ADULT HIV CARE

Selecting an Initial ART Regimen

Medical Care Criteria Committee, April 2017

Introduction: The New York State (NYS) Department of Health (DOH) AIDS Institute (AI) Medical Care Criteria Committee (MCCC) recommendations for prescribing antiretroviral therapy (ART) regimens for treatment-naïve, nonpregnant adults with HIV-1 infection and without acquired resistance are based on a comprehensive review of available clinical trial data. In formulating its recommendations for New York State, 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 patients to manage. Ranking of regimens in this manner is designed to inform discussion and decision-making with patients. For a comparison of recommended initial regimens from key guidelines (NYSDOH AI, U.S. Department of Health and Human Services [1], and the International Antiviral Society-USA [2]), see Table 1, below. 

How to use this guideline: Tables presenting preferred and alternative regimens appear first (see this guideline’s section on Available ART Regimens, 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 (TDF) and the conflicting data on cardiac risk with abacavir (ABC); see Specific Factors to Consider and Discuss with Patients.

Scope: This guideline addresses initial treatment of HIV-1 infection with ART in nonpregnant adults. For information regarding ART in pregnant women and women who may become pregnant, please refer to the DHHS guideline, Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States [3]. Please refer to the NYSDOH AI guideline on HIV-2 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 [4].

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

 

Table 1. Comparison of Recommendations for Preferred Initial ART Regimens [a]
 ART Regimen NYSDOH AI Rating DHHS [b] IAS-USA [c]

Abacavir/Lamivudine/Dolutegravir (ABC/3TC/DTG)

AI

AI

 AIa
Tenofovir Alafenamide/Emtricitabine/

Cobicistat/Elvitegravir (TAF/FTC/COBI/EVG)

AI

AI (with TAF or TDF)

AIa
Tenofovir Alafenamide/
Emtricitabine plus Dolutegravir
(TAF/FTC plus DTG)

AIII

AII (with TAF)

AI (with TDF)

AIa
Tenofovir Alafenamide/Emtricitabine plus Raltegravir
(TAF/FTC plus RAL)

AIII

AII (with TAF)

AI (with TDF)

AIII
Darunavir/Ritonavir plus either Tenofovir Disoproxil Fumarate/Emtricitabine or Tenofovir Alafenamide/Emtricitabine
(DRV and RTV plus either TDF/FTC)

AII (with TAF)

AI (with TDF) 

3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; RAL, raltegravir; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir alafenamide.

  1. The DHHS panel has expanded the definition of evidence rating II to include supporting data from bioavailability/bioequivalence studies or randomized switch studies, and includes TDF-based regimens as well as ritonavir-boosted darunavir with TDF/FTC or TAF/FTC as preferred.  The IAS panel rates TAF/FTC plus DTG as AIa.
  2. Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel. JAMA 2016;316:191-210. [PMID: 27404187]
  3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. 2016 Jul 14; http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 4/22/2017.
References:
  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2016 Jul 14. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/. Accessed on April 22, 2017.
  2. Gunthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA 2016;316(2):191-210. [PMID: 27404187]
  3. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. 2016 Oct 26. https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0. Accessed on April 22, 2017.
  4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Management of the Treatment-Experienced Patient: Regimen Switching in the Setting of Virologic Suppression. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2017 Jan 16. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/16/regimen-switching-in-the-setting-of-virologic-suppression. Accessed on April 22, 2017.

Available ART Regimens

Medical Care Criteria Committee, April 2017                                            Print a Pocket Guide

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

RECOMMENDATIONS
  • Clinicians should involve their patients when deciding which ART regimen is most likely to result in patient adherence (AIII).
  • Clinicians should perform the following when initiating ART:
    • Assessment for comorbidities that may affect the choice of regimen for initial therapy (AIII).
    • Genotypic resistance testing for the protease and reverse transcriptase genes at diagnosis or at the initial visit if not done previously (AII). See the guideline section on Specific Factors to Consider and Discuss with Patients.
  • Baseline testing is not recommended for either integrase resistance or tropism (AIII).
  • For patients who have delayed initiation of ART and have engaged in high-risk behaviors associated with acquisition of HIV superinfection, genotypic resistance testing should be repeated before choosing the ART regimen (BIII).
  • Clinicians should consult with a care provider experienced in ART management when:
    • Baseline resistance requires treatment with a regimen other than the listed preferred or alternative regimens (AIII).
    • Selecting a regimen for patients with extensive comorbidities (BIII), impaired renal function (BIII), HBV or HCV co-infections (BIII), or very high viral loads (BIII).
  • Clinicians should:
  • A single-tablet regimen or regimen with once-daily dosing is preferred unless contraindicated by drug-drug interactions, intolerance, allergy, or access (AII). 
  • For ART-naïve patients, clinicians should (AI):
    • ­­Select an initial ART regimen that is preferred; see Table 2, Preferred Initial ART regimens, below.
    • Select an alternative or other regimen only when a preferred initial regimen cannot be used; see Table 3, Alternative Initial ART Regimens, below, or Table 3, below, for Other ART Regimens, Not Preferred or Alternative. 
  • Two-drug regimens are not recommended as initial therapy (AII).
  • Clinicians or clinical staff should follow up, by telephone or other methods, within 2 weeks after treatment initiation to assess tolerance and adherence. Adherence should be reinforced at regular intervals (AIII).
  • Clinicians should obtain a viral load test within 4 weeks after initiation to assess response to therapy (AIII); see the NYSDOH AI guideline Virologic and Immunologic Monitoring for more information.

Available Antiretroviral Agents and Regimens

KEY POINT
  • In general, a preferred regimen should be selected (Table 2, below), although there may be times when an alternative regimen may be a better choice for an individual patient (Table 3, below).

Each regimen listed below in Tables 2 and 3, preferred and alternative initial ART regimens, and in Table 4, Other ART Regimens, Not Preferred or Alternative, is expected to have excellent efficacy, but they differ in tolerability, possible toxicities, convenience, and the potential for drug-drug interactions, all of which can affect overall adherence and suppression rates.

Based on renal and bone mineral density data from randomized trials of tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir (TAF/FTC/COBI/EVG) versus tenofovir disoproxil fumarate/emtricitabine/cobicistat/elvitegravir (TDF/FTC/COBI/EVG) in ART-naïve patients or previously suppressed patients on TDF/FTC/COBI/EVG [1-3], this Committee recommends TAF over TDF as part of the backbone in preferred regimens. These data, combined with bioequivalence and switch studies [4,5], provide support for the use of TAF/FTC rather than TDF/FTC when combined with dolutegravir (DTG) or raltegravir (RAL) as part of a preferred regimen. This Committee does not yet recommend TAF/FTC in combination with boosted protease inhibitors (PIs), as noted below (see the guideline section on Specific Factors to Consider and Discuss with Patients). TDF-containing regimens remain safe and efficacious as alternative regimens (Table 3, below). An integrase strand transfer inhibitor (INSTI) as the third drug is preferred over PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) based on tolerability and a lower incidence of drug-drug interactions. Because the use of tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV) is limited by viral load and CD4 parameters and is contraindicated with proton-pump inhibitors (PPIs), this regimen is listed as an alternative regimen (Table 3, below).

Efavirenz (EFV)-containing regimens (see Table 4, below), although efficacious, have been shown to be less well-tolerated than the preferred or alternative regimens in Tables 2 and 3, below. Lopinavir/ritonavir (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.

Initial regimens should be selected on the basis of patient preferences and clinical characteristics, and a preferred regimen should be used whenever possible (Table 2, below). Regimens in the tables below are listed alphabetically. (For more information, including drug trade names, see all FDA-Approved HIV Medications.)

Single-Tablet Regimens versus Multi-Tablet Regimens

The advantages of single-tablet regimens (STR) compared with multi-tablet regimens (MTR) include simplicity, convenience, and lower chance of selective non-adherence [6]. A recent meta-analysis demonstrated that STR regimens had better adherence rates when compared with MTRs of any frequency (daily or twice daily) and had higher 48-week viral suppression rates with comparable side effects [7]. 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-based INSTI therapy was more durable [8]. In the same study, STR for NNRTI-based therapy led to greater rates of suppression than MTR NNRTI therapy [8]. Other studies have demonstrated better efficacy and adherence, lower costs to patients, and fewer hospital admissions associated with single-tablet regimens [8-18]. Another study examined once-daily dosing of LPV/RTV and found better adherence than with twice-daily dosing [19].

However, as preferred regimens, the choice of STR is limited to two, ABC/3TC/DTG and TAF/FTC/COBI/EVG, and these regimens may contain one or more components that are not appropriate for the individual patient, do not allow for adjustment of individual components for renal function, and 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, including MTRs dosed twice daily, which can be used when an STR or once-daily dosing 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 might do well on TAF/FTC with RAL dosed twice daily. Similarly, if cobicistat and abacavir need to be avoided, but DTG is an option, the MTR TAF/FTC with DTG once daily is a good preferred option. 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. For more detailed instructions on dosage adjustments for impaired renal function, see Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment.

Table 2, below, 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 (listed on the left) and/or the package insert for the drugs listed below.

Table 2: Preferred Initial ART Regimens for Non-Pregnant Adults
(listed alphabetically; for specific details, see Specific Factors to Consider or drug package inserts)
 Regimen Comments  Rating
Available as a Single-Tablet Formulation   
Abacavir/lamivudine/dolutegravir
(ABC/3TC/DTG)
  • Initiate only in patients with CrCl ≥50 mL/min
  • Initiate only in patients negative for HLA-B*5701
  • Consider underlying risk of coronary heart disease
  • To date, there has been no documented DTG resistance after initiation in treatment-naïve patients
 AI
Tenofovir alafenamide/emtricitabine/
cobicistat/elvitegravir
(TAF 10 mg/FTC/COBI/EVG)
  • Initiate only in patients with CrCl ≥30 mL/min
  • Carefully consider drug-drug interactions with COBI
  • Contains 10 mg of TAF, boosted with COBI
 AI
Available as Multi-Tablet Regimen with Once-Daily Dosing
Tenofovir alafenamide/emtricitabine and dolutegravir

(TAF 25 mg/FTC and DTG)

  • Initiate only in patients with CrCl ≥30 mL/min
  • To date, there has been no documented DTG resistance after initiation in treatment-naïve patients
  • To date, no clinical trials have been conducted; data are based on bioequivalence pharmacokinetic studies
  • Contains 25 mg of TAF, unboosted
 AIII
Available as Multi-Tablet Regimen Twice-Daily Dosing
Tenofovir alafenamide/emtricitabine and raltegravir

(TAF 25 mg/FTC and RAL)

  • Initiate only in patients with CrCl ≥30 mL/min
  • To date, no clinical trials have been conducted; data are based on bioequivalence pharmacokinetic studies
  • Contains 25 mg of TAF, unboosted
  • TAF/FTC once daily and RAL twice daily
 AIII

Notes: 1) In all cases, FTC and 3TC are interchangeable when not being used in fixed-dose combinations; 2) because of their drug-interaction profiles, COBI and RTV should not be considered interchangeable; 3) TAF 10 mg and TAF 25 mg are not interchangeable; 4) refer to Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment for adjustment based on renal or hepatic function.

 

Table 3: Alternative Initial ART Regimens for Non-Pregnant Adults
(listed alphabetically; for specific details, see Specific Factors to Consider or drug package inserts)
 Regimen Comments Rating
Available as a Single-Tablet Formulation  

Tenofovir alafenamide/emtricitabine/rilpivirine
(TAF 25 mg/FTC/RPV)

  • Initiate only in patients with CrCl of ≥30 mL/min
  • Initiate only in patients with CD4 cell count ≥200 cells/mm3 and viral load <100,000 copies/mL
  • 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
  • Contraindicated with PPIs
  • Use H2-blockers with caution and separate dosing by 12 hours
  • Must take with food
  • Contains 25 mg of TAF, unboosted
 BIII
Tenofovir disoproxil fumarate/emtricitabine/ cobicistat/elvitegravir
(TDF/FTC/COBI/EVG)
  • Initiate only in patients with CrCl ≥70 mL/min
  • Carefully consider drug-drug interactions with COBI
  • Consider bone mineral density
 BI
Available as Multi-Tablet Regimen with Once-Daily Dosing
Tenofovir disoproxil fumarate/emtricitabine and darunavir/cobicistat
(TDF/FTC and DRV/COBI)
  • Initiate only in patients with CrCl ≥70 mL/min
  • Carefully consider drug-drug interactions with COBI
  • Consider bone mineral density 
 BII
Tenofovir disoproxil fumarate/emtricitabine and darunavir and ritonavir
(TDF/FTC and DRV and RTV)
  • Initiate only in patients with CrCl ≥50 mL/min
  • Carefully consider drug-drug interactions with RTV
  • Consider bone mineral density
 BI
Tenofovir disoproxil fumarate/emtricitabine and dolutegravir
(TDF/FTC and DTG)
  • Initiate only in patients with CrCl ≥50 mL/min
  • To date, there has been no documented DTG resistance after initiation in treatment-naïve patients
  • Consider bone mineral density
 BI
Available as Multi-Tablet Regimen with Twice-Daily Dosing   

Tenofovir disoproxil fumarate/emtricitabine and raltegravir
(TDF/FTC and RAL)

  • Initiate only in patients with CrCl ≥50 mL/min
  • Consider bone mineral density
  • TDF/FTC once daily and RAL twice daily
BI
Notes: 1) In all cases, FTC and 3TC are interchangeable when not being used in fixed-dose combinations; 2) because of their drug-interaction profiles, COBI and RTV should not be considered interchangeable; 3) TAF 10 mg and TAF 25 mg are not interchangeable; 4) refer to Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment for adjustment based on renal or hepatic function.
 
Table 4. Other ART Regimens That Are Not Preferred or Alternative for Non-Pregnant Adults
(listed alphabetically; for specific details, see Specific Factors to Consider or drug package inserts)
Regimen Comments  Rating
Available as Single-Tablet Regimen
Tenofovir disoproxil fumarate/
emtricitabine/efavirenz
(TDF/FTC/EFV)
  • Initiate only in patients with CrCl ≥50 mL/min
  • Use with caution in patients with depression or a history of suicidality
  • Consider bone mineral density
BI
Tenofovir disoproxil fumarate/
emtricitabine/rilpivirine
(TDF/FTC/RPV)
  • Initiate only in patients with CrCl ≥50 mL/min and CD4 cell count ≥200 cells/mm3 and viral load <100,000 copies/mL
  • 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
BI
Available as Multi-Tablet Regimen with Once-Daily Dosing
Abacavir/lamivudine and atazanavir and ritonavir
(ABC/3TC and ATV and RTV)
  • Initiate only in patients with viral load <100,000 copies/mL
  • Initiate only in patients negative for HLA-B*5701
  • Carefully consider drug-drug interactions with RTV
  • Consider underlying risk of coronary heart disease
  • Scleral icterus from benign hyperbilirubinemia may be a patient concern
CI
Abacavir/lamivudine and darunavir/cobicistat
(ABC/3TC and DRV/COBI)
  • Initiate only in patients negative for HLA-B*5701
  • Carefully consider drug-drug interactions with COBI
  • Consider underlying risk of coronary heart disease
BIII
Abacavir/lamivudine and darunavir and ritonavir
(ABC/3TC and DRV and RTV)
  • Initiate only in patients negative for HLA-B*5701
  • Carefully consider drug-drug interactions with RTV
  • Consider underlying risk of coronary heart disease
BII
Abacavir/lamivudine and efavirenz
(ABC/3TC and EFV)
  • Initiate only in patients with viral load <100,000 copies/mL
  • Use with caution in patients with depression or a history of suicidality
  • Initiate only in patients negative for HLA-B*5701
  • Consider underlying risk of coronary heart disease
CI
Tenofovir alafenamide/emtricitabine and efavirenz
(TAF 25 mg/FTC and EFV)
  • Initiate only in patients with CrCl ≥50 mL/min
  • Use with caution in patients with depression or a history of suicidality
  • Consider bone mineral density
  • Contains 25 mg of TAF, unboosted
BIII
Tenofovir disoproxil fumarate/emtricitabine and atazanavir/cobicistat
(TDF/FTC and ATV/COBI)
  • Initiate only in patients with CrCl ≥70 mL/min
  • Scleral icterus from benign hyperbilirubinemia may be a patient concern
  • Carefully consider drug-drug interactions with COBI
  • Consider bone mineral density
BI
Tenofovir disoproxil fumarate/
emtricitabine and atazanavir and ritonavir
(TDF/FTC and ATV and RTV)
  • Initiate only in patients with CrCl ≥50 mL/min
  • Scleral icterus from benign hyperbilirubinemia may be a patient concern
  • Carefully consider drug-drug interactions with RTV
  • Consider bone mineral density
BI
Available as Multi-Tablet Regimen with Twice-Daily Dosing

Abacavir/lamivudine and raltegravir
(ABC/3TC and RAL)

  • Initiate only in patients negative for HLA-B*5701
  • Consider underlying risk of coronary heart disease
  • ABC/3TC once daily, RAL twice daily
BI
Notes: 1) In all cases, FTC and 3TC are interchangeable when not being used in FDCs; 2) because of their drug-interaction profiles, COBI and RTV should not be considered interchangeable; 3) TAF 10 mg and TAF 25 mg are not interchangeable; 4) refer to Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment for adjustment based on renal or hepatic function
References:
  1. 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):2606-15. [PMID: 25890673]
  2. 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]
  3. 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):530-7. [PMID: 26627107]
  4. Zack J, Chu H, Chuck S, Rhee M, Koziara J, et al. (2016) Bioequivalence of Two Co-formulations of Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combinations with 200/10 mg and 200/25 mg. J Bioequiv Availab 8:068-073. doi:10.4172/jbb.1000270.
  5. Zack J, Chuck S, Chu H, Graham H, Cao H, et al (2016) Bioequivalence of the Rilpivirine/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen. J Bioequiv Availab 8:049-054. doi:10.4172/jbb.1000266.
  6. 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]
  7. 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]
  8. 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/The-Impact-of-Antiretroviral-Tablet-Burden-and. Accessed May 1, 2017.
  9. 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]
  10. 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]
  11. 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):587-96. [PMID: 24326606]
  12. 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). [PMID: 23906955]
  13. Raboud J, Li M, Walmsley S, et al. Once daily dosing improves adherence to antiretroviral therapy. AIDS Behav 2011;15(7):1397-409. [PMID: 20878227]
  14. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007;120(8):713-9. [PMID: 17679131]
  15. 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]
  16. 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]
  17. 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; 2016 Oct 26-30; New Orleans, LA. https://idsa.confex.com/idsa/2016/webprogram/Paper58740.html. Accessed May 1, 2017.
  18. 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):1297-307. [PMID: 24457345]
  19. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses 2007;23(12):1505-14. [PMID: 18160008]

General Principles in Choosing an Initial ART Regimen

Medical Care Criteria Committee, April 2017

Goals of ART: The issue of when to start ART was settled with the publication of the START (Strategic Timing of Antiretroviral Treatment) and TEMPRANO (Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis Against Tuberculosis in HIV-infected Adults) studies early in 2015 [1,2]. Treatment is now recommended for all patients with confirmed HIV infection regardless of CD4 cell count or viral load (see the NYSDOH guideline When to Initiate ART). 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 [3].

Since the approval of zidovudine (ZDV) on March 19, 1987, there have been 26 individual agents approved for the treatment of HIV and one pharmacokinetic enhancer (or booster), cobicistat (COBI), which is currently used to enhance the pharmacokinetics of elvitegravir (EVG), atazanavir (ATV), or darunavir (DRV). Ritonavir (RTV) at treatment doses is poorly tolerated and is used only at lower doses for pharmacokinetic boosting of PIs. An additional 14 FDA-approved fixed-dose combination tablets (FDCs) are also available. These FDCs include so-called single-tablet regimens, of which there are six currently available that provide a complete and effective treatment regimen for HIV that is combined into one pill for use in properly selected individuals. The goal of initial therapy is to start a regimen that suits a patient’s lifestyle and is appropriate given existing baseline medical comorbidities.

Three active drugs from at least two different classes: Although regimen options for treatment-naïve, nonpregnant patients are constantly evolving, the same general principles that were established with the first effective and durable therapies are still true today [4]. Patients should receive three active drugs from at least two different classes. The “backbone” of therapy remains two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) paired with one of the following: an NNRTI, a boosted PI, or a boosted or unboosted INSTI. In one large meta-analysis, INSTIs, also knows as integrase inhibitors, were superior to other drug classes as a third drug [5], and dolutegravir (DTG) may have specific advantages because of the lack, to date, of documented resistance developing in ART-naïve patients who initiate DTG-containing regimens [6]. Two other classes of approved medications, entry inhibitors and fusion inhibitors, are not recommended for initial therapy (see Table 5, below) but may have a role in treatment-experienced patients with extensive drug resistance (see All FDA-Approved Medications, including generic and trade names). 

 

KEY POINT
  • Although dual or even monotherapy regimens have been and continue to be studied [7-13], they cannot be recommended currently as initial therapy until more data are available. Existing studies show limitations with these regimens in ART-naïve individuals based on pill burden, toxicities, and efficacy, particularly in patients with viral loads >100,000 or CD4 counts <200 cells/mm3, compared with recommended therapy.

TAF, which is a newer pro-drug formulation for tenofovir, was developed as an alternative to TDF and has been approved as part of two single-tablet regimens, TAF 10 mg/FTC/COBI/EVG and TAF 25 mg/FTC/RPV [14,15], and the fixed-dose combination TAF 25 mg/FTC [16]. 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 [17-19]. 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 [20,21]. A switch study showed good maintenance of viral suppression when changing TDF/FTC to TAF 10 mg/FTC if the third drug was a boosted PI or TAF 25 mg/FTC if the third drug was an unboosted NNRTI or INSTI [22]. (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 creatinine clearance (CrCl) <50 mL/min.

COBI-boosted DRV was approved based on bioavailability studies [23,24] and has demonstrated comparable efficacy to RTV-boosted DRV in a single-arm study [25]. However, because COBI-boosted DRV has not yet been studied in randomized clinical trials, it has a lower evidence strength. COBI-boosted ATV showed non-inferiority when compared with RTV-boosted ATV with a TDF/FTC backbone in a randomized double-blind study [26].

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 abacavir/lamivudine (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 [27-29].
  • DTG is as efficacious as (i.e., non-inferior to) raltegravir (RAL)[30] and superior to both RTV-boosted DRV [31] and co-formulated TDF/FTC/EFV [32]. DTG was superior at 48 weeks when combined with ABC/3TC as compared to TDF/FTC [33].
  • RAL, although dosed twice daily, has a favorable tolerability profile and provides durable virologic control [34-36] and was superior to both RTV-boosted DRV and RTV-boosted ATV based on the cumulative incidence of virologic failure and tolerability [34].
  • TAF/FTC/COBI/EVG as a single-tablet regimen was non-inferior to the single-tablet regimen TDF/FTC/COBI/EVG, with fewer adverse effects on kidney function and bone mineral density [17].
  • RPV has excellent efficacy relative to EFV when baseline viral load is <100,000 copies/mL and is better tolerated [37-41] but should not be initiated in patients with baseline viral load >100,000 copies/mL or CD4 counts <200 cells/mm3.
  • Co-formulated TDF/FTC/COBI/EVG was non-inferior to both TDF/FTC with RTV-boosted ATV at 48 and 96 weeks [42,43] and co-formulated TDF/FTC/EFV [44,45].
  • RTV-boosted DRV once daily is better tolerated and non-inferior to either RTV-boosted ATV or LPV/RTV [34,46]. Although LPV/RTV shows excellent efficacy when combined with either commonly used NRTI backbone [47] and when compared with RTV-boosted ATV [48]. One open-label study using ABC/3TC as the backbone combined with RTV-boosted DRV showed good safety and efficacy [49].

Table 5: Individual ARVs or Combinations to Avoid in Initial Therapy for Non-Pregnant Adults

ARV

Comments

Nevirapine (NVP)

Life-threatening rash: Stevens-Johnson syndrome and toxic epidermal necrolysis are possible

  • Stavudine (d4T)
  • Didanosine (ddI)

Serious toxicities: Potentially fatal lactic acidosis, peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis are possible

Delavirdine (DLV)

Thrice-daily dosing and inferior efficacy

Etravirine (ETR)

ETR does not have an FDA indication in ART-naïve patients

Maraviroc (MVC) NRTI-only regimens, either triple or quadruple

Inferior efficacy and durability

Zidovudine (ZDV)

Not well tolerated because of bone marrow suppression (notably anemia), headache, myopathies

Unboosted PIs

Inferior efficacy relative to boosted PIs

  • Fosamprenavir (FPV)
  • Indinavir (IDV)
  • Tipranavir (TPV)
  • Nelfinavir (NFV)

Either not well studied or limited by dosing and side effects relative to recommended PIs

References:
  1. Group ISS, Lundgren JD, Babiker AG, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med 2015;373(9):795-807. [PMID: 26192873]
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  4. 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):35-9. [PMID: 10877738]
  5. 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]
  6. 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;18:20824. [PMID: 26642452]
  7. 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]
  8. 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):2113-22. [PMID: 21857490]
  9. 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):1942-51. [PMID: 25103176]
  10. 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):572-80. [PMID: 24783988]
  11. 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]
  12. Cahn P, Rolón MJ, Figueroa MI, et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: 48 week results of the PADDLE trial. 21st International AIDS Conference; 2016 Jul 18-22; Durban, South Africa.
  13. 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]
  14. Genvoya package insert. Food and Drug Administration; 2016.
  15. Odefsey package insert. Food and Drug Administration; 2016.
  16. Descovy package insert. Food and Drug Administration; 2016.
  17. 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):2606-15. [PMID: 25890673]
  18. 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]
  19. 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):530-7. [PMID: 26627107]
  20. Zack J, Chu H, Chuck S, Rhee M, Koziara J, et al. (2016) Bioequivalence of Two Co-formulations of Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combinations with 200/10 mg and 200/25 mg. J Bioequiv Availab 8:068-073. doi:10.4172/jbb.1000270.
  21. Zack J, Chuck S, Chu H, Graham H, Cao H, et al (2016) Bioequivalence of the Rilpivirine/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen. J Bioequiv Availab 8:049-054. doi:10.4172/jbb.1000266. 
  22. Gallant JE, 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):e158-65. [PMID: 27036991]
  23. Prezcobix prescribing information. Available from: https://www.prezcobix.com/sites/www.prezcobix.com/files/prescribing-information-prezcobix.pdf. Accessed April 22, 2017.
  24. 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):949-57. [PMID: 24644095]
  25. 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]
  26. Gallant JE, 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):32-9. [PMID: 23532097]
  27. 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):1191-201. [PMID: 21917892]
  28. 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]
  29. 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):2230-40. [PMID: 19952143]
  30. 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):927-35. [PMID: 24074642]
  31. 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]
  32. 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):515-9. [PMID: 26262777]
  33. 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):1807-18. [PMID: 24195548]
  34. 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):461-71. [PMID: 25285539]
  35. 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):228-32. [PMID: 22849964]
  36. 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):260-9. [PMID: 21126956]
  37. 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]
  38. 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):939-50. [PMID: 23211772]
  39. 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):989-97. [PMID: 24508782]
  40. 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):251-9. [PMID: 26684822]
  41. 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):168-75. [PMID: 24660840]
  42. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012;379(9835):2429-38. [PMID: 22748590]
  43. Rockstroh JK, DeJesus E, Henry K, et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013;62(5):483-6. [PMID: 23337366]
  44. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012;379(9835):2439-48. [PMID: 22748591]
  45. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013;63(1):96-100. [PMID: 23392460]
  46. 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]
  47. 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):1547-56. [PMID: 19542866]
  48. 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):646-55. [PMID: 18722869]
  49. 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):335-42. [PMID: 23195671]

 

General Considerations with Initial ART Regimens

Medical Care Criteria Committee, April 2017

The recommended antiretroviral therapy (ART) regimens should work well for the majority of properly selected patients, but some circumstances may make one regimen more favorable than another for a given individual. In general, an integrase strand transfer inhibitor (INSTI)-based regimen will be the best option for most patients [1,2]. To date, no resistance has been reported in ART-naïve patients treated with dolutegravir (DTG), suggesting that this ARV may be an excellent choice, particularly given its tolerability and lack of drug-drug interactions [3]. Regimens containing a boosted-PI or DTG may be more appropriate when adherence is a concern given the higher barrier to resistance. For urgent treatment when genotypic information is not yet available, for example 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. Consultation with an experienced HIV care provider is recommended when choosing a regimen for patients with extensive comorbidities, impaired renal function, HBV or HCV co-infections, or very high viral loads.

KEY POINT
  • INSTI-based regimens are generally the best choice for most patients because of tolerability and reduced frequency of dosing.

Early clinical trials in HIV used surrogate markers, such as viral load and CD4 cell count, or clinical end points, 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 indinavir (IDV) compared IDV alone versus zidovudine (ZDV) plus lamivudine (3TC) versus ZDV plus 3TC plus indinavir (IDV) in ZDV treatment-experienced patients, given that, at the time, dual-nucleoside (or nucleotide) analogue reverse transcriptase inhibitor (NRTI) treatment was considered acceptable [4]. 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 non-inferiority 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 single-tablet regimens and fixed-dose combinations (FDCs) have been approved primarily based on bioequivalence studies when compared with the individual components, such as  tenofovir disoproxil fumarate/emtricitabine /efavirenz (TDF/FTC/EFV), abacavir/lamivudine/dolutegravir (ABC/3TC/DTG), tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV), TAF/FTC, and cobicistat/darunavir (COBI/DRV).

Some of the cutoff values used for comparisons, such as viral load <100,000 copies/mL or CD4 cell 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 one showed that RPV worked even less well than EFV-based therapy at a viral load of ≥500,000 copies/mL [5].

Some agents have been approved based on non-inferiority 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 non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations when transmitted drug resistance occurs has prompted most experts to avoid NNRTI-based regimens if treatment is indicated prior to the availability of genotypic information [6-8]. Although co-formulated TDF/FTC/COBI/EVG is approved for use at any starting viral load, reports of failure, with resistance, have been documented at very high baseline viral loads over 1,000,000 copies/mL [7,9]. 

A paucity of data is available demonstrating how different antiretrovirals (ARVs) perform based on race and gender, although studies have suggested, for instance, that ritonavir (RTV)-boosted DRV is less well tolerated in women than in men and that blacks have higher discontinuation rates on RTV-boosted DRV compared with other populations [10,11].

References
  1. 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]
  2. Mills A, Fusco J, Schulman K, et al., editors. The Impact of Antiretroviral Tablet Burden and Polypharmacy on Viral Suppression in Treatment Naïve atients. Open Forum Infectious Diseases; 2016: Oxford University Press.
  3. 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;18:20824. [PMID: 26642452]
  4. 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):734-9. [PMID: 9287228]
  5. Domingo P, Ribera E. [Data on rilpivirine in treatment-naive patients. Lessons from ECHO, THRIVE and STaR]. Enferm Infecc Microbiol Clin 2013;31 Suppl 2:20-9. [PMID: 24252530]
  6. 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):228-36. [PMID: 26413846]
  7. 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]
  8. 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]
  9. 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):175-80. [PMID: 26308882]
  10. 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):366-76. [PMID: 23092052]
  11. 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):349-57. [PMID: 20855799]

Specific Factors to Consider and Discuss with Patients

Medical Care Criteria Committee, April 2017

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

Age: As HIV-infected patients age, they have a higher prevalence of comorbidities than younger patients and are likely to be on more non-HIV-specific medications, particularly cardiovascular or gastrointestinal agents, posing a higher risk for adverse interactions [1]. For patients over 50 years of age, careful regimen selection with the use of integrase strand inhibitors (INSTIs) when possible, rather than cytochrome P450 inhibitors such as cobicistat (COBI) or ritonavir (RTV), can help minimize interactions, while using tenofovir alafenamide (TAF) 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.

Cost: Single-tablet regimens 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 versus twice daily): Most patients express a preference for once-daily dosing, especially those who are not taking other medications or are taking other medications that are dosed once daily. If patients are already on twice-daily dosing of other medications and report no adherence issues, twice-daily dosing is an acceptable option.

Drug-drug interactions: Some key interactions exist (Table 6, below), such as avoiding use of proton-pump inhibitors (PPIs) with rilpivirine (RPV), which is especially important to discuss with patients, given the availability of over-the-counter PPIs and the possibility that these drugs may be prescribed by someone other than the HIV care provider. To avoid unnecessary regimen changes once started, even patients who are not currently on PPIs should be asked whether they have needed PPIs in the past or may need them in the future.

RTV and COBI have many significant and important interactions, including with cardiac medications. Methadone maintenance requirements may also change with some antiretroviral agents (ARVs). A detailed review of all medications, including over-the-counter medications or supplements, is mandatory. Using automated drug-drug interaction software embedded in the electronic medical record or consulting an up-to-date database, such as the Database of Antiretroviral Drug Interactions, for interactions with currently prescribed medications BEFORE prescribing a regimen, can help avoid serious problems.

Table 6: Select Drug-Drug Interactions to Discuss before Initiating ART in Treatment-Naive Patients

Drugs

ARV(s): Comments

H2-blockers
Antacids

  • ATV: In treatment-naïve 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
  • RPV: Use with caution; administer at least 12 hours before or at least 4 hours after RPV

Inhaled steroids
Statins

  • COBI; RTV: Alternatives or dose adjustments may be needed
Polyvalent cations [a]
  • 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
PPIs
  • ATV: Contraindicated with ATV in treatment-experienced patients; in treatment-naïve patients, use no more than equivalent of 20 mg of omeprazole with ATV, separated by 12 hours
  • RPV: Contraindicated
Ethinyl estradiol and norethindrone [b]
  • EFV; COBI/ATV; COBI/DRV; RTV and DRV: Use alternative or additional (e.g. barrier) contraceptive methods or choose alternative ART regimen
  • ATV; RTV and ATV: Use with caution; see manufacturer’s package insert for specific dosing information
Factor Xa inhibitors
  • COBI; RTV:
    • Apixiban: 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)
    • 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

Drug name abbreviations: atazanavir (ATV); cobicistat (COBI);  darunavir (DRV); dolutegravir (DTG); efavirenz (EFV); raltegravir (RAL); rilpivirine (RPV); ritonavir (RTV)

  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 patients may have a strong preference for taking medication with or without food, it is important to discuss which pills must be taken on an empty stomach, which must be taken with food, and which can be taken with or without food, as listed below.

  • ARVs that can be taken with or without food: lamivudine (3TC); abacavir (ABC); DTG; emtricitabine (FTC); RAL; TAF; tenofovir disoproxil fumarate (TDF)
  • ARVS that must be taken with food: ATV/COBI; ATV and RTV; DRV/COBI; DRV and RTV; elvitegravir (EVG); RPV; TAF/FTC/COBI/EVG; TDF/FTC/COBI/EVG
  • ARV that must be taken on an empty stomach: EFV

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

Number of pills: Some patients feel strongly that the fewer the number of pills, the better. For other patients, 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 single-tablet regimen may be attractive depending on pill size. In rare cases, patients 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. A full list that gives greater detail is available.

Table 7: Alternatives to the Tablet Form of ART Medications

Drug

Available as Liquid, Powder, or Chewable Tablet

Can Tablet be Split/Crushed/Dissolved?

Single-Tablet Formulations

Abacavir/lamivudine/dolutegravir
(ABC/3TC/DTG)

No

Probably acceptable to split/crush

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine
(EVG/COBI/TAF/FTC)

No

No data; not recommended

Tenofovir alafenamide/emtricitabine/rilpivirine
(TAF/FTC/RPV)

No

No data; not recommended

Tenofovir disoproxil fumarate/emtricitabine/efavirenz
(TDF/FTC/EFV)

No

No data; not recommended

Tenofovir disoproxil fumarate/emtricitabine/rilpivirine
(TDF/FTC/RPV)

No

No data; not recommended

Tenofovir disoproxil fumarate/emtricitabine/cobicistat/elvitegravir
(TDF/FTC/COBI/EVG)

No

No data; not recommended

Fixed-Dose Combinations

Abacavir/lamivudine
(ABC/3TC)

See individual components below

Probably acceptable to split/crush

Darunavir/cobicistat
(DRV/COBI)

No

No

(Tenofovir alafenamide/emtricitabine)
(TAF/FTC)

No

No

(Tenofovir disoproxil fumarate/emtricitabine)
(TDF/FTC)

See individual components below

Acceptable to crush/dissolve

Zidovudine/lamivudine
(ZDV/3TC)

See individual components below

Probably acceptable to split/crush

Individual Drugs

Abacavir (ABC)

Oral solution (20 mg/mL)

No data

Atazanavir (ATV)

Oral dispersible powder
(50 mg/packet)

Can open capsule and sprinkle contents

Darunavir (DRV)

Oral suspension
(100 mg/mL)

Probably acceptable to crush

Dolutegravir (DTG)

No

Acceptable to crush

Efavirenz (EFV)

No

No

Elvitegravir (EVG)

No

No data

Emtricitabine (FTC)

Oral solution (10 mg/mL)

Acceptable to open and dissolve in water

Lamivudine (3TC)

Oral solution (10 mg/mL)

Acceptable to crush or split

Raltegravir (RAL)

Chewable tablet (25 mg, 100 mg); oral powder for suspension (100 mg/packet); neither is bioequivalent to the 400 mg adult dose

Not recommended

Rilpivirine (RPV)

No

No data, not recommended

Ritonavir (RTV)

Oral solution (80 mg/mL)

No

Tenofovir disoproxil fumarate (TDF)

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 (examples of visual guides include those of AIDSinfo and HIV i-Base). TDF/FTC/RPV and TAF/FTC/RPV are the smallest single-tablet regimens; although neither is rated AI, they may be excellent regimens if the appropriate baseline characteristics are met.

Pregnancy or conception planning: Female patients of child-bearing age should receive a pregnancy test and be assessed for use of contraception. When selecting an initial regimen for women who are not using effective contraception, clinicians should consult the Department of Health and Human Services (DHHS) guideline, Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Both male and female patients should be assessed for conception plans; this can be an opportunity to discuss pre-exposure prophylaxis (PrEP) for uninfected partners (see New York State Department of Health AIDS Institute Guidance for Use of PrEP). 

Reference
  1. 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):2107-11. [PMID: 21680580]

 

Special Considerations for Comorbid Conditions

Medical Care Criteria Committee, April 2017

Bone disease: TDF causes a decrease in bone mineral density in all patients after initiation of therapy and should be used with caution in patients with pre-existing severe osteoporosis [1-3]. Some experts recommend baseline bone densitometry screening for osteoporosis in postmenopausal women and in men older than 50 years who have HIV infection [4]. The tenofovir alafenamide (TAF) formulation available currently in tenofovir alafenamide/emtricitabine (TAF/FTC), tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir (TAF/FTC/COBI/EVG), and tenofovir alafenamide/emtricitabine /rilpivirine (TAF/FTC/RPV), is a better alternative with less bone toxicity [5,6].

Cardiovascular Risks: Cobicistat (COBI)- or ritonavir (RTV)-containing regimens typically elevate lipids; tenofovir disoproxil fumarate (TDF)-containing regimens can have a beneficial effect [7]. Abacavir (ABC) has been associated with a higher risk of myocardial infarction in some studies [8-12], whereas other studies have not confirmed this association [13-16]. Based on the available data, ABC should be used with caution in those 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 setting, such as a patient with impaired renal function, the use of ABC would be acceptable [17]. 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 antiretrovirals (ARVs) may be required depending on the severity of hepatic impairment (see Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment).

Mental health and substance use: Modifiable factors that may influence adherence should be addressed.

KEY POINT
  • Neither mental health nor substance use disorders are contraindications to initiating therapy, although, in some cases, delay of initiation may be appropriate (see the New York State Department of Health AIDS Institute guideline, When to Initiate ART).

Renal function: TDF can cause renal tubular dysfunction, such as acquired Fanconi syndrome [18,19]. The risk of renal impairment has been shown to be elevated in patients with pre-existing renal disease, longer treatment duration, low body weight, and when used in conjunction with RTV- or COBI-boosted regimens [20,21]. In general, full-dose TDF should be used with caution in patients with baseline creatinine clearance (CrCl) <70 mL/min and should be adjusted or changed to an alternative agent if CrCl decreases to <50 mL/min. Use of the TAF formulation 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 RTV-boosted atazanavir (ATV/r) and lopinavir/RTV (LPV/r) have also been independently associated with a greater decrease in renal function over time compared with NNRTI-based regimens [22,23]. COBI, and to a lesser extent dolutegravir (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 [24-26].

Although DTG is highly bound to plasma proteins and therefore is unlikely to be removed by dialysis, it has not been studied in this population [27]; therefore, raltegravir (RAL) or a boosted-protease inhibitor (PI) with renally-adjusted lamivudine (3TC) lamivudine and either ABC or once weekly TDF are usually the regimens of choice in this setting.

Additional information on prescribing agents in the setting of reduced renal function is available in Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment.

Very high viral loads (>750,000 copies/mL): In some cases, experts will recommend use of both boosted DRV and DTG when the viral load is very high, with possible simplification once viral suppression is achieved. Numerous switch studies have demonstrated the safety of simplifying ART regimens in suppressed patients with no pre-existing resistance [28-31]. Consultation with an experienced HIV care provider in these situations is helpful.

KEY POINTS
  • COBI and DTG can both cause decreased tubular excretion of creatinine and will dependably 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 more hyperlipidemia than unboosted INSTIs.
  • Consultation with an experienced HIV care provider is advised when a patient’s baseline viral load is very high.
References:
  1.  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):963-72. [PMID: 20828304]
  2. 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):1791-801. [PMID: 21606537]
  3. 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):72-4. [PMID: 19265350]
  4. 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]
  5. 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):530-7. [PMID: 26627107]
  6. 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):409-19. [PMID: 26642079]
  7. 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):186-98. [PMID: 23582562]
  8. Group DADS, Sabin CA, Worm SW, 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):1417-26. [PMID: 18387667]
  9. Strategies for Management of Anti-Retroviral Therapy I, Groups DADS. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008;22(14):F17-24. [PMID: 18753925]
  10. 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):130-6. [PMID: 19682101]
  11. Choi AI, Vittinghoff E, Deeks SG, et al. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011;25(10):1289-98. [PMID: 21516027]
  12. 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):413-9. [PMID: 26536316]
  13. 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]
  14. 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):929-40. [PMID: 21427402]
  15. 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):441-7. [PMID: 22932321]
  16. 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):20-8. [PMID: 19282778]
  17. Llibre JM, Hill A. Abacavir and cardiovascular disease: A critical look at the data. Antiviral Res 2016;132:116-21. [PMID: 27260856]
  18. 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):1070-3. [PMID: 12684922]
  19. 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):283-90. [PMID: 16355343]
  20. 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]
  21. 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]
  22. 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):102-8. [PMID: 18171292]
  23. 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):865-72. [PMID: 26008219]
  24. 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]
  25. 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):350-7. [PMID: 24646860]
  26. 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):990-6. [PMID: 22905856]
  27. Tivicay prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf. Accessed April 22, 2017.
  28. 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]
  29. 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):581-9. [PMID: 24908551]
  30. Mills AM, 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):216-23. [PMID: 24144898]
  31. 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):562-8. [PMID: 19561519]

Pre-ART-Initiation Laboratory Testing

Medical Care Criteria Committee, April 2017

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

Baseline viral load: Some regimens should not be used when the viral load is ≥100,000 copies/mL: see Table 8, below; comments in Table 4: Alternative Initial ART Regimens; and Table 5: Other ART Regimens, Not Preferred or Alternative

Co-infections: Hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis (TB) infection status should be assessed. The ART regimen for those with chronic HBV infection should treat both HIV and HBV when possible (see the New York State Department of Health AIDS Institute guideline on 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.

Creatinine clearance: Some antiretroviral agents (ARVs) are contraindicated below a given creatinine clearance (CrCl) level, and some may need adjustments that require the use of individual elements of fixed-dose combination or a single-tablet regimen rather than the single-tablet version of the drug. See Table 9: ARV Dose Adjustments for Renal and Hepatic 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 guideline section on Special Considerations for Comorbid Conditions and Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment.

HIV genotypic resistance profile: Genotypic resistance testing that includes the protease and reverse transcriptase genes should be obtained at diagnosis (or initial visit if not done previously) [1,2]. Consultation with a 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 prior to the availability of genotypic resistance testing, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens should be avoided because of the higher prevalence of transmitted resistance in NNRTIs versus protease inhibitors (PIs) or integrase strand transfer inhibitors (INSTIs) [3-5]. In this situation, for example symptomatic acute infection or advanced HIV with an opportunistic infection, some experts would include DTG, boosted-DRV or both together with the NRTI backbone given the possibility of transmitted NRTI-resistance, with possible simplification once genotypic information is available. Because of the low prevalence, to date, of transmitted integrase resistance in ART-naïve patients [6,7], routine integrase resistance testing is not recommended in these patients. However, in cases where integrase resistance is suspected, this test can be ordered as a supplement to protease and reverse transcriptase testing.

HLA-B*5701 testing: To avoid potentially serious or life-threatening hypersensitivity reactions, HLA-B*5701 testing is mandatory before initiating ART that includes abacavir (ABC) [8,9].

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

Table 8: Contraindicated ART Regimens Based on Routine Baseline* Laboratory Parameters
Lab Parameter Contraindicated ART Regimens
Viral load ≥100,000 copies/mL
  • ABC/3TC and COBI/ATV
  • ABC/3TC and EFV
  • ABC/3TC and RTV and ATV
  • RAL and RTV and DRV
  • TAF/FTC/RPV
  • TDF/FTC/RPV
CD4 <200 cells/mm3
  • TAF/FTC/RPV
  • TDF/FTC/RPV
CrCl <70 mL/min
  • TDF/FTC and COBI/ATV
  • TDF/FTC and COBI/DRV
  • TDF/FTC/COBI/EVG
CrCl <50 mL/min
  • ABC/3TC
  • ABC/3TC/DTG
  • TDF/FTC/EFV
  • TDF/FTC/RPV
CrCl <30 mL/min
  • TAF/FTC
  • TAF/FTC/COBI/EVG
  • TAF/FTC/RPV
  • TDF/FTC

Drug name abbreviations: abacavir (ABC); atazanavir (ATV); cobicistat (COBI); darunavir (DRV); dolutegravir (DTG); efavirenz (EFV); elvitegravir (EVG); emtricitabine (FTC); lamivudine (3TC); raltegravir (RAL); rilpivirine (RPV); ritonavir (RTV); tenofovir alafenamide (TAF); tenofovir disoproxil fumarate (TDF)

*For renal adjustment of FDCs and single-tablet regimens while on therapy, see Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment.

References:
  1. 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):988-95. [PMID: 17725415]
  2. 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):867-70. [PMID: 18269317]
  3. 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):228-36. [PMID: 26413846]
  4. 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]
  5. 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]
  6. Volpe JM, Yang O, Petropoulos CJ, et al. Absence of integrase inhibitor resistant HIV-1 transmission in the California AIDS Healthcare Foundation Network.  Interscience Conference on Antimicrobial Agents and Chemotherapy; 2016 Sep 17-21; San Diego, CA.
  7. Garcia-Diaz A, McCormick A, Booth C, et al. Analysis of transmitted HIV-1 drug resistance using 454 ultra-deep-sequencing and the DeepChek((R))-HIV system. J Int AIDS Soc 2014;17(4 Suppl 3):19752. [PMID: 25397497]
  8. 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):1111-8. [PMID: 18444831]
  9. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358(6):568-79. [PMID: 18256392]

ARV Dose Adjustments for Renal and Hepatic Impairment

Medical Care Criteria Committee, April 2017

Table 9: ARV Dose Adjustments for Renal and Hepatic Impairment
Formulation and Usual Adult Dose Renal Insufficiency Dosing* Hepatic Impairment Dosing*
Single-Tablet Regimens

Abacavir/Lamivudine/Dolutegravir
(ABC/3TC/DTG)

  • 1 pill once daily
  • CrCl <50 mL/min: do not use
  • Child-Pugh A, B, C: do not use

Tenofovir Alafenamide/Emtricitabine/
Cobicistat/Elvitegravir
(TAF/FTC/COBI/EVG)

  • 1 pill once daily
  • CrCl <30 mL/min: do not use
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: do not use

Tenofovir Alafenamide/Emtricitabine/
Rilpivirine
(TAF/FTC/RPV)

  • 1 pill once daily
  • CrCl <30 mL/min: do not use
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Tenofovir Disoproxil Fumarate/
Emtricitabine/ Cobicistat/Elvitegravir
(TDF/FTC/COBI/EVG)

  • 1 pill once daily
  • CrCl <70 mL/min: do not initiate
  • CrCl <50 mL/min: discontinue
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Tenofovir Disoproxil Fumarate/
Emtricitabine/Efavirenz

(TDF/FTC/EFV)

  • 1 pill once each night
  • CrCl <50 mL/min: do not use
  • Child-Pugh A: no adjustment
  • Child-Pugh B, C: no data

Tenofovir Disoproxil Fumarate/
Emtricitabine/Rilpivirine
(TDF/FTC/RPV)

  • 1 pill once daily
  • CrCl <50 mL/min: do not use
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data
Fixed-Dose Combinations

Abacavir/Lamivudine
(ABC/3TC)

  • 1 pill once daily
  • CrCl <50 mL/min: do not use
  • Child-Pugh A, B, C: do not use

Tenofovir Alafenamide/
Emtricitabine
(TAF/FTC)

1 pill once daily

  • CrCl <30 mL/min: do not use
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Tenofovir Disoproxil
Fumarate/Emtricitabine
(TDF/FTC)

  • 1 pill once daily
  • CrCl 30-49 mL/min: 1 once daily every 48 hr
  • CrCl <30 mL/min: do not use
  • No adjustment
Individual Drug Components

Abacavir (ABC)

  • 300 mg twice daily or 600 mg once daily
  • No adjustment
  • Child-Pugh A: 200 mg twice daily as solution
  • Child-Pugh B, C: do not use

Atazanavir (ATV)

  • 300 mg daily with RTV 100 mg once daily or 400 mg once daily
  • No adjustment, but use only 300 mg dose with 100 mg RTV
  • Treatment-experienced patients on dialysis: do not use
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Atazanavir/Cobicistat
(ATV/COBI)

  • 1 pill once daily
  • CrCl <70 L/min with TDF-containing regimen: do not use
  • Treatment-experienced patients on dialysis: do not use
  • No data; not recommended

Darunavir (DRV)

  • Treatment naïve: 800 mg daily with ritonavir 100 mg once daily
  • Treatment experienced or ≥1 mutation associated with DRV resistance: 600 mg twice daily with ritonavir 100 mg twice daily
  • No adjustment
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Darunavir/Cobicistat
(DRV/COBI)

  • Treatment naïve: 1 pill once daily
  • Treatment experienced or ≥1 mutation associated with DRV resistance: do not use
  • CrCl <70 L/min with TDF-containing regimen: do not use
  • No data on dose adjustments
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Dolutegravir (DTG)

  • Treatment naïve or no DTG resistance mutations: 50 mg once daily
  • Known INSTI mutations or given with CYP3A inducers (e.g., EFV, LPV/RTV): 50 mg twice daily
  • No adjustment, but not studied in dialysis
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Efavirenz (EFV)

  • 600 mg daily or at night
  • No adjustment
No data; use with caution

Elvitegravir (EVG)

  • Not commonly used as single agent, see package insert for dosing with boosted PIs
  • No adjustment
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Emtricitabine (FTC)

  • 200 mg once daily or 240 mg once daily of suspension
  • CrCl 30-49 mL/min: 200 mg every 48 hr
  • CrCl 15-29 mL/min: 200 mg every 72 hr
  • CrCl <15 mL/min: 200 mg every 96 hr or solution 120/80/60 every 24 hr
  • No adjustment

Lamivudine (3TC)

  • 150 mg twice daily or 300 mg once daily
  • CrCl > 50 mL/min: 150 mg twice daily or 300 mg once daily
  • CrCl 30-49 mL/min: 150 mg once daily
  • CrCl 15-29 mL/min: 150 mg first dose then 100 mg once daily
  • CrCl 5-14 mL/min: 150 mg first dose then 50 mg once daily
  • CrCl <5 mL/min: HD 50 mg first dose then 25 mg once daily
  • No adjustment

Raltegravir (RAL)

  • 400 mg twice daily
  • No adjustment
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Rilpivirine (RPV)

  • 25 mg once daily
  • No adjustment
  • Child-Pugh A, B: no adjustment
  • Child-Pugh C: no data

Tenofovir disoproxil fumarate (TDF)

  • 300 mg once daily

 

  • CrCl 30-49 mL/min: 300 mg every 48 hr
  • CrCl 10-29 mL/min: 300 mg every 72 to 96 hr
  • Dialysis: 300 mg every 7 days
  • No adjustment

*From drug package inserts

All Recommendations: Selecting an Initial ART Regimen

Medical Care Criteria Committee, April 2017

All RECOMMENDATIONS: SELECTING AN INITIAL ART REGIMEN
  • Clinicians should involve their patients when deciding which ART regimen is most likely to result in patient adherence (AIII).
  • Clinicians should perform the following when initiating ART:
    • Assessment for comorbidities that may affect the choice of regimen for initial therapy (AIII).
    • Genotypic resistance testing for the protease and reverse transcriptase genes at diagnosis or at the initial visit if not performed previously (AII). See this guideline section Specific Factors to Consider and Discuss with Patients.
  • Baseline testing is not recommended for either integrase resistance or tropism (AIII).
  • For patients who have delayed initiation of ART and have engaged in high-risk behaviors associated with acquisition of HIV superinfection, genotypic resistance testing should be repeated before choosing the ART regimen (BIII).
  • Clinicians should consult with a provider experienced in ART management when:
    • Baseline resistance requires treatment with a regimen other than the recommended preferred or alternative regimens (AIII).
    • Selecting a regimen for patients with extensive comorbidities (BIII), impaired renal function (BIII), HBV or HCV co-infections (BIII), or very high viral loads (BIII).
  • Clinicians should:
  • A single-tablet regimen or regimen with once-daily dosing is preferred unless contraindicated by drug-drug interactions, intolerance, allergy, or access (AII). 
  • For ART-naïve patients, clinicians should (AI):
    • ­­Select an initial ART regimen that is preferred; see Table 2: Preferred Initial ART Regimens.
    • Select an alternative or other regimen only when a preferred initial regimen cannot be used; see Tables 3 and 4, Alternative Initial ART Regimens and Other ART Regimens. 
  • Two-drug regimens are not recommended as initial therapy (AII).
  • Clinicians or clinical staff should follow up, by telephone or other methods, within 2 weeks after treatment initiation to assess tolerance and adherence. Adherence should be reinforced at regular intervals (AIII).
  • Clinicians should obtain a viral load test within 4 weeks after initiation to assess response to therapy (AIII); see the NYSDOH AI guideline Virologic and Immunologic Monitoring for more information.

See the following tables:

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