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Discussion

WHO Guidelines: Antiretroviral Therapy for Adults and Adolescents

The introduction and subsequent expansion of antiretroviral therapy has led to dramatic declines in AIDS-related morbidity and mortality in regions where these medications have become widely available[1]. The World Health Organization (WHO) has published recommendations regarding the optimal use of antiretroviral therapy in resource-limited settings since 2002, emphasizing a public-health approach that underscores the urgent need for rapid scale-up of ART programs in many of the countries most affected by the HIV pandemic. The WHO released the most recent update to these guidelines in early 2010[2] and these updated guidelines utilize the standard WHO clinical staging system (Figure 1WHO Clinical Stage 1WHO Clinical Stage 2WHO Clinical Stage 3WHO Clinical Stage 1Figure Source). The following discussion will focus on the indications for initiating antiretroviral therapy in resource-limited settings. Specific cases are in development that will discuss recommended antiretroviral regimens and the use of antiretroviral therapy to prevent mother-to-child HIV transmission in resource-limited settings.

Indications for Initiating Antiretroviral Therapy for Adults and Adolescents

Reflecting an increasing body of evidence favoring earlier initiation of antiretroviral therapy, the 2010 WHO guidelines expand the eligibility criteria for HIV-infected adults and adolescents significantly beyond the 2006 WHO criteria (Figure 2) and include the following key recommendations regarding initiation of antiretroviral therapy in HIV-infected adults and adolescents[2].

  • All patients with absolute CD4 counts less than 350 cells/mm3 should initiate therapy, regardless of clinical stage.
  • All patients with WHO clinical stage 3 or 4 disease should initiate therapy, regardless of CD4 count.
  • All patients with WHO clinical stage 1 or 2 disease should have access to CD4 testing to determine whether therapy should be initiated.
  • All patients with active tuberculosis or active hepatitis B virus (HBV) co-infection that requires therapy should have antiretroviral therapy initiated, regardless of CD4 count.

Evidence Base for the 2010 WHO Guidelines

The WHO based the 2010 antiretroviral treatment recommendations on a systematic review of the evidence[3]. From this review, the WHO concluded "moderate-quality evidence supports strong recommendations for the timing of ART initiation for the critical outcomes of absolute risk of death, disease progression (including tuberculosis), and the occurrence of serious adverse events[1]." These conclusions were based primarily upon one randomized controlled trial—the CIPRA HT-001 trial[4], one post-hoc analysis from a nested randomized controlled trial—the SMART trial[5,6], and observational studies[7,8].

CIPRA HT-001: The CIPRA HT-001 trial, performed in Haiti, randomized 816 asymptomatic ART-naïve patients with CD4 counts between 200 and 350 cells/mm3 to either initiate therapy immediately versus wait until either the CD4 count dropped below 200 cells/mm3 or a clinical stage 3 or 4 condition developed[4]. The primary endpoint of this trial was survival; incidence of tuberculosis disease was a secondary endpoint. The investigators halted the study after a median patient follow-up of 21 months due to significantly lower risks of death and incident TB in the early-therapy group (Figure 3 and Figure 4).

SMART Trial: The SMART trial[5], originally designed to evaluate the clinical utility of structured treatment interruptions, randomized more than 5000 participants from both high- and low-resource settings to receive either continuous antiretroviral treatment (the "viral suppression" arm) versus deferring ART until the CD4 count dropped below 250 cells/mm3 (the "drug conservation" arm). A total of 477 patients with CD4 counts over 350 cells/mm3 who were ART-naïve or who had not received ART for the six months prior to study entry were thus randomized to start ART immediately versus defer ART initiation until after their CD4 count dropped to below 250 cells/mm3. In this subset analysis[6], earlier initiation of therapy was associated with a significant reduction of disease progression and serious non-AIDS events (Figure 5).

Observation Studies: The findings in the CIPRA and SMART trials, which suggested a clinical benefit of initiating therapy for asymptomatic HIV-infected patients at higher CD4 counts, are also supported by multiple observational studies, including the ART-CC[7] and NA-ACCORD[8] studies, though these studies did not involve patients in resource-limited settings.

Global Levels of Coverage for these Guidelines

Compared with the last set of guidelines published by the WHO in 2006, these treatment recommendations represent a significant expansion of the pool of HIV-infected individuals for whom antiretroviral therapy is indicated. Countries already struggling to achieve universal coverage under prior guidelines now face additional challenges to further expand access to ART despite limited health resources. Although ART coverage has expanded steadily over the past decade (Figure 6), significant gaps in access remain: as of December 2009[1], the overall coverage of individuals living in resource-limited settings who merit ART based on the 2010 WHO Guidelines was estimated to be 36% (5.2 million out of 14.6 million), including only 31% in East/South/South-east Asia, and just 11% in North Africa and the Middle-East (Figure 7).

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    Figure 1: WHO Clinical Staging of HIV Disease in Adults and Adolescents. Image 1. WHO Clinical Stage 1
    Figure 1

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    Figure 2. Recommendations from the 2010 World Health Organization Guidelines Regarding Initiation of Antiretroviral Therapy for HIV-infected Adults and Adolescents

    Source: World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach (2010 version). WHO, 2010.


    Figure 2
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    Figure 3. CIPRA-001 HT trial: Kaplan-Meier Estimates of Survival in the Early-Treatment and Standard-Treatment Groups.

    In this open label trial conducted in Haiti, 816 HIV-infected individuals with absolute CD4 counts between 200 and 350 cells/mm3 were randomized to either early-treatment (immediate initiation of HAART) or standard-treatment (initiation of HAART when CD4 count dropped to 200 cells/mm3 or less or when clinical AIDS developed). There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P = 0.001).

    Source: Severe P, Juste MAJ, Ambroise A et al. Early versus Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti. N Engl J Med. 2010;363:257-65. Reproduced with permission from the Massachusetts Medical Society, Inc. Copyright 2010 © Massachusetts Medical Society, Inc. All rights reserved.


    Figure 3
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    Figure 4. CIPRA-001 HT trial: Kaplan-Meier Estimates of the Probability of Remaining Free from Active Tuberculosis in the Early-Treatment and Standard-Treatment Groups.

    In this open-label trial conducted in Haiti, 816 HIV-infected individuals with absolute CD4 counts between 200 and 350 cells/mm3 were randomized to either early-treatment (immediate initiation of HAART) or standard-treatment (initiation of HAART when CD4 count dropped to 200 cells/mm3 or less or when clinical AIDS developed). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P = 0.01).

    Source: Severe P, Juste MAJ, Ambroise A et al. Early versus Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti. N Engl J Med. 2010;363:257-65. Reproduced with permission from the Massachusetts Medical Society, Inc. Copyright 2010 © Massachusetts Medical Society, Inc. All rights reserved.


    Figure 4
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    Figure 5. SMART Substudy

    In this sub-study of the SMART trial, clinical outcomes were tracked among 477 trial participants not on antiretroviral therapy who had a CD4 count greater than 350 cells/mm3 at baseline and who were randomized to either initiate continuous antiretroviral therapy (Viral Suppression group) versus defer therapy until the CD4 count dropped below 250 cells/mm3 (Drug Conservation group). Compared with the Viral Suppression group, the Drug Conservation group a higher incidence of Opportunistic Disease (OD) or Death, opportunistic diseases, and serious non-AIDS events.

    Source: Strategies for Management of Antiretroviral Therapy (SMART) Study Group, Lundgren JD, Babiker A, et al. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ cell counts and HIV RNA levels during follow-up. J Infect Dis. 2008;197:1145-55.


    Figure 5
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    Figure 6. Number of people receiving antiretroviral therapy in low- and middle-income countries, by region, 2002–2009

    The total number of patients living with HIV in low- and middle-income countries who received antiretroviral therapy rose substantially between 2002 and 2009

    Source: World Health Organization, UNAIDS, UNICEF. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010.


    Figure 6
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    Figure 7. Estimated percentage coverage with antiretroviral therapy in low- and middle-income countries by region, based on WHO 2010 and 2006 guidelines, December 2009

    Despite the expansion of antiretroviral therapy in low- and middle-income countries, less than half of persons living with HIV who are eligible for antiretroviral therapy under the latest WHO guidelines are receiving antiretroviral therapy.

    Source: World Health Organization, UNAIDS, UNICEF. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010.


    Figure 7