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. 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 and these updated guidelines utilize the standard WHO clinical staging system (Figure 1). 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.
- 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. 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.". These conclusions were based primarily upon one randomized controlled trial—the CIPRA HT-001 trial, one post-hoc analysis from a nested randomized controlled trial—the SMART trial,[,] and observational studies.[,]
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. 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).
SMART Trial: The SMART trial, 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 antiretroviral-naïve or who had not received antiretroviral therapy for the 6 months prior to study entry were thus randomized to start antiretroviral therapy immediately versus defer antiretroviral therapy initiation until after their CD4 count dropped to below 250 cells/mm3. In this subset analysis, earlier initiation of therapy was associated with a significant reduction of disease progression and serious non-AIDS events (Figure 4).
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 and NA-ACCORD 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 5), significant gaps in access remain: as of December 2009, 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 6).