Statement by the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents Regarding Results from the START and TEMPRANO Trials
Results for two pivotal randomized controlled trials (START1 and TEMPRANO2) were recently published, both demonstrating that the clinical benefits of antiretroviral therapy (ART) are greater when ART is started early, with pre-treatment CD4 T lymphocyte (CD4) counts >500 cells/mm3, than when initiated at a lower CD4 cell count threshold. The Panel already recommends ART for all HIV-infected patients to reduce the risk of disease progression. However, until the results of these two studies became available, the Panel’s recommendations for starting ART in patients with CD4 cell counts 350 to 500 cells/mm3 (AII)a and >500 cells/mm3 (BIII)a were primarily based on data from observational cohort studies and expert opinion.
With the availability of the START and TEMPRANO trial results, the Panel’s overall recommendation remains the same: ART is recommended for all HIV-infected patients regardless of pre-treatment CD4 count. However, the strength of the recommendation will be changed to AIa (strong recommendation based on data from randomized controlled trials) for all patients.
The additional benefit of ART in reducing the risk of HIV transmission further underscores the potential public health value of this recommendation. The Panel continues to emphasize that patients starting ART should be willing and able to commit to treatment and to understand the benefits and risks of therapy and the importance of adherence. On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but therapy should be initiated as soon as is feasible.
It should be noted that neither of these trials included adolescents. However, our recommendations have been extrapolated to adolescents based on the expectation that they will derive benefits from early ART similar to those observed in adults.
Below are summaries of the results from these two randomized controlled trials.
START (Strategic Timing of AntiRetroviral Treatment) Trial1
The START trial is a large, multinational, randomized controlled clinical trial designed to evaluate the role of early ART in asymptomatic HIV-infected patients in reducing a composite clinical endpoint of AIDS-defining illnesses, serious non-AIDS events, or death. In this study, HIV-infected ART-naive adults (aged >18 years) with CD4 counts >500 cells/mm3 were randomized to either initiate ART immediately (early arm) or wait until CD4 counts declined to <350 cells/mm3 or until the development of a clinical indication for therapy (deferred arm).
A total of 4,685 participants were enrolled in this study, with a mean follow-up of three years. In May 2015, interim study data reviewed by the study’s independent Data and Safety Monitoring Board (DSMB) showed a significantly greater number of clinical events in the deferred therapy arm than in the early therapy arm. On the basis of these interim results, the DSMB concluded that the data provided significant evidence of the benefit of early ART and recommended that the study sponsor make the results available to the public and offer treatment to any study participants in the deferred therapy arm not yet on ART. The study participants will continue to be followed in this study until the end of 2016.
When the randomized arms of the study were closed, the primary endpoint of serious AIDS or non-AIDS events was reported in 42 participants (1.8%, or 0.60 events/100 person-years) in the early ART arm and 96 participants (4.1%, or 1.38 events/100 person-years) in the deferred ART arm (hazard ratio, 0.43, favoring early ART [95% confidence interval (CI), 0.30–0.62, P < .001]). The most common clinical events reported were tuberculosis and AIDS and non-AIDS malignancies.
TEMPRANO ANRS 12136 Study2
The TEMPRANO study is a randomized controlled trial conducted in Cote d’Ivoire. Using a two-by-two (2 X 2) factorial design, HIV-infected participants with CD4 counts <800 cells/mm3 were randomized to either immediate ART or deferred ART (based on the national guidelines criteria for starting treatment) and with or without isoniazid for prevention of tuberculosis for six months. The primary study endpoint was a combination of all-cause deaths, AIDS diseases, non-AIDS malignancies, and non-AIDS invasive bacterial diseases. More than 2,000 participants enrolled in the trial, with a median follow-up of 30 months. Among the participants, 849 had baseline CD4 counts >500 cells/mm3. In the analysis of this high CD4 count subgroup, 68 primary outcome events were reported in 61 patients. The risk of primary events was lower with immediate ART than with deferred ART, with a hazard ratio of 0.56 in favor of early ART (CI, 0.33–0.94). On the basis of these results, the study team concluded that early ART is beneficial in reducing the number of these clinical events.
a.Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
1. INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. Jul 20 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26192873.
2. Temprano ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. Jul 20 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26193126.