When to initiate antiretroviral therapy in HIV-infected patients
- John G Bartlett, MD
John G Bartlett, MD
- Editor-in-Chief — Infectious Diseases
- Section Editor — HIV; Pulmonary Infections
- Professor Emeritus
- Johns Hopkins University School of Medicine
- Paul E Sax, MD
Paul E Sax, MD
- Section Editor — HIV
- Clinical Director, Division of Infectious Diseases
- Brigham and Women's Hospital
- Professor of Medicine
- Harvard Medical School
Epidemiologic data have demonstrated that potent three-drug antiretroviral therapy (ART) regimens, which were introduced in 1996, have led to remarkable declines in morbidity and mortality among HIV-infected patients [1-3]. Initially, there was a "hit hard and hit early" approach to treatment, implying that all patients should be treated with combination therapy as soon as possible . In the early 2000s, providers started to withhold therapy in patients with relatively preserved CD4 counts given the toxicity of early ART and the lack of clinical evidence proving a benefit of therapy for those with normal CD4 counts. However, advances in HIV therapy in the last decade have shifted the risk-benefit ratio back to earlier treatment. The standard of care today is to treat essentially all HIV-infected patients with ART.
This topic will discuss when to initiate ART and will review the evidence supporting early initiation of therapy. The selection of specific medications, patient evaluation, and laboratory monitoring are discussed elsewhere. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient" and "Patient monitoring during HIV antiretroviral therapy".)
BENEFITS OF ANTIRETROVIRAL THERAPY
In HIV-infected individuals, antiretroviral therapy (ART) reduces mortality as well as serious AIDS- and non-AIDS-related complications. It also prevents transmission of HIV to others.
For the patient — For HIV-infected patients, ART can result in sustained suppression of HIV RNA. This leads to improvements in cellular immunity (ie, CD4 count), and a subsequent reduction in AIDS-related morbidity and mortality. Suppression in HIV RNA can also result in a reduction in HIV-immune activation (eg, proinflammatory cytokines, chronic inflammation, and T-cell activation), which can otherwise lead to end-organ damage (eg, coronary artery disease, liver and kidney disease, neurologic disease, malignancy) .
The benefits of ART can vary based upon the CD4 count. As an example, the patient's baseline CD4 count can impact treatment outcomes. This was illustrated in a collaborative study of 62,760 treatment-naïve patients in Europe and the United States . Over a mean follow-up of 3.3 years, 2039 patients died. Although the overall risk of mortality was reduced by approximately 50 percent among those who initiated ART compared with those who did not, the absolute survival benefit depended upon the patient’s level of immunocompromise before treatment. In analyses stratified by CD4 count, the corresponding hazard ratios for all-cause mortality for treated versus untreated patients were:To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- 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 1998; 338:853.
- Marschner IC, Collier AC, Coombs RW, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis 1998; 177:40.
- Sterne JA, Hernán MA, Ledergerber B, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005; 366:378.
- Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995; 333:450.
- Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 1999; 179:859.
- HIV-CAUSAL Collaboration, Ray M, Logan R, et al. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010; 24:123.
- Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009; 360:1815.
- Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients, Lodwick RK, Sabin CA, et al. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study. Lancet 2010; 376:340.
- Hogg RS, Yip B, Chan KJ, et al. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA 2001; 286:2568.
- Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725.
- Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998; 351:543.
- Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 1987; 317:185.
- When To Start Consortium, Sterne JA, May M, et al. 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.
- Rodríguez B, Sethi AK, Cheruvu VK, et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 2006; 296:1498.
- May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS 2007; 21:1185.
- Strategies for Management of Antiretroviral Therapy (SMART) Study Group, Emery S, Neuhaus JA, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008; 197:1133.
- Jaén A, Esteve A, Miró JM, et al. Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain). J Acquir Immune Defic Syndr 2008; 47:212.
- HIV-CAUSAL Collaboration, Cain LE, Logan R, et al. 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.
- Phillips AN, Gazzard B, Gilson R, et al. Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AIDS 2007; 21:1717.
- Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010; 363:257.
- Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis 2014; 14:281.
- 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:e5575.
- INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med 2015; 373:795.
- TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, et al. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med 2015; 373:808.
- Neuhaus J, Angus B, Kowalska JD, et al. Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV. AIDS 2010; 24:697.
- Lucas GM, Eustace JA, Sozio S, et al. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS 2004; 18:541.
- Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren J, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283.
- Lichtenstein KA. CD4+ T-cell counts < 350 cells/mm3 are a risk factor for cardiovascular disease in the HIV Outpatient Study (HOPS). XVII International AIDS Conference. 2008. Mexico City, Mexico.
- Borges ÁH, Neuhaus J, Babiker AG, et al. Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection. Clin Infect Dis 2016; 63:1668.
- Bower M, Palmieri C, Dhillon T. AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis 2006; 19:14.
- Tedaldi E, Peters L, Neuhaus J, et al. Opportunistic disease and mortality in patients coinfected with hepatitis B or C virus in the strategic management of antiretroviral therapy (SMART) study. Clin Infect Dis 2008; 47:1468.
- Tedaldi EM, Baker RK, Moorman AC, et al. Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2003; 36:363.
- Centers for Disease Control and Prevention (CDC). Mortality among patients with tuberculosis and associations with HIV status --- United States, 1993-2008. MMWR Morb Mortal Wkly Rep 2010; 59:1509.
- Uthman OA, Okwundu C, Gbenga K, et al. Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. Ann Intern Med 2015; 163:32.
- Günthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA 2016; 316:191.
- Phillips AN, Leen C, Wilson A, et al. Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study. Lancet 2007; 370:1923.
- Khanna N, Opravil M, Furrer H, et al. CD4+ T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapy. Clin Infect Dis 2008; 47:1093.
- Nash D, Katyal M, Brinkhof MW, et al. Long-term immunologic response to antiretroviral therapy in low-income countries: a collaborative analysis of prospective studies. AIDS 2008; 22:2291.
- García 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 2004; 36:702.
- Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet 2007; 370:407.
- Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 2009; 48:787.
- Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis 2014; 58:1312.
- Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009; 51:130.
- Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011; 365:1492.
- 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.
- 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.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf (Accessed on October 17, 2017).
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on October 18, 2017).
- Kamya P, Tsoukas CM, Boulet S, et al. T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers. AIDS Res Ther 2011; 8:20.
- Okulicz JF, Lambotte O. Epidemiology and clinical characteristics of elite controllers. Curr Opin HIV AIDS 2011; 6:163.
- Boufassa F, Saez-Cirion A, Lechenadec J, et al. CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory. PLoS One 2011; 6:e18726.
- Okulicz JF, Grandits GA, Weintrob AC, et al. CD4 T cell count reconstitution in HIV controllers after highly active antiretroviral therapy. Clin Infect Dis 2010; 50:1187.
- World Health Organization. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. September 2015. http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1 (Accessed on September 30, 2015).
- BENEFITS OF ANTIRETROVIRAL THERAPY
- For the patient
- - Patients with a CD4 count ≤350 cells/microL
- - Patients with a CD4 count >350 cells/microL
- - HIV-related comorbidities
- - Hepatitis B or C coinfection
- - Tuberculosis
- To reduce HIV transmission
- WHOM TO TREAT
- URGENCY OF ART INITIATION
- General approach
- Increased urgency
- - CD4 count ≤200 cells/microL
- - Patients with HIV-related conditions
- - Patients with opportunistic infections
- - Pregnant women
- - Chronic hepatitis B virus infection
- - Patients with acute HIV infection
- HIV CONTROLLERS
- PATIENTS IN RESOURCE-LIMITED SETTINGS
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS