir) tablets for oral use. 2013 June. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022145s029lbl.pdf [accessed 2020 May 14].

Juluca: FDA. Juluca (dolutegravir and rilpivirine) tablets, for oral use. 2017 Nov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210192s000lbl.pdf [accessed 2020 Mar 5].

Odefsey: FDA. Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) tablets, for oral use. 2016 Mar. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208351s000lbl.pdf [accessed 2020 Mar 5].

Reyataz: FDA. Reyataz (atazanavir) capsules, for oral use. 2016 Sept. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021567s039,206352s004lbl.pdf [accessed 2020 May 14].

Stribild: FDA. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets, for oral use. 2016 Sep. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203100s024lbl.pdf [accessed 2020 Mar 5].

Symfi Lo: FDA. Symfi lo (efavirenz, lamivudine, and tenofovir disoproxil fumarate) tablets, for oral use. 2018 Feb. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208255s000lbl.pdf [accessed 2020 Mar 5].

Symtuza: FDA. Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use. 2018 Jul. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210455s000lbl.pdf [accessed 2020 Mar 5].

Triumeq: FDA. Triumeq (abacavir, dolutegravir, and lamivudine) tablets, for oral use. 2017 Nov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205551s011lbl.pdf [accessed 2020 Mar 5].

Truvada: FDA. Truvada (emtricitabine/tenofovir disoproxil fumarate) tablets, for oral use. 2004. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021752s047lbl.pdf [accessed 2020 Mar 5].

Tivicay: FDA. Tivicay (dolutegravir) tablets, for oral use. 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf [accessed 2020 Apr 13].

References

DHHS. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. 2021 Aug 16. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelines [accessed 2018 May 1]

Eron JJ, Lelievre JD, Kalayjian R, et al. Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial. Lancet HIV 2018;6(1):e15-24. [PMID: 30555051

Fischetti B, Shah K, Taft DR, et al. Real-world experience with higher-than-recommended doses of lamivudine in patients with varying degrees of renal impairment. Open Forum Infect Dis 2018;5(10):ofy225. [PMID: 30302352

German P, Wei X, Mizuno V, et al. Pharmacokinetics of elvitegravir and cobicistat in subjects with severe renal impairment. 13th International Workshop on Clinical Pharmacology of HIV Therapy; 2012 Apr 16-18; Barcelona, Spain. http://www.natap.org/2012/pharm/Pharm_29.htm

Michienzi SM, Schriever CA, Badowski ME. Abacavir/lamivudine/dolutegravir single tablet regimen in patients with human immunodeficiency virus and end-stage renal disease on hemodialysis. Int J STD AIDS 2019;30(2):181-187. [PMID: 30381029

Zhang H, Shao Y, Garner W, et al. The effect of hepatic or renal impairment on bictegravir pharmacokinetics. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy; 2017 Jun 14-17; Chicago, IL. http://www.natap.org/2017/Pharm/Pharm_31.htm

All Recommendations

Reviewed and updated: Antonio E. Urbina, MD, with the Medical Care Criteria Committee; October 2021

ALL RECOMMENDATIONS: SELECTING AN INITIAL ART REGIMEN
Regimen Selection
  • When selecting an initial ART regimen for treatment naive-patients, clinicians should:
    • Perform genotypic HIV resistance testing results for protease (A2), reverse transcriptase (A2), and integrase (B2) genotypic resistance if the testing has not already been performed or results are not otherwise available.
    • Inform patients of the regimen options and engage in shared decision-making to optimize the likelihood of adherence. (A3)
    • Assess for comorbidities and chronic coadministered medications that may affect the choice of regimen for a patient’s initial ART. (A3)
    • Choose a preferred ART regimen unless one of the alternative regimens is a better choice based on individual patient factors. (A1)
    • Recommend a single-tablet regimen or a regimen with once-daily dosing unless those regimens are contraindicated by HIV resistance, drug-drug interactions, intolerance, allergy, or access. (A2)
    • Ask patients about their reproductive plans [a] and discuss the use of contraception. (A3)
  • With the exception of dolutegravir/lamivudine (DTG/3TC), clinicians should not prescribe 2-drug regimens as initial ART. (A3) Clinicians should prescribe DTG/3TC only after:
    • HIV resistance and hepatitis B virus (HBV) status are known. (A1)
    • Genotypic resistance testing results have confirmed that a patient does not have a major reverse transcriptase mutation, including the M184V/I resistance mutation. DTG/3TC is contraindicated in patients with these resistance-associated mutations. (A1)
Expert Consultation
  • Clinicians should consult with an experienced HIV care provider when selecting an initial ART regimen for a patient who has:
    • Baseline genotypic testing results indicating the need for an ART regimen other than the available preferred or alternative regimens. (A3)
    • Extensive comorbidities, including metabolic complications and obesity; comedications; impaired renal function; HBV or hepatitis C virus coinfection; or active opportunistic infections. (B3)
      • The NYSDOH Clinical Education Initiative (CEI) provides access to HIV specialists through their toll-free CEI Line: 1-866-637-2342.
Follow-up
  • Clinicians or clinical support staff should follow up by telephone or other methods, preferably within 2 weeks after treatment initiation, to assess tolerance and adherence; adherence should be reinforced at regular intervals. (A3)
  • Clinicians should obtain a viral load test within 4 weeks after ART initiation to assess initial response to therapy. (A3)

——–

[a] Refer to the DHHS guideline in choosing an initial ART regimen for a patient who is pregnant or planning a pregnancy: Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States.

Guideline Updates, Development, and Ratings

Guideline Information
Developer and Funding Source

New York State Department of Health AIDS Institute (NYSDOH AI)

Intended Users

NYS clinicians who are initiating therapy in nonpregnant, ART-naive adults with HIV

Development

See Guideline Development and Recommendation Ratings Scheme, below.

Updates

October 8, 2021; MCCC with Antonio E. Urbina, MD

  • New recommendation regarding 2-drug initial ART: With the exception of dolutegravir/lamivudine (DTG/3TC), clinicians should not prescribe 2-drug regimens as initial ART. (A3) Clinicians should prescribe DTG/3TC only after:
    • HIV resistance and hepatitis B virus (HBV) status are known. (A1)
    • Genotypic resistance testing results have confirmed that a patient does not have a major reverse transcriptase mutation, including the M184V/I resistance mutation. DTG/3TC is contraindicated in patients with these resistance-associated mutations. (A1)
  • TDF vs. TAF: The MCCC now recommends either formulation of tenofovir (TAF or TDF) as part of the backbone for preferred initiation ART regimens. See the new table: Important Clinical Considerations With Either TDF/FTC or TAF/FTC as Initial Antiretroviral Therapy.
  • Changes to the table of preferred initial ART regimens:
    •  Added: Dolutegravir/lamivudine (DTG/3TC; Dovato)
    • Deleted:
      • TAF 25 mg/FTC + DTG (Descovy + Tivicay)
      • TAF 25 mg/FTC + RAL HD (Descovy + Isentress HD)
      • TDF/FTC + DTG (Truvada + Tivicay)
      • TDF/FTC + RAL HD (Truvada + Isentress HD)

January 2019

Boosted TDF-containing Regimens No Longer Recommended

Available ART Regimens

  • Moved from Table 1 (Preferred Initial ART Regimens) to Table 2 (Alternative initial ART Regimens): Tenofovir alafenamide fumarate 10 mg/emtricitabine/cobicistat/elvitegravir (TAF 10 mg/FTC/COBI/EVG; Genvoya)
  • The following comments were added throughout Tables 1 (Preferred Initial ART Regimens for Nonpregnant Adults), 2 (Alternative Initial ART Regimens for Nonpregnant Adults), and 3 (Other ART Regimens Not Included as Preferred or Alternative for Nonpregnant Adults):
    • For regimens containing dolutegravir and bictegravir: Take magnesium- or aluminum-containing antacids 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food.
    • For regimens containing RAL HD: Magnesium- or aluminum-containing antacids are contraindicated; co-administration of calcium-containing antacids is not recommended with RAL HD.
    • For regimens containing EVG: Separate dosing of antacids by 2 hours, either before or after dose of EVG.
    • For regimens containing RPV: When a “rapid-start” or “test-and-treat” initiation of ART occurs before a patient’s viral load and CD4 count are available, avoid use of RPV.
    • For regimens containing RAL: Magnesium- or aluminum-containing antacids are contraindicated; calcium-containing antacids are acceptable with RAL.
    • For ABC/3TC and ATV and RTV:
      • In treatment-naive patients on boosted ATV, H2-blockers should be either taken simultaneously with ATV or, if simultaneous dosing is not possible, separated from ATV by 10 hours; prescribe no more than 20 mg of famotidine or equivalent for one dose and no more than 40 mg twice daily of famotidine or equivalent for daily dose.
      • Use no more than equivalent of 20 mg of omeprazole with ATV, separated by 12 hours.
  • Added to Table 2 (Alternative Initial ART Regimens for Nonpregnant Adults) and additional tables throughout the rest of the guideline:
    • Tenofovir alafenamide fumarate 10 mg/emtricitabine/cobicistat/darunavir (TAF 10 mg/FTC/COBI/DRV; Symtuza)
    • Tenofovir disoproxil fumarate/lamivudine/doravirine (TDF/3TC/DOR; Delstrigo)
    • Abacavir/lamivudine and doravirine (ABC/3TC and DOR; Epzicom and Pifeltro)
    • Tenofovir alafenamide 25 mg/emtricitabine and doravirine (TAF 25 mg/FTC and DOR; Descovy and Pifeltro)

General Principles in Choosing an Initial ART Regimen

  • New citation: In 2 separate trials of treatment-naive individuals, TDF/3TC/doravirine (DOR) was non-inferior to TDF/FTC/EFV, or RTV-boosted DRV with either TDF/FTC or ABC/3TC [Molina, et al. 2018; Orkin, et al. 2018].

Specific Factors to Consider and Discuss with Patients

  • Addition to Table 5 (Select Drug-Drug Interactions to Discuss before Initiating ART in Treatment-Naive Patients): If [Metformin is] used concomitantly, total daily dose of metformin should not exceed 1,000 mg without clinical evaluation of efficacy and adverse events.

ART-Initiation Laboratory Testing

  • Key Point added: When initiating therapy at the time of diagnosis (“rapid start”) it is not necessary to have the results of baseline laboratory tests immediately available. Labs, as indicated below, should be ordered at the time of initiation of antiretroviral therapy (ART), and any necessary adjustments to therapy should be made as soon as the results are available (such as for renal function or evidence of resistance). Abacavir (ABC)-containing regimens should not be used for rapid start without documentation of negative HLA-B*5701 testing.
  • Footnote added to Table 7 (Contraindicated ART Regimens Based on Routine Baseline [a] Laboratory Parameters): TAF/FTV/COBI/EVG is contraindicated for patients with CrCl <30 mL/min unless the patient’s CrCl is <15 mL/min and the patient is on chronic hemodialysis.

June 2018

Available Antiretroviral Agents: Single-Tablet Regimens versus Multi-Tablet Regimens

  • Bictegravir (BIC; Biktarvy) added as a preferred initial ART regimen for patients with CrCl >30 mL/min, with related updates throughout all sections of the guideline.
  • New footnote (6) added to all regimen tables: “When a ‘rapid start’ or ‘test and treat’ initiation of ART occurs before baseline laboratory test results are available, avoid use of abacavir until a patient’s HLA-B*5701 is confirmed negative.”

General Principles in Choosing an Initial ART Regimen

  • New citations of evidence added to general conclusions that can be drawn based on currently available evidence: 1) “In a study of ART-naïve patients RAL HD 1200 mg once daily was non-inferior to 400 mg tablets dosed twice daily [Cahn et al. 2017]”; and 2) “In two separate trials of treatment-naïve individuals, TAF/FTC/BIC was non-inferior to both TAF/FTC and DTG [Sax et al. 2017] and ABC/3TC/DTG [Gallant J et al. 2017].”

 May 2018

Changes made in the Available ART Regimens section in May 2018 are described below.

Added the following note at the beginning of the section:

Revised the sixth recommendation:

Table 1: Preferred Initial ART Regimens for Non-Pregnant Adults:

Table 2: Alternative Initial ART Regimens for Non-Pregnant Adults:

Table 3: Other ART Regimens That Are Not Preferred or Alternative for Non-Pregnant Adults:

 November 2017

Changes made in the Available ART Regimens section in November 2017 are described below.

Revisions:

  • Revised the fifth recommendation to add active opportunistic infections to the list of extensive comorbidities that should prompt consultation with a care provider experienced in ART management when selecting an initial ART regimen. 
  • Revised text to state that with full adherence, any of the preferred or alternative regimens should lead to full suppression, including MTRs, which can be used when an STR is not possible or not tolerated. For example, a patient who is HLA-B*5701 positive on medications that have significant drug interactions with cobicistat and who did not tolerate DTG could use TAF/FTC with RAL.
  • Added reference Cahn P, Kaplan R, Sax PE, et al. 2017.

Table 1: Preferred Initial ART Regimens for Non-Pregnant Adults

  • Added the regimen “Tenofovir alafenamide/emtricitabine and raltegravir (TAF 25 mg/FTC and RAL HD; Descovy and Isentress HD)” to the “Available as Multi-Tablet Regimens with Once-Daily Dosing” section of table 1.
  • Added footnote 5: “When dosing RAL once daily use the HD formulation of 600 mg tablets dosed at 1200 mg.” 

Table 2: Alternative Initial ART Regimens for Non-Pregnant Adults

  • Moved the regimen “Tenofovir disoproxil fumarate/emtricitabine and raltegravir (TDF/FTC and RAL HD; Truvada and Isentress HD)” to the “Available as Multi-Tablet Regimen with Once-Daily Dosing” section of table 2. 
  • The rating was changed from a BI to BIII for the regimen “Tenofovir alafenamide/emtricitabine and raltegravir (TAF 25 mg/FTC and RAL; Descovy and Isentress)” in the “Available as Multi-Tablet Regimen with Twice-Daily Dosing” section of table 2.
  • Added footnote 5: “For once-daily dosing of RAL, use the HD formulation dosed at 1200 mg (2 x 600 mg tablets).”

Table 3: Other ART Regimens That Are Not Preferred or Alternative for Non-Pregnant Adults:

  • Moved the regimen “Abacavir/lamivudine and raltegravir (ABC/3TC and RAL HD; Epzicom and Isentress HD)” to the “Available as Multi-Tablet Regimen with Once-Daily Dosing” section of table 3.
  • Added footnote 5: “For once-daily dosing of RAL, use the HD formulation dosed at 1200 mg (2 x 600 mg tablets).”
Guideline Development: New York State Department of Health AIDS Institute Clinical Guidelines Program
Developer New York State Department of Health AIDS Institute (NYS DOH AI) Clinical Guidelines Program
Funding Source NYSDOH AI
Program Manager

Clinical Guidelines Program, Johns Hopkins University School of Medicine, Division of Infectious Diseases. See Program Leadership and Staff.

Mission To produce and disseminate evidence-based, state-of-the-art clinical practice guidelines that establish uniform standards of care for practitioners who provide prevention or treatment of HIV, viral hepatitis, other sexually transmitted infections, and substance use disorders for adults throughout New York State in the wide array of settings in which those services are delivered.
Expert Committees

The NYSDOH AI Medical Director invites and appoints committees of clinical and public health experts from throughout NYS to ensure that the guidelines are practical, immediately applicable, and meet the needs of care providers and stakeholders in all major regions of NYS, all relevant clinical practice settings, key NYS agencies, and community service organizations.

Committee Structure
  • Leadership: AI-appointed chair, vice chair(s), chair emeritus, clinical specialist(s), JHU Guidelines Program Director, AI Medical Director, AI Clinical Consultant, AVAC community advisor
  • Contributing members
  • Guideline writing groups: Lead author, coauthors if applicable, and all committee leaders
Conflicts of Interest Disclosure and Management
  • Annual disclosure of financial relationships with commercial entities for the 12 months prior and upcoming is required of all individuals who work with the guidelines program, and includes disclosure for partners or spouses and primary professional affiliation.
  • The NYSDOH AI assesses all reported financial relationships to determine the potential for undue influence on guideline recommendations and, when indicated, denies participation in the program or formulates a plan to manage potential conflicts.
  • Disclosures are listed for each committee member.
Evidence Collection and Review
  • Literature search and review strategy is defined by the guideline lead author based on the defined scope of a new guideline or update.
  • A comprehensive literature search and review is conducted for a new guideline or an extensive update using PubMed, other pertinent databases of peer-reviewed literature, and relevant conference abstracts to establish the evidence base for guideline recommendations.
  • A targeted search and review to identify recently published evidence is conducted for guidelines published within the previous 3 years.
  • Title, abstract, and article reviews are performed by the lead author. The JHU editorial team collates evidence and creates and maintains an evidence table for each guideline.
Recommendation Development
  • The lead author drafts recommendations to address the defined scope of the guideline based on available published data.
  • Writing group members review the draft recommendations and evidence and deliberate to revise, refine, and reach consensus on all recommendations.
  • When published data are not available, support for a recommendation may be based on the committee’s expert opinion.
  • The writing group assigns a 2-part rating to each recommendation to indicate the strength of the recommendation and quality of the supporting evidence. The group reviews the evidence, deliberates, and may revise recommendations when required to reach consensus. 
Review and Approval Process
  • Following writing group approval, draft guidelines are reviewed by all contributors, program liaisons, and a volunteer reviewer from the AI Community Advisory Committee.
  • Recommendations must be approved by two-thirds of the full committee. If necessary to achieve consensus, the full committee is invited to deliberate, review the evidence, and revise recommendations when required.
  • Final approval by the committee chair and the NYSDOH AI Medical Director is required for publication.
External Reviewers
  • External peer reviewers recognized for their experience and expertise review guidelines for accuracy, balance, clarity, and practicality and provide feedback.
  • Peer reviewers may include nationally known experts from outside of New York State.
Update Process
  • JHU editorial staff ensure that each guideline is reviewed and determined to be current upon the 3-year anniversary of publication; guidelines that provide clinical recommendations in rapidly changing areas of practice may be reviewed annually. Published literature is surveilled to identify new evidence that may prompt changes to existing recommendations or development of new recommendations.
  • If changes in the standard of care, newly published studies, new drug approval, new drug-related warning, or a public health emergency indicate the need for immediate change to published guidelines, committee leadership will make recommendations and immediate updates.
  • All contributing committee members review and approve substantive changes to, additions to, or deletions of recommendations; JHU editorial staff track, summarize, and publish ongoing guideline changes.
Recommendation Ratings Scheme
Strength Quality of Evidence
Rating Definition Rating Definition
A Strong 1 Based on published results of at least 1 randomized clinical trial with clinical outcomes or validated laboratory endpoints.
B Moderate * Based on either a self-evident conclusion; conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.
C Optional 2 Based on published results of at least 1 well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.
  2† Extrapolated from published results of well-designed studies (including nonrandomized clinical trials) conducted in populations other than those specifically addressed by a recommendation. The source(s) of the extrapolated evidence and the rationale for the extrapolation are provided in the guideline text. One example would be results of studies conducted predominantly in a subpopulation (e.g., one gender) that the committee determines to be generalizable to the population under consideration in the guideline.
3 Based on committee expert opinion, with rationale provided in the guideline text.