The prevailing opinion among experts regarding the optimal CD4 T-cell count at which to start patients on antiretroviral therapy (ART) has shifted several times during the evolution of HIV treatment. These shifts reflect attempts to strike a balance between preventing HIV-associated illness and death and minimizing medication-related toxicity. Two large randomized controlled clinical trials, the START study and the TEMPRANO study, now demonstrate that earlier treatment with ART is most beneficial to boost immune recovery and prevent clinical events.
The Strategic Timing of Antiretroviral Treatment (START) study was a randomized trial initiated in 2009 across 6 geographic regions: Africa, Europe and Israel, North America, South America and Mexico, Australia, and Asia. It assigned 4,685 patients with CD4 counts of >500 cells/µL (median 651 cells/µL) to two groups: immediate initiation of ART vs delay of ART until CD4 counts were <350 cells/µL or until development of another condition that warranted initiation of ART. Subjects were followed for an average of 3 years, but the study was halted by the Data Safety Monitoring Board when the benefits of immediate initiation of ART were seen--there was a more than 50% decrease in primary outcomes (any serious event [AIDS related or non-AIDS related] or death) in the immediate group (1.8%) vs the delayed group (4.8%). The most common events included cardiovascular events, non-AIDS-defining cancers, and tuberculosis. The hazard ratio (HR) for developing any serious event or death in the immediate group compared with the deferred group was 0.43 (95% confidence interval [CI]: 0.30-0.62; p < .001). The study authors did not find any differential benefits of immediate ART associated with characteristics such as sex, age, baseline CD4 count or viral load, or geographic region.
The TEMPRANO study was conducted in 2,056 HIV-1- or HIV-2-infected patients with CD4 counts of ≤800 cells/µL in Ivory Coast. It used a 2x2 factorial design to assess 4 potential treatment strategies: deferred ART (until the patient met World Health Organization criteria for initiation), immediate ART, 6 months of preventative isoniazid therapy, or a combination of immediate ART plus 6 months of isoniazid. As with the START study, the primary outcome was a composite that included development of an AIDS-defining condition, occurrence of non-AIDS cancers, non-AIDS bacterial diseases, or all-cause death after 30 months. The hazard of death or serious HIV-related disease was substantially lower with the early ART initiation group compared with the deferred ART group (HR = 0.56; 95% CI: 0.41-0.76) and also lower with isoniazid compared with no isoniazid (HR = 0.65; 95% CI: 0.48-0.88). The efficacy of the interventions was mainly driven by the treatments' prevention of tuberculosis.
Although the U.S. Department of Health and Human Services HIV treatment guidelines already recommend starting ART regardless of CD4 cell count, these recommendations were based on observational studies (Level of Evidence = AII) that suggested the benefits of early initiation. START and TEMPRANO are landmark studies because they provide the highest level of evidence, randomized controlled trial data (Level of Evidence = AI), to support this important recommendation.