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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Treatment Goals

(Last updated:3/27/2012; last reviewed:3/27/2012)

Eradication of HIV infection cannot be achieved with available antiretroviral (ARV) regimens even when new, potent drugs are added to a regimen that is already suppressing plasma viral load below the limits of detection of commercially available assays [1]. This is chiefly because the pool of latently infected CD4 T cells is established during the earliest stages of acute HIV infection [2] and persists with a long half-life, despite prolonged suppression of plasma viremia [3-7]. Therefore the primary goals for initiating antiretroviral therapy (ART) are to:

  • reduce HIV-associated morbidity and prolong the duration and quality of survival,
  • restore and preserve immunologic function,
  • maximally and durably suppress plasma HIV viral load (see Plasma HIV RNA Testing), and
  • prevent HIV transmission.
ART has reduced HIV-related morbidity and mortality [8-11] and has reduced perinatal [12] and behavior-associated transmission of HIV [13-17]. HIV suppression with ART may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in HIV-infected cohorts. (See Initiating Antiretroviral Therapy.) Maximal and durable suppression of plasma viremia delays or prevents the selection of drug-resistance mutations, preserves CD4 T-cell numbers, and confers substantial clinical benefits, all of which are important treatment goals [18-19].

Achieving viral suppression requires the use of ARV regimens with at least two, and preferably three, active drugs from two or more drug classes. Baseline resistance testing and patient characteristics should guide design of the specific regimen. (See What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient.) When initial suppression is not achieved or is lost, rapidly changing to a new regimen with at least two active drugs is required. (See Virologic and Immunologic Failure.) The increasing number of drugs and drug classes makes viral suppression below detection limits an appropriate goal in all patients.

Viral load reduction to below limits of assay detection in an ART-naive patient usually occurs within the first 12–24 weeks of therapy. Predictors of virologic success include:
  • high potency of ARV regimen,
  • excellent adherence to treatment regimen [20],
  • low baseline viremia [21],
  • higher baseline CD4 count (>200 cells/mm3) [22], and
  • rapid reduction of viremia in response to treatment [21, 23].
Successful outcomes are usually observed, although adherence difficulties may lower the success rate in clinical practice to below the 90% rate commonly seen in clinical trials [24].

Strategies to Achieve Treatment Goals

Achieving treatment goals requires a balance of sometimes competing considerations, outlined below. Providers and patients must work together to define individualized strategies to achieve treatment goals.

Selection of Initial Combination Regimen

Several preferred and alternative ARV regimens are recommended for use. (See What to Start.) Many of these regimens have comparable efficacy but vary to some degree in dosing frequency and symmetry, pill burden, drug interactions, and potential side effects. Regimens should be tailored for the individual patient to enhance adherence and thus improve long-term treatment success. Individual regimen choice is based on such considerations as expected side effects, convenience, comorbidities, interactions with concomitant medications, and results of pretreatment genotypic drug-resistance testing.

Pretreatment Drug-Resistance Testing

Current studies suggest a 6% to 16% prevalence of HIV drug resistance in ART-naive patients [25-29], and some studies suggest that the presence of transmitted drug-resistant viruses may lead to suboptimal virologic responses [30]. Therefore, pretreatment genotypic resistance testing should be used to guide selection of the most optimal initial ARV regimen. (See Drug-Resistance Testing.)

Improving Adherence

Suboptimal adherence may result in reduced treatment response. Incomplete adherence can result from complex medication regimens; patient factors, such as active substance abuse and depression; and health system issues, including interruptions in patient access to medication and inadequate treatment education and support. Conditions that promote adherence should be maximized before and after initiation of ART. (See Adherence to Antiretroviral Therapy.)

References

  1. Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. Jun 9 2009;106(23):9403-9408.
  2. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A. Jul 21 1998;95(15):8869-8873.
  3. Chun TW, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. Nov 25 1997;94(24):13193-13197.
  4. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. Nov 14 1997;278(5341):1295-1300.
  5. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. May 1999;5(5):512-517.
  6. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. Nov 14 1997;278(5341):1291-1295.
  7. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. Jun 2003;9(6):727-728.
  8. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet. Nov 28 1998;352(9142):1725-1730.
  9. Palella FJ, Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. Mar 26 1998;338(13):853-860.
  10. Vittinghoff E, Scheer S, O'Malley P, Colfax G, Holmberg SD, Buchbinder SP. Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. J Infect Dis. Mar 1999;179(3):717-720.
  11. ART CC AC. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. Jul 26 2008;372(9635):293-299.
  12. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. Aug 5 1999;341(6):385-393.
  13. Wood E, Kerr T, Marshall BD, et al. Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 among injecting drug users: prospective cohort study. BMJ. 2009;338:b1649.
  14. 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. Mar 30 2000;342(13):921-929.
  15. Dieffenbach CW, Fauci AS. Universal voluntary testing and treatment for prevention of HIV transmission. JAMA. Jun 10 2009;301(22):2380-2382.
  16. Montaner JS, Hogg R, Wood E, et al. The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic. Lancet. Aug 5 2006;368(9534):531-536.
  17. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. Aug 11 2011;365(6):493-505.
  18. O'Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS. N Engl J Med. Feb 15 1996;334(7):426-431.
  19. Garcia F, de Lazzari E, Plana M, et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr. Jun 1 2004;36(2):702-713.
  20. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. Jul 4 2000;133(1):21-30.
  21. Powderly WG, Saag MS, Chapman S, Yu G, Quart B, Clendeninn NJ. Predictors of optimal virological response to potent antiretroviral therapy. AIDS. Oct 1 1999;13(14):1873-1880.
  22. Yamashita TE, Phair JP, Munoz A, et al. Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study. AIDS. Apr 13 2001;15(6):735-746.
  23. Townsend D, Troya J, Maida I, et al. First HAART in HIV-infected patients with high viral load: value of HIV RNA levels at 12 weeks to predict virologic outcome. J Int Assoc Physicians AIDS Care (Chic Ill). Sep-Oct 2009;8(5):314-317.
  24. Moore RD, Keruly JC, Gebo KA, Lucas GM. An improvement in virologic response to highly active antiretroviral therapy in clinical practice from 1996 through 2002. J Acquir Immune Defic Syndr. Jun 1 2005;39(2):195-198.
  25. Weinstock HS, Zaidi I, Heneine W, et al. The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis. Jun 15 2004;189(12):2174-2180.
  26. Bennett D, McCormick L, Kline R, et al. US surveillance of HIV drug resistance at diagnosis using HIV diagnostic sera. Paper presented at: 12th Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2005; Boston, MA.
  27. Wheeler W, Mahle K, Bodnar U, et al. Antiretroviral drug-resistance mutations and subtypes in drug-naive persons newly diagnosed with HIV-1 infection, US, March 2003 to October 2006. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles, CA.
  28. Ross L, Lim ML, Liao Q, et al. Prevalence of antiretroviral drug resistance and resistance-associated mutations in antiretroviral therapy-naive HIV-infected individuals from 40 United States cities. HIV Clin Trials. Jan-Feb 2007;8(1):1-8.
  29. Vercauteren J, Wensing AM, van de Vijver DA, et al. Transmission of drug-resistant HIV-1 is stabilizing in Europe. J Infect Dis. Nov 15 2009;200(10):1503-1508.
  30. 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. Aug 2007;23(8):988-995