ADULT HIV CARE

Antiretroviral Therapy Guideline

Initiating ART

Medical Care Criteria Committee, April 2015

Antiretroviral therapy (ART) refers to the use of pharmacologic agents that have specific inhibitory effects on HIV replication. The use of less than three active agents is not recommended for initiating treatment. These agents belong to six distinct classes of drugs: the nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs, NtRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), the protease inhibitors (PIs), the fusion inhibitors (FIs), the CCR5 co-receptor antagonists, and the integrase strand transfer inhibitors (INSTIs). See all commercially available antiretroviral drugs that are FDA-approved for the treatment of HIV/AIDS.

Benefits and Risks of Antiretroviral Therapy

Medical Care Criteria Committee, November 2017

RECOMMENDATIONS
  • Clinicians should recommend antiretroviral therapy to all HIV-infected patients. (AI)

Benefits

Effective antiretroviral therapy (ART) has led to dramatic reductions in HIV-associated morbidity and mortality [1]. In resource-rich settings, life expectancy of patients with HIV infection with access to early ART is approaching that of the general population [2]. A number of randomized clinical trials have demonstrated the benefits of ART in reducing HIV-related morbidity and mortality, irrespective of the degree of immune suppression at treatment initiation [3,4]. Thus, ART should be recommended to all individuals with HIV infection (See When to Initiate ART).

With proper selection of an initial regimen (see Selecting an Initial ART Regimen) and good patient adherence, durable virologic suppression (i.e., lifetime control of viral load) is achieved in virtually all patients with HIV infection. Virologic suppression almost invariably leads to immunological recovery, followed by reductions in the incidence of opportunistic infections and malignancies.

The measurable goals of treatment include:

  • Viral suppression as measured by HIV-1 RNA level below the limits of detection.
  • Immune reconstitution as measured by an increase in the CD4 cell count.
  • Reduction in HIV-associated complications, including AIDS- and non-AIDS-related conditions.

ART also reduces morbidity and mortality from non-HIV-related causes. In a randomized study comparing continuous ART with CD4-guided treatment interruption, a mortality benefit was observed in subjects on continuous ART [5]. This benefit was attributed to a reduction in deaths from cardiovascular, renal, and hepatic causes. ART decreases the inflammatory milieu associated with ongoing HIV replication. It is postulated that ART-mediated reductions in proinflammatory cytokines lead to lower rates of clinical complications associated with the proinflammatory state [6].

Reducing HIV transmission: In addition to its direct health benefit to the individual with HIV infection, ART is a critical component of the overarching public health goal of eliminating HIV transmission. Antiretroviral treatment as prevention (TasP) is associated with greater reductions in HIV transmission than any preventative modality studied to date. In HPTN 052, a large randomized clinical trial of serodiscordant couples, early treatment of the infected partner was associated with a 96% reduction in HIV transmission compared with a delayed treatment approach [7]. In long-term follow-up of study participants, linked transmissions between partners were thought to occur only when the index partner was viremic [8]. In the observational PARTNERS study, no phylogenetically linked HIV transmission was observed in serodiscordant couples in which the index partner was virologically suppressed on ART [9]. The evidence thus suggests that risk of sexual transmission of HIV during virological suppression is negligible. ART should be recommended to all patients with HIV infection in order to prevent transmission to sex partners and, by extrapolation, to needle-sharing partners. Despite its potent benefit in reducing HIV transmission, ART does not obviate the use of condoms or clean syringes. Those harm reduction measures, along with the use of PrEP for partners who do not have HIV infection, will help reduce the incidence of other STIs and viral hepatitis and should be integrated into patient counseling at ART initiation.

Risks

Despite the excellent tolerability of contemporary ART regimens, adverse reactions, side effects, long-term drug toxicities, and drug-drug interactions continue to pose some relative or limited risks. Patients must be counseled about the potential for ART-associated adverse events in the short and long term. These risks include tolerability issues, which may affect quality of life, as well as possible long-term toxicities primarily a low relative risk of renal and cardiovascular disorders, or decreased bone density of uncertain clinical significance [10-12]. Renal and bone density issues are largely eliminated with newer formulations of ARVs. Fatal drug reactions from ART are exceedingly rare.

Many ART combinations are now available in single-pill, fixed-dose combination formulations. Thus, the pill burden associated with early antiretroviral regimens has been largely eliminated. Nevertheless, lifelong adherence to medications may constitute a challenge to some, particularly when treatment with a single daily tablet is not feasible.

When compared with early antiretroviral combinations, contemporary ART regimens (see Selecting an Initial ART Regimen) are associated with higher rates of durable virologic suppression. Lack of virologic suppression in a patient on ART should prompt the clinician to evaluate patient adherence and provide intensive support for those reporting challenges in this domain. Failure to achieve and maintain virologic suppression may lead to the emergence of resistance-associated mutations (RAMs). A large cohort study has demonstrated that virologic failure with contemporary ART regimens is associated with the infrequent emergence of RAMs [13]. Nevertheless, RAMs can emerge with current first-line therapies. Resistance to antiretrovirals may compromise the potential for long-term virologic suppression, simple dosing schedules, and the tolerability of future treatment options.

ART initiation is associated with a risk of immune reconstitution inflammatory syndrome (IRIS). IRIS is a clinical syndrome characterized by new or worsening infectious and non-infectious complications observed after the initiation of ART (see Management of IRIS guideline). The risk of IRIS increases when ART is begun at low CD4 cell counts (<100 cells/mm3) or with the presence of specific opportunistic infections. Although the risk of IRIS is not a contraindication to initiating ART, clinicians and patients should be aware that the risk of developing IRIS is increased among persons with lower CD4 counts. Patients at increased risk should be informed of the potential for a paradoxical clinical worsening after ART initiation. 

References
  1. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Division of AIDS Prevention. Mortality Slide Series. [accessed 2017 Jun 27]. https://www.cdc.gov/hiv/pdf/statistics_surveillance_hiv_mortality.pdf
  2. Siddiqi AE, Hall HI, Hu X, et al. Population-Based Estimates of Life Expectancy After HIV Diagnosis: United States 2008-2011. J Acquir Immune Defic Syndr 2016;72(2):230-6. [PMID: 26890283]
  3. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010;363(3):257-65. [PMID: 20647201]
  4. 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]
  5. El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355(22):2283-96. [PMID: 17135583]
  6. Hileman CO, Funderburg NT. Inflammation, Immune Activation, and Antiretroviral Therapy in HIV. Curr HIV/AIDS Rep 2017;14(3):93-100. [PMID: 28434169]
  7. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365(6):493-505. [PMID: 21767103]
  8. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med 2016;375(9):830-9. [PMID: 27424812]
  9. Rodger AJ, Cambiano V, Bruun T, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. Jama 2016;316(2):171-81. [PMID: 27404185]
  10. Friis-Moller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil 2010;17(5):491-501. [PMID: 20543702]
  11. Monteiro N, Branco M, Peres S, et al. The impact of tenofovir disoproxil fumarate on kidney function: four-year data from the HIV-infected outpatient cohort. J Int AIDS Soc 2014;17(4 Suppl 3):19565. [PMID: 25394072]
  12. Hoy JF, Grund B, Roediger M, et al. Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial. J Bone Miner Res 2017. [PMID: 28650589]
  13. Scherrer AU, von Wyl V, Yang WL, et al. Emergence of Acquired HIV-1 Drug Resistance Almost Stopped in Switzerland: A 15-Year Prospective Cohort Analysis. Clin Infect Dis 2016;62(10):1310-17. [PMID: 26962075]
  14. Naidoo K, Yende-Zuma N, Padayatchi N, et al. The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial. Ann Intern Med 2012;157(5):313-24. [PMID: 22944873]
  15. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009;4(5):e5575. [PMID: 19440326]

 

Benefits and Risks of Antiretroviral Therapy: Appendix A: Risk of Progression to AIDS-Defining Illness

CD4 ≤200 Plasma Viral Load (copies/mL) [a] % AIDS (AIDS-Defining Complication) [b]
bDNA RT-PCR n 3 years 6 years 9 years
≤500 ≤1,500 0 [c]
501-3,000 1,501-7,000 3 [c]
3,001-10,000 7,001-20,000 7 14.3 28.6 64.3
10,001-30,000 20,001-55,000 20 50.0 75.0 90.0
>30,000 >55,000 70 85.5 97.9 100.0
CD4 201-350 Plasma Viral Load (copies/mL) [d] % AIDS (AIDS-Defining Complication) [d]
bDNA RT-PCR n 3 years 6 years 9 years
≤500 ≤1,500 3c
501-3,000 1,501-7,000 27 0 20.0 32.2
3,001-10,000 7,001-20,000 44 6.9 44.4 66.2
10,001-30,000 20,001-55,000 53 36.4 72.2 84.5
>30,000 >55,000 104 64.4 89.3 92.9
CD4 >350 Plasma Viral Load (copies/mL) % AIDS (AIDS-Defining Complication) [b]
bDNA RT-PCR n 3 years 6 years 9 years
≤500 ≤1,500 119 1.7 5.5 12.7
501-3,000 1,501-7,000 227 2.2 16.4 30.3
3,001-10,000 7,001-20,000 342 6.8 30.1 53.5
10,001-30,000 20,001-55,000 323 14.8 51.2 73.5
>30,000 >55,000 262 39.6 71.8 85.0

Note: Adapted from the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents (2006).

  1. Data from the Multi-Center AIDS Cohort Study (MACS).
  2. MACS numbers reflect plasma HIV RNA values obtained by version 2.0 bDNA testing. RT-PCR values are consistently 2- to 2.5-fold higher than bDNA values, as indicated. It should be noted that the current generation bDNA assay (3.0) gives similar HIV-1 RNA values as RT-PCR except at the lower end of the linear range (<1,500 copies/mL).
  3. In this study, AIDS was defined according to the 1987 CDC definition and does not include asymptomatic individuals with CD4 T cell counts <200 mm3.
  4. Too few subjects were in the category to provide a reliable estimate of AIDS risk.
  5. A recent evaluation of data from the MACS cohort of 231 individuals with CD4 T cell counts >200 and <350 cells/mm3 demonstrated that of 40 (17%) individuals with plasma HIV RNA <10,000 copies/mL, none progressed to AIDS by 3 years (Alvaro Munoz, personal communication). Of 28 individuals (29%) with plasma viremia of 10,000-20,000 copies/mL, 4% and 11% progressed to AIDS at 2 and 3 years, respectively. Plasma HIV RNA was calculated as RT-PCR values from measured bDNA values.

Benefits and Risks of Antiretroviral Therapy: Appendix B: Prognosis According to CD4 Cell Count and Viral Load in the Pre-HAART and HAART Eras

Click to enlarge: Reprinted with permission from Elsevier (The Lancet, 2002, Vol. 360, 19-29).

Click to enlarge: Reprinted with permission from Elsevier (The Lancet, 2002, Vol. 360, 19-29).

 

Appendix B: Prognosis According to CD4 Cell Count and Viral Load in the Pre-HAART and HAART Eras: Appendix C: FDA Pregnancy Categories

Category A: Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during later trimesters).

Category B. Animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted.

Category C. Animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted.

Category D. Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

Category X. Studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit.

When to Initiate ART

June 2016

RECOMMENDATIONS 
  • Clinicians should recommend ART for all patients with a diagnosis of HIV infection. (AI)
  • Clinicians should counsel patients with seronegative partners about the reduction of HIV transmission risk when effective ART is initiated and viral suppression is achieved, and should strongly recommend ART for patients with seronegative partners. (AI)
  • Clinicians should evaluate and prepare patients for ART initiation as follows:
    • Discuss risks and benefits of ART with the patient (AIII) (see Counseling and Education Before Initiating ART)
    • Assess patient readiness (AIII)
    • Identify and ameliorate factors that might interfere with successful adherence to treatment, including inadequate access to medication, inadequate supportive services, psychosocial factors, active substance use, or mental health disorders (AII)
  • Clinicians should refer patients for supportive services as necessary to address modifiable barriers to adherence. An ongoing plan for coordination of care should be established. (AIII)
  • Clinicians should involve patients in the decision-making process regarding initiation of ART. The patient should make the final decision of whether and when to initiate ART. (AIII)
  • When the decision to initiate treatment is made, ART should be prescribed and monitored by, or in consultation with, clinicians who have experience in managing ART. (AII)

Notes:

  1. For recommendations on initiating ART in HIV-infected pregnant women, refer to the DHHS Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
  2. HAND is currently used to encompass a hierarchy of progressive patterns of central nervous system involvement ranging from asymptomatic neurocognitive impairment (ANI), to minor neurocognitive disorder (MND), to the more severe HIV-associated dementia (HAD) (see Cognitive Disorders Guideline).
  3. Initial ART regimens for patients with chronic hepatitis B must include NRTIs that are active against hepatitis B (see HBV-HIV Coinfection guideline).
  4. In co-infected patients with HCV, attention should be paid to interactions between the planned ART and HCV therapy.

Results from the START trial [1] and strong cohort data show that untreated HIV infection leads to increased morbidity and mortality from both HIV-related and non-HIV-related conditions, even at high CD4 counts. Together with the dramatic reduction of transmission risk with effective treatment, these data support the initiation of ART regardless of CD4 count in all adequately prepared patients, including patients diagnosed with acute HIV infection (for more discussion see Diagnosis and Management of Acute Infection). Patients in care who are documented long-term nonprogressors or elite controllers are a group that may warrant special consideration (see Deferring ART). Patients with chronic infection and higher CD4 counts are at low risk for short-term adverse outcomes, allowing time for proper assessment, education, and engagement of the patient in the decision to treat.

In START, a randomized trial initiating ART in treatment-naïve patients with CD4 counts >500 cells/mm3 versus waiting for a decrease to ≤350 cells/mm3 before initiation showed a 53% reduction in serious illness and death in the early ART group [1]. Data from NA-ACCORD, a large observational cohort study, showed that both morbidity and mortality were improved by initiation of ART in patients with CD4 counts in the high or even normal range [2]. A significantly decreased risk of death was observed in patients who initiated therapy at CD4 counts >500 cells/mm3 compared to those who deferred to <500 cells/mm3, as well as in the cohort who initiated ART in the 350-500 cells/mm3 range compared with those deferring to <350 cells/mm3 [2]. Although other cohort studies demonstrated only a minimal survival advantage [3] or no survival advantage among those starting ART at the highest CD4 counts, they did confirm the benefits of initiating ART at levels ≤500 cells/mm3 [4-6]. Another showed an approximately 33% reduction in the risk of death from end-stage liver disease, non-AIDS infections, and non-AIDS-defining cancers with each 100 cells/mm3 increase in CD4 count [7]. A randomized study of early versus deferred therapy in patients with CD4 counts in the 350-550 cells/mm3 range showed no mortality benefit [8]; however, this study has significant limitations, most notably a relatively brief follow-up period.

Accumulating evidence suggests that patients who initiate ART earlier or spend less cumulative time with detectable plasma viremia are less likely to suffer certain complications, such as cardiovascular disease [7,9-12], neurocognitive dysfunction [13-16], decreased risk of severe bacterial infections [17], and some non-HIV-related malignancies [18-21]. Cohort data also demonstrate that although older patients are likely to achieve virologic suppression, they are less likely to achieve an immunologic response, as measured by an increase of CD4 count by 100 cells/mm3, and that patients >55 years old may be at higher clinical risk even after starting therapy [22]. The poor immunologic recovery seen in older patients is associated with higher morbidity and mortality, particularly cardiovascular events [23]. In one study, men ≥50 years of age who initiated ART with CD4 counts in the 351-500 cells/mm3 range were able to achieve similar immunologic responses as younger men who initiated at lower CD4 counts [24].

Studies have shown that, for HIV-infected pregnant women, the administration of ART during pregnancy and/or intrapartum significantly reduces the risk of mother-to-child transmission (MTCT) of HIV [25,26]. In addition, a large study showed a 96% reduction in transmission between serodiscordant heterosexual couples when the positive partner was receiving ART [8], adding to the body of evidence that lower viral load reduces transmission risk. ART is now part of the established strategy aimed at reducing HIV transmission and is an essential component of prevention interventions along with risk-reduction counseling, safer-sex practices, and avoidance of needle-sharing. Although the majority of patients both in New York and worldwide present later in the course of their HIV infection [27-29], ongoing efforts to offer universal HIV testing to all patients over age 13 may begin to identify patients earlier in their disease who can benefit from immediate treatment.

KEY POINT
  • For HIV therapy to be successful over time, the initiation of ART should involve both the selection of the most appropriate regimen and the acceptance of the regimen by the patient, bolstered by education and adherence counseling. All are critical in achieving the goal of durable and complete viral suppression. See NYSDOH AIDS Institute guideline: Selecting an Initial ART Regimen.
RESOURCES
 References:
  1. INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015 [Epub ahead of print]. [PubMed]
  2. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1897-1899. [PubMed
  3. Wright ST, Carr A, Woolley I, et al. CD4 cell responses to combination antiretroviral therapy in patients starting therapy at high CD4 cell counts. J Acquir Immune Defic Syndr 2011;58:72-79. [PubMed
  4. Writing Committee for the CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med 2011;171:1560-1569. [PubMed]
  5. Cain LE, Logan R, Robins JM, et al, and the HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: An observational study. Ann Intern Med 2011;154:509-515. [PubMed
  6. The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. CD4 cell count and the risk of AIDS or death in HIV-infected adults on combination antiretroviral therapy with a suppressed viral load: A longitudinal cohort study from COHERE. PLoS Med 2012;9:e1001194. [PubMed
  7. Marin B, Thiébaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009;23:1743-1753. [PubMed]
  8. Cohen MS, Chen YQ, McCauley M, et al., HPTN 052 Study Team Prevention of HIV-infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505. [PubMed
  9. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JH, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-2296. [PubMed
  10. Ho JE, Deeks SG, Hecht FM, et al. Initiation of antiretroviral therapy at higher nadir CD4+ T-cell counts is associated with reduced arterial stiffness in HIV-infected individuals. AIDS 2010;24:1897-1905. [PubMed
  11. Ho JE, Scherzer R, Hecht FM, et al. The association of CD4+ T-cell count on cardiovascular risk in treated HIV disease. AIDS 2012;26:1115-1120. Epub ahead of print. [PubMed
  12. Lichtenstein KA, Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV Outpatient Study. Clin Infect Dis 2010;51:435-447. [PubMed
  13. Tozzi V, Balestra P, Bellagamba R, et al. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: Prevalence and risk factors. J Acquir Immune Defic Syndr 2007;45:174-182. [PubMed] T
  14. Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials 2011;12:333-338. [PubMed
  15. Winston A, Puls R, Kerr SJ, et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: A randomized, controlled study. HIV Med 2012;13:245-251. [PubMed
  16. Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011;25:1747-1751. [PubMed
  17. O’Connor J, Vjecha MJ, Phillips AN, et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial. Lancet HIV 2017; Jan 4. pii: S2352-3018(16)30216-8. [Epub ahead of print]. (PubMed)
  18. Silverberg MJ, Chun C, Leyden W, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev 2011;20:2551-2559. [PubMed]
  19. Bruyand M, Thiébaut R, Lawson-Ayayi S, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis 2009;49:1109-1116. [PubMed
  20. Guiget M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): A prospective cohort study. Lancet Oncol 2009;10:1152-1159. [PubMed
  21. Sigel K, Wisnivesky J, Gordon K, et al. HIV as an independent risk factor for incident lung cancer. AIDS 2012;26:1017-1025. [PubMed
  22. Sabin CA, Smith CJ, d’Arminio Monforte A, et al., Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group. Response to combination antiretroviral therapy: Variation by age. AIDS 2008;22:1463-1473. [PubMed
  23. van Lelyveld SFL, Gras L, Kesselring A, et al., on behalf of the ATHENA national observational cohort study. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS 2012;26:465-474. [PubMed
  24. Li X, Margolick JB, Jamieson BD, et al. CD4 T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2011;57:421-428. [PubMed
  25. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-80. [PubMed]
  26. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354(9181):795-802. [PubMed]
  27. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis 2010;50:1512-1520. [PubMed]
  28. Centers for Disease Control and Prevention. Reported CD4+ T-lymphocyte results for adults and adolescents with HIV infection—37 States, 2005–2007. HIV Surveillance Supplemental Report 2010;16(No. 1). Published March 2011. Available at:http://www.cdc.gov/hiv/pdf/statistics_2005_2008_HIV_Surveillance_Report_vol_16_no1.pdf
  29. Centers for Disease Control and Prevention. Diagnoses of HIV infection and AIDS in the United States and dependent areas, 2008. Vol. 20. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2010. Published June 2010. Available at:http://www.cdc.gov/hiv/pdf/statistics_2008_hiv_surveillance_report_vol_20.pdf

When to Initiate ART: Counseling and Education Before Initiating ART

RECOMMENDATIONS
  • Counseling and education should include the following:
    • Basic education about HIV, CD4 cells, viral load, and resistance (AIII)
    • Available treatment options and potential risks and benefits of therapy (AIII) (see text)
    • The need for strict adherence to avoid the development of viral drug resistance (AII) 
    • Use of safer-sex practices and avoidance of needle-sharing activity, regardless of viral load, to prevent HIV transmission or superinfection (AIII)
  • Clinicians should involve the patient in the decision-making process regarding initiation of ART. (AIII)

Discussion of ART should occur at the start of care for all HIV-infected patients, regardless of CD4 count. The clinician and patient should discuss the benefits of early ART (see below) and individual factors that may affect the decision to initiate, such as patient readiness or reluctance and adherence barriers. Clinicians should involve the patient in the decision-making process regarding initiation of ART [1]. When clinicians and patients engage in shared decision-making, patients are more likely to choose to initiate ART and to achieve an undetectable viral load [2]. Misconceptions about treatment initiation should be addressed, including the implication that starting ART represents advanced HIV illness. Initiating ART before symptoms occur allows patients to stay healthier and live longer.

The risks and benefits of early ART to discuss with patients when making the decision of whether and when to initiate ART are outlined below.

BENEFITS of early ART in asymptomatic patients: 
(early therapy = initiation at CD4 counts >500 cells/mm3)

  • Earlier treatment reduces both HIV-related and non-HIV-related morbidity and mortality [3-11]
  • Delay or prevention of immune system compromise [12]
  • Possible lower risk of antiretroviral resistance [13]
  • Decreased risk of sexual transmission of HIV [14-17] (The risk of viral transmission still exists even when the plasma viral load is undetectable; ART is not a substitute for primary HIV prevention measures, such as avoiding needle sharing, practicing safer sex [18].)
  • Decreased risk of several severe bacterial infections [19]

DISADVANTAGES of early ART in asymptomatic patients:

  • Potential drug-related reduction in quality of life in otherwise asymptomatic individuals [20-22]
  • Possibility of greater cumulative side effects from ART [23]
  • Possibility for earlier development of drug resistance and limitation in future [24] antiretroviral options if adherence and viral suppression are suboptimal
  • Possibility for earlier onset of treatment fatigue
  • Higher prescription drug costs for the individual
RESOURCES

Patients who do not have health insurance may qualify for Medicaid or the NYSDOH HIV Uninsured Care Program, which provides access to free health care (HIV drugs, primary care, home care, and the ADAP Plus Insurance Continuation Program, or APIC) for residents who are HIV-infected but uninsured or underinsured. The program is open Monday-Friday, 8:00AM-5:00PM and can be reached: in state 1-800-542-2437; out-of-state 1-518-459-1641; TDD 1-518-459-0121.If eligible, patients may also consider treatment options through enrollment in clinical trials. A resource that may help with this process is the AIDS Clinical Trials Information Service (1-800-TRIALS-A).

References:
  1. Salzburg Statement on Shared Decision Making. Salzburg Global Seminar, February 7, 2011.
  2. Beach MC, Duggan PS, Moore RD. Is patients’ preferred involvement in health decisions related to outcomes for patients with HIV? Gen Intern Med 2007;22:1119-1124. [PubMed]
  3. INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015 [Epub ahead of print]. [PubMed]
  4. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1897-1899. [PubMed
  5. Marin B, Thiébaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009;23:1743-1753. [PubMed]
  6. Ho JE, Scherzer R, Hecht FM, et al. The association of CD4+ T-cell count on cardiovascular risk in treated HIV disease. AIDS 2012;26:1115-1120. Epub ahead of print. [PubMed
  7. Silverberg MJ, Chun C, Leyden W, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev 2011;20:2551-2559. [PubMed]
  8. When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: A collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-1363. [PubMed
  9. HIV-Causal Collaboration. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010;24:123-37. [PubMed
  10. Phillips AN, Gazzard B, Gilson R, et al. Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naïve individuals with high CD4 cell count. AIDS 2007;21:1717-1721. [PubMed
  11. Lewden C, Bouteloup V, De Wit S, et al, The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. All-cause mortality in treated HIV-infected adults with CD4 >500 cells mm3 compared with the general population: Evidence from a large European observational cohort collaboration. Int J Epidemiol 2012;41:433-445. [PubMed
  12. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007;46:72-77. [PubMed
  13. Uy J, Armon C, Buchacz K, et al. Initiation of HAART at higher CD4 cell counts is associated with a lower frequency of antiretroviral drug resistance mutations at virologic failure. J Acquir Immune Defic Syndr 2009;51:450-453. [PubMed
  14. Cohen MS, Chen YQ, McCauley M, et al., HPTN 052 Study Team Prevention of HIV-infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505. [PubMed
  15. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000;342:921-929. [PubMed
  16. Castilla J, del Romero J, Hernando V, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005;40:96-101. [PubMed
  17. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: A prospective cohort analysis. Lancet 2010;375:2092-2098. [PubMed
  18. Politch JA, Mayer KH, Welles SL, et al. Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AIDS 2012;26:1535-1543. Epub ahead of print. [PubMed]
  19. O’Connor J, Vjecha MJ, Phillips AN, et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial. Lancet HIV 2017; Jan 4. pii: S2352-3018(16)30216-8. [Epub ahead of print]. [PubMed]
  20. Erikkson LE, Bratt GA, Sandrström E, et al. The two-year impact of first generation protease inhibitor based antiretroviral therapy (PI-ART) on health-related quality of life. Health Qual Life Outcomes 2005;3:32. [PubMed]
  21. Guaraldi G, Murri R, Orlando G, et al. Severity of lipodystrophy is associated with decreased health-related quality of life. AIDS Patient Care STDs 2008;22:577-578. [PubMed
  22. Burgoyne RW, Tan DH. Prolongation and quality of life for HIV-infected adults treated with highly active antiretroviral therapy (HAART): A balancing act. J Antimicrob Chemother 2008;61:469-473. [PubMed]
  23. Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet 2010;376:49-62. [PubMed]
  24. Barth RE, Aitken SC, Tempelman H, et al. Accumulation of drug resistance and loss of therapeutic options precede commonly used criteria for treatment failure in HIV-1 subtype-C-infected patients. Antivir Ther 2012;17:377-386. [PubMed

When to Initiate ART: Special Considerations

Barriers to Adherence

RECOMMENDATIONS
  • In patients with advanced HIV (or AIDS), ART should be initiated even if barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support (see NYSDOH Linkage, Retention, and Treatment Adherence Initiative). (AII)
  • Although ART is recommended for all patients with HIV, the urgency of initiation is increased under the following circumstances:
    • AIDS-defining condition(AI) (see Initiating ART Following Acute Opportunistic Infections, below)
    • Pregnancy [a] (AI)
    • Symptomatic from HIV, including any of the following:
      • HIV-associated neurocognitive disorder (HAND) [b] (AII)
      • Severe thrombocytopenia (AII)
      • HIV-associated nephropathy (AII)
      • HIV-related malignancies (AII)
      • Chronic hepatitis B or C infection [c,d] (AII)
      • Age 50 or older (AII)
  • Except in cases when initiation of treatment is urgent (see Initiating ART Following Acute Opportunistic Infections, below), clinicians should educate and prepare patients before initiating ART in those with barriers to adherence, including active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system. (AIII)

Patients who are at high risk for poor adherence may benefit if initiation of ART is temporarily deferred while further patient education efforts are undertaken. In these patients, the risk of viral resistance and eventual treatment failure may outweigh any clinical benefit from earlier treatment before strict adherence can be expected [1]. These patients should remain under particularly close observation for clinical and laboratory signs of disease progression [2]. ART should be initiated as soon as the patient seems prepared to adhere to a treatment regimen. In patients who are pregnant, or have HIV-related malignancies, HIV-associated nephropathy, symptomatic HIV, older age, severe thrombocytopenia from HIV, chronic hepatitis, or advanced AIDS, it is appropriate to initiate ART even if some barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support.

Although the current first-line regimens used for ART are much easier to tolerate with fewer side effects than earlier combinations, they are not free of side effects. Their use requires a lifelong commitment from the patient. Patients who prefer not to take medication, or who do not understand the significance of skipping doses, are at high risk for poor adherence and subsequent viral resistance. Except when initiation of treatment is clinically urgent, more than one visit before initiating ART is advisable to ensure adequate understanding of the importance of adherence and to address barriers or impediments to therapy. These may include but are not limited to active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system. These barriers should not necessarily preclude initiation of ART; some may not be completely modifiable before starting therapy and will require ongoing attention and use of supportive services throughout the course of therapy.

Long-Term Nonprogressors and Elite Controllers

 
  • Decisions to initiate ART in long-term nonprogressors (AII) and elite controllers (AIII) should be individualized.
  • Clinicians should consult with a provider experienced in the management of ART when considering whether to initiate ART in long-term nonprogressors and elite controllers. (AIII)
  • Long-term nonprogressors demonstrate a lack of disease progression, marked by no symptoms and low viral loads in the absence of therapy during long-term follow-up. Most published studies of long-term nonprogressors include 7-10 years of follow-up [3].
  • Elite controllers suppress HIV to low but detectable levels (<50-75 copies/mL) for many years [4].

The role of early ART initiation in long-term nonprogressors or elite controllers is unclear. At this time, there are not enough data to recommend for or against initiation of ART in long-term nonprogressors and elite controllers. Close monitoring of CD4 count and viral load level may be an acceptable approach. Declines in CD4 count should prompt consideration of initiation of ART. Elite controllers have demonstrated CD4 cell increases after initiation of ART [4]. Another study found higher rates of hospitalizations in elite controllers compared to treatment suppressed patients, particularly for cardiovascular and psychiatric conditions [5]; however, there were important limitations in this analysis and it does not provide definitive evidence in favor of treating this rare population based on current information [6]. The clinician and patient should discuss the current data on the risks and benefits of early ART as well as individual factors that may affect the decision to initiate, such as patient readiness and reluctance, adherence barriers, CD4 cell count and viral load, comorbidities, age, and partner serodiscordance. If treatment is delayed, clinicians should counsel patients about the risk of HIV transmission to partners.

References:
  1. Politch JA, Mayer KH, Welles SL, et al. Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AIDS 2012;26:1535-1543. Epub ahead of print. [PubMed]
  2. Wallis CL, Papathanasopolous MA, Fox M, et al. Low rates of nucleoside reverse transcriptase inhibitor resistance in a well-monitored cohort in South Africa on antiretroviral therapy. Antivir Ther 2012;17:313-320. [PubMed
  3. Casado C, Colombo S, Rauch A, et al. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression. PLoS One 2010;5:e11079. [PubMed]
  4. Okulicz JF, Grandits GA, Weintrob, et al. CD4 T cell count reconstitution in HIV controllers after highly active antiretroviral therapy. Clin Infect Dis 2010;50:1187-1191. [PubMed]
  5. Crowell TA, Gebo KA, Blankson JN, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis 2015;211(11):1692-702. [PubMed]
  6. Karris MY, Haubrich RH. Antiretroviral therapy in the elite controller: justified or premature? J Infect Dis 2015;211(11):1689-91. [PubMed]

When to Initiate ART: Initiating ART Following Acute Opportunistic Infections

RECOMMENDATIONS
  • Clinicians should recommend that patients beginning treatment for acute opportunistic infections (OIs) initiate ART within 2 weeks of OI diagnosis (see next recommendation for exceptions). (AI)
  • Clinicians should not immediately initiate ART in patients with tuberculous meningitis or cryptococcal meningitis. (AI)
  • Consultation with a clinician with experience in management of ART in the setting of acute OIs is recommended. (AIII)
  • For all other manifestations of tuberculosis (TB), clinicians should initiate ART in HIV-infected patients as follows:
    • For patients with CD4 counts ≥50 cells/mm3: as soon as they are tolerating anti-TB therapy and no later than 8-12 weeks after initiating anti-TB therapy (AI)
    • For patients with CD4 counts <50 cells/mm3: within 2 weeks of initiating anti-TB therapy (AI)

In a randomized study, patients who initiated ART at a median of 12 days from start of OI therapy had better outcomes, as measured by disease progression and death, without an increase in adverse events, compared to those who initiated ART at a median of 45 days from presentation [1]. Although this study excluded patients with active TB, three randomized controlled trials in patients newly diagnosed with HIV and pulmonary TB have demonstrated a significant mortality benefit when ART was initiated during the first 2 months of starting anti-TB therapy and a further benefit when those who were severely immunocompromised initiated therapy in the first 2 weeks [2-4]. Although antiretroviral agents and anti-TB medications can have overlapping toxicities, ART should be initiated within the first 8 to 12 weeks of starting anti-TB therapy. Patients with CD4 counts <50 cells/mm3 should receive ART within the first 2 weeks of initiating anti-TB therapy.

Tuberculous meningitis and cryptococcal meningitis are exceptions; there are data showing that early initiation of ART increases adverse events and mortality in this setting [5-9]. Close attention should be paid to possible drug-drug interactions between OI therapy and ART. In some cases, determining the optimal timing for initiating ART in patients with OIs can be complex and may require consultation with a clinician with experience in management of ART in this context.

After initiating ART, clinicians need to be alert to the possibility of immune reconstitution syndromes as CD4 cell counts are restored (see Immune Reconstitution Inflammatory Syndrome).

References:

  1. Zolopa A, Anderson J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: A multicenter randomized strategy trial. PLoS ONE 2009;4:e5575. [PubMed
  2. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471-1481. [PubMed]
  3. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482-1491. [PubMed]
  4. Abdool Karim S, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492-1501. [PubMed]
  5. Lawn SD, Torok ME, Wood R. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Curr Opin Infect Dis 2011;24:34-42. [PubMed]
  6. National Institute of Allergy and Infectious Diseases. Bulletin: HIV treatment study in patients with cryptococcal meningitis ends enrollment early: Higher mortality rate found with early antiretroviral therapy. May 30, 2012. [Bulletin]
  7. Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Clin Infect Dis 2011;52(11):1374-83. [PubMed]
  8. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014;370(26):2487-98. [PubMed]
  9. Bisson GP, Molefi M, Bellamy S, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis 2013;56(8):1165-73. [PubMed]

When to Initiate ART: All Recommendations

ALL RECOMMENDATIONS: WHEN TO INITIATE ART
  • ART should be recommended for all patients with a diagnosis of HIV infection. (AI)
  • Patients with seronegative partners should be counseled about the reduction of HIV transmission risk when effective ART is initiated and viral suppression is achieved; ART is strongly recommended in patients with seronegative partners. (AI)
  • Evaluation and preparation for ART initiation includes each of the following essential components:
    • Discussion with the patient about risks and benefits of ART (AIII) (see Counseling and Education Before Initiating ART)
    • Assessment of patient readiness (AIII)
    • Identification and amelioration of factors that might interfere with successful adherence to treatment, including inadequate access to medication, inadequate supportive services, psychosocial factors, active substance use, or mental health disorders (AII)
  • Clinicians should refer patients for supportive services as necessary to address modifiable barriers to adherence. An ongoing plan for coordination of care should be established. (AIII)
  • Clinicians should involve patients in the decision-making process regarding initiation of ART. The patient should make the final decision of whether and when to initiate ART. (AIII)
  • When the decision to initiate treatment is made, ART should be prescribed and monitored by, or in consultation with, clinicians who have experience in managing ART. (AII)
 Counseling and Education Before Initiating ART
  • Counseling and education should include the following:
    • Basic education about HIV, CD4 cells, viral load, and resistance (AIII)
    • Available treatment options and potential risks and benefits of therapy (AIII) (see text)
    • The need for strict adherence to avoid the development of viral drug resistance (AII) 
    • Use of safer-sex practices and avoidance of needle-sharing activity, regardless of viral load, to prevent HIV transmission or superinfection (AIII)
  • Clinicians should involve the patient in the decision-making process regarding initiation of ART. (AIII)
Special Considerations
  • In patients with advanced HIV (or AIDS), ART should be initiated even if barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support (see NYSDOH Linkage, Retention, and Treatment Adherence Initiative). (AII)
  • Although ART is recommended for all patients with HIV, the urgency of initiation is increased under the following circumstances:
    • AIDS-defining condition(AI) (see Initiating ART Following Acute Opportunistic Infections, below)
    • Pregnancy [a] (AI)
    • Symptomatic from HIV, including any of the following:
      • HIV-associated neurocognitive disorder (HAND) [b] (AII)
      • Severe thrombocytopenia (AII)
      • HIV-associated nephropathy (AII)
      • HIV-related malignancies (AII)
      • Chronic hepatitis B or C infection [c,d] (AII)
      • Age 50 or older (AII)
  • Except in cases when initiation of treatment is urgent (see Initiating ART Following Acute Opportunistic Infections, below), clinicians should educate and prepare patients before initiating ART in those with barriers to adherence, including active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system. (AIII)
  • Decisions to initiate ART in long-term nonprogressors (AII) and elite controllers (AIII) should be individualized.
  • Clinicians should consult with a provider experienced in the management of ART when considering whether to initiate ART in long-term nonprogressors and elite controllers. (AIII)
Initiating ART Following Acute Opportunistic Infections
  • Clinicians should recommend that patients beginning treatment for acute opportunistic infections (OIs) initiate ART within 2 weeks of OI diagnosis (see next recommendation for exceptions). (AI)
  • Clinicians should not immediately initiate ART in patients with tuberculous meningitis or cryptococcal meningitis. (AI)
  • Consultation with a clinician with experience in management of ART in the setting of acute OIs is recommended. (AIII)
  • For all other manifestations of tuberculosis (TB), clinicians should initiate ART in HIV-infected patients as follows:
    • For patients with CD4 counts ≥50 cells/mm3: as soon as they are tolerating anti-TB therapy and no later than 8-12 weeks after initiating anti-TB therapy (AI)
    • For patients with CD4 counts <50 cells/mm3: within 2 weeks of initiating anti-TB therapy (AI)
Notes:
  1. For recommendations on initiating ART in HIV-infected pregnant women, refer to the DHHS Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
  2. HAND is currently used to encompass a hierarchy of progressive patterns of central nervous system involvement ranging from asymptomatic neurocognitive impairment (ANI), to minor neurocognitive disorder (MND), to the more severe HIV-associated dementia (HAD) (see Cognitive Disorders Guideline).
  3. Initial ART regimens for patients with chronic hepatitis B must include NRTIs that are active against hepatitis B (see HBV-HIV Coinfection guideline).
  4. In co-infected patients with HCV, attention should be paid to interactions between the planned ART and HCV therapy.

When to Initiate ART: Updates and Changes to this Guideline

5/23/2017

  • Revised recommendation: Update states, with no qualifiers, that ART should be recommended for all patients with a diagnosis of HIV infection. (AI)
  • Revised section theme: Changed “Deferring ART” to “Special Considerations”
  • Added a recommendation to “Special Considerations”: Although ART is recommended for all patients with HIV, the urgency of initiation is increased in patients with an AIDS-defining condition (AI); who are pregnant (AI); who are symptomatic from HIV, including HIV-associated neurocognitive disorder (AII); severe thrombocytopenia (AII); HIV-associated nephropathy (AII); HIV-related malignancies (AII); chronic hepatitis B or C infection; (AII) or who are aged 50 years or older (AII).
  • Revised text to specify the following:  In patients who are pregnant, or have HIV-related malignancies, HIV-associated nephropathy, symptomatic HIV, older age, severe thrombocytopenia from HIV, chronic hepatitis, or advanced AIDS, it is appropriate to initiate ART even if some barriers to adherence are present.

Selecting an Initial ART Regimen

Medical Care Criteria Committee, Updated November 2017

Purpose of this guideline: 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-naïve adults living with HIV. The guideline aims to achieve the following goals:

  • Provide a clear and concise roadmap to choosing from among several equally efficacious ART regimens based on individual patient characteristics and preferences.
  • Provide a list of regimens to avoid.
  • Provide dosing considerations for patients 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 managing patients with extensive co-morbidities.

The NYSDOH AI is publishing this guideline at a critical time: 1) Initiation of ART is now recommended for all patients diagnosed with HIV infection; 2) Identifying and linking patients with HIV infection 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 New York State to properly select initial antiretroviral therapy is key to the successful treatment of patients with HIV infection.

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. 

How to use this guideline: Tables presenting preferred and alternative regimens appear first (see this guideline’s section on Available ART Regimens, Tables 1 and 2). 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.

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.

Selecting an Initial ART Regimen: Updates to this Guideline

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 Cahn P, Kaplan R, Sax PE, et al. as reference 6.

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).”

Selecting an Initial ART Regimen: Available ART Regimens

Medical Care Criteria Committee, updated November 2017                                            

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), active opportunistic 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):
  • 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 1, below), although there may be times when an alternative regimen may be a better choice for an individual patient (Table 2, below).

Each regimen listed below in Tables 1 and 2, preferred and alternative initial ART regimens, and in Table 3, 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. In a study of ART-naïve patients RAL HD 1200 mg once daily was non-inferior to 400 mg tablets dosed twice daily and is thus preferred [6]. 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 2, 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 3, below), although efficacious, have been shown to be less well-tolerated than the preferred or alternative regimens in Tables 1 and 2, 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 1, 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 [7]. 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 [8]. 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 [9]. In the same study, STR for NNRTI-based therapy led to greater rates of suppression than MTR NNRTI therapy [9]. Other studies have demonstrated better efficacy and adherence, lower costs to patients, and fewer hospital admissions associated with single-tablet regimens [9-19]. Another study examined once-daily dosing of LPV/RTV and found better adherence than with twice-daily dosing [20].

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, 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. 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 8: ARV Dose Adjustments for Renal and Hepatic Impairment.

Table 2, below, includes initial ART regimens preferred by this Committee; Table 2 lists alternative initial regimens. Table 3 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 1: 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; Triumeq)
  • 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; Genvoya)
  • 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; Descovy and Tivicay)
  • 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

Tenofovir alafenamide/emtricitabine and raltegravir
(TAF 25 mg/FTC and RAL HD; Descovy and Isentress HD)

  • 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 HD 1200 mg once daily dosed as two 600 mg HD tablets
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; 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
(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; Odefsey)

  • 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; Stribild)
  • 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; Truvada and Prezcobix)
  • 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; Truvada and Prezista and Norvir)
  • 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; Truvada and Tivicay)
  • 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
Tenofovir disoproxil fumarate/emtricitabine and raltegravir
(TDF/FTC and RAL HD; Truvada and Isentress HD)
  • Initiate onlyin patients with CrCl ≥50 mL/min
  • Consider bone mineral density
  • TDF/FTC once daily and RAL HD 1200 mg once daily dosed as two 600 mg HD tablets
BI
Available as Multi-Tablet Regimen with Twice-Daily Dosing

Tenofovir alafenamide/emtricitabine and raltegravir
(TAF 25 mg/FTC and RAL; Descovy and Isentress)

  • Initiate only in patients with CrCl ≥50 mL/min
  • Consider bone mineral density
  • TDF/FTC once daily and RAL twice daily
BIII
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; 5) When dosing RAL once daily use the HD formulation of 600 mg tablets dosed at 1200 mg.
 
Table 3. 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; Atripla)
  • 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; Complera)
  • 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; Epzicom and Reyataz and Norvir)
  • 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; Epzicom and Prezcobix)
  • 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; Epzicom and Prezista and Norvir)
  • 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; Epzicom and Sustiva)
  • 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; Descovy and Epzicom)
  • 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; Truvada and Evotaz)
  • 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; Truvada and Reyataz and Norvir)
  • 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

Abacavir/lamivudine and raltegravir
(ABC/3TC and RAL HD; Epzicom and Isentress HD)

  • Initiate only in patients negative for HLA-B*5701
  • Consider underlying risk of coronary heart disease
  • ABC/3TC once daily, RAL HD 1200 mg once daily dosed as two 600 mg HD tablets 
BIII

Available as Multi-Tablet Regimen with Twice-Daily Dosing

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

  • Initiate only in patients with CrCl ≥50 mL/min
  • Consider bone mineral density
  • TDF/FTC once daily and RAL 400 mg twice daily
BI
Abacavir/lamivudine and raltegravir
(ABC/3TC and RAL; Epzicom and Isentress)
  • Initiate only in patients negative for HLA-B*5701
  • Consider underlying risk of coronary heart disease
  • ABC/3TC once daily and RAL 400 mg 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; 5) When dosing RAL once daily use the HD formulation of 600 mg tablets dosed at 1200 mg.
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. 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 Sep 11. pii: S2352-3018(17)30128-5. [PMID: 28918877]
  7. 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]
  8. 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]
  9. 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.
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. 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.
  19. 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]
  20. 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]

Selecting an Initial ART Regimen: 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 known 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 copies/mL 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 4: Individual ARVs or Combinations to Avoid in Initial Therapy for Non-Pregnant 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-naïve 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, 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

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]

 

Selecting an Initial ART Regimen: 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 durability.

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]

Selecting an Initial ART Regimen: 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 5, 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 5: 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
  • EVG: Separate dosing by 2 hours, either before or after dose of EVG
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
Metformin
  • DTG: Metformin levels are significantly raised when co-administered with DTG. The dose of metformin should not exceed 1,000 mg.
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 6, 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 6: 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; Triumeq)

No

Probably acceptable to split/crush

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

No

No data; not recommended

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

No

No data; not recommended

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

No

No data; not recommended

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

No

No data; not recommended

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

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

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

Rilpivirine (RPV; Edurant)

No

No data, not recommended

Ritonavir (RTV; Norvir)

Oral solution (80 mg/mL)

No

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 (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 PrEP to Prevent HIV Acquisition Guideline). 

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]

 

Selecting an Initial ART Regimen: 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 8: 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 8: 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]

Selecting an Initial ART Regimen: 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 7, 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 7, below; comments in Table 2: Alternative Initial ART Regimens; and Table 3: 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 8: 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 8: 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 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 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 7, below, is contraindicated based on the listed baseline laboratory parameters.

Table 7: 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 (Epzicom and Evotaz)
  • ABC/3TC and EFV (Epzicom and Sustiva)
  • ABC/3TC and RTV and ATV (Epzicom and Norvir and Reyataz)
  • RAL and RTV and DRV (Isentress and Norvir and Prezista)
  • TAF/FTC/RPV (Odefsey)
  • TDF/FTC/RPV (Complera)
CD4 <200 cells/mm3
  • TAF/FTC/RPV (Odefsey)
  • TDF/FTC/RPV (Complera)
CrCl <70 mL/min
  • TDF/FTC and COBI/ATV (Truvada and Evotaz)
  • TDF/FTC and COBI/DRV (Truvada and Prezcobix)
  • TDF/FTC/COBI/EVG (Stribild)
CrCl <50 mL/min
  • ABC/3TC (Epzicom)
  • ABC/3TC/DTG (Triumeq)
  • TDF/FTC/EFV (Atripla)
  • TDF/FTC/RPV (Complera)
CrCl <30 mL/min
  • TAF/FTC (Descovy)
  • TAF/FTC/COBI/EVG (Genvoya)
  • TAF/FTC/RPV (Odefsey)
  • TDF/FTC (Truvada)

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 8: 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]

Selecting an Initial ART Regimen: ARV Dose Adjustments for Renal and Hepatic Impairment

Medical Care Criteria Committee, April 2017

Table 8: 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; Triumeq)

  • 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; Stribild))

  • 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; Odefsey)

  • 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; Genvoya)

  • 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; Atripla)

  • 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; Complera)

  • 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; Epzicom)

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

Tenofovir alafenamide/emtricitabine
(TAF/FTC; Descovy)

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 Truvada)

  • 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; Ziagen)

  • 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; Reyataz)

  • 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; Evotaz)

  • 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; Prezista)

  • 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; Prezcobix)

  • 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; Tivicay)

  • 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; Sustiva)

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

Elvitegravir (EVG; Vitekta)

  • 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; Emtriva)

  • 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; Epivir)

  • 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; Isentress)

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

Rilpivirine (RPV; Edurant)

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

Tenofovir disoproxil fumarate (TDF; Viread)

  • 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

Selecting an Initial ART Regimen: All Recommendations: Selecting an Initial ART Regimen

Medical Care Criteria Committee, Updated November 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), active opportunistic 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 1: Preferred Initial ART Regimens.
    • Select an alternative or other regimen only when a preferred initial regimen cannot be used; see Tables 2 and 3, 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:

All Recommendations: Initiating ART

Medical Care Criteria Committee, September 2015

ALL RECOMMENDATIONS: INITIATING ART
Goals, Benefits, and Risks 
  • Clinicians should prescribe an ART regimen that is best able to delay disease progression, prolong survival, and maintain quality of life through maximal viral suppression (see text). (I)
  • The clinician should involve the patient in the decision-making process when determining whether to implement ART. The clinician should review the benefits and risks of treatment for each individual patient. (III)
When to Initiate 
  • ART should be recommended for all patients with a diagnosis of HIV infection. (AI)
  • Patients with seronegative partners should be counseled about the reduction of HIV transmission risk when effective ART is initiated and viral suppression is achieved; ART is strongly recommended in patients with seronegative partners. (AI)
  • Evaluation and preparation for ART initiation includes each of the following essential components:
    • Discussion with the patient about risks and benefits of ART (AIII) (see Counseling and Education Before Initiating ART)
    • Assessment of patient readiness (AIII)
    • Identification and amelioration of factors that might interfere with successful adherence to treatment, including inadequate access to medication, inadequate supportive services, psychosocial factors, active substance use, or mental health disorders (AII)
  • Clinicians should refer patients for supportive services as necessary to address modifiable barriers to adherence. An ongoing plan for coordination of care should be established. (AIII)
  • Clinicians should involve patients in the decision-making process regarding initiation of ART. The patient should make the final decision of whether and when to initiate ART. (AIII)
  • When the decision to initiate treatment is made, ART should be prescribed and monitored by, or in consultation with, clinicians who have experience in managing ART. (AII)
Counseling and Education before ART Initiation 
  •  Counseling and education should include the following:
    • Basic education about HIV, CD4 cells, viral load, and resistance (AIII)
    • Available treatment options and potential risks and benefits of therapy (AIII) (see text)
    • The need for strict adherence to avoid the development of viral drug resistance (AII) (see Adherence)
    • Use of safer-sex practices and avoidance of needle-sharing activity, regardless of viral load, to prevent HIV transmission or superinfection (AIII)
  • Clinicians should involve the patient in the decision-making process regarding initiation of ART. (AIII)
Special Considerations
  • In patients with advanced HIV (or AIDS), ART should be initiated even if barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support (see NYSDOH Linkage, Retention, and Treatment Adherence Initiative). (AII)
  • Although ART is recommended for all patients with HIV, the urgency of initiation is increased under the following circumstances:
    • AIDS-defining condition (AI) (see Initiating ART Following Acute Opportunistic Infections, below)
    • Pregnancy [a] (AI)
    • Symptomatic from HIV, including any of the following:
      • HIV-associated neurocognitive disorder (HAND) [b] (AII)
      • Severe thrombocytopenia (AII)
      • HIV-associated nephropathy (AII)
      • HIV-related malignancies (AII)
      • Chronic hepatitis B or C infection [c,d] (AII)
      • Age 50 or older (AII)
  • Except in cases when initiation of treatment is urgent (see Initiating ART Following Acute Opportunistic Infections), clinicians should educate and prepare patients before initiating ART in those with potential barriers to adherence, including active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system. (AIII)
  • Decisions to initiate ART in long-term nonprogressors (AII) and elite controllers (AIII) should be individualized.
  • Clinicians should consult with a provider experienced in the management of ART when considering whether to initiate ART in long-term nonprogressors and elite controllers. (AIII)
Initiating ART Following Acute OIs
  • Clinicians should recommend that patients beginning treatment for acute opportunistic infections (OIs) initiate ART within 2 weeks of OI diagnosis (see next recommendation for exceptions). (AI)
  • Clinicians should not immediately initiate ART in patients with tuberculous meningitis or cryptococcal meningitis. (AI)
  • Consultation with a clinician with experience in management of ART in the setting of acute OIs is recommended. (AIII)
  • For all other manifestations of tuberculosis (TB), clinicians should initiate ART in HIV-infected patients as follows:
    • For patients with CD4 counts ≥50 cells/mm3: as soon as they are tolerating anti-TB therapy and no later than 8-12 weeks after initiating anti-TB therapy (AI)
    • For patients with CD4 counts 3: within 2 weeks of initiating anti-TB therapy (AI)

Notes

  1. For recommendations on initiating ART in HIV-infected pregnant women, refer to the DHHS Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.

  2. HAND is currently used to encompass a hierarchy of progressive patterns of central nervous system involvement ranging from asymptomatic neurocognitive impairment (ANI), to minor neurocognitive disorder (MND), to the more severe HIV-associated dementia (HAD) (see Cognitive Disorders Guideline).

  3. Initial ART regimens for patients with chronic hepatitis B must include NRTIs that are active against hepatitis B (see Hepatitis B Virus guideline).

  4. In co-infected patients with HCV, attention should be paid to interactions between the planned ART and HCV therapy.