Initiating Antiretroviral Therapy in Patients with CD4 T-Cell Counts > 500 cells/mcL May Reduce HIV Infection-Related Morbidity Compared to Later Initiation

EBM Focus - Volume 10, Issue 34

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References - START Trial (N Engl J Med 2015 Jul 20 early online), TEMPRANO ANRS 12136 Trial (N Engl J Med 2015 Jul 20 early online) (level 2 [mid-level] evidence)

Antiretroviral therapy (ART) is the cornerstone of HIV infection management, significantly reducing HIV morbidity and mortality by controlling viral replication. Determining when to initiate treatment can be challenging, especially in low-resource settings. Physicians must take into account factors such as CD4 T-cell count and viral load, as well as other factors including adverse reactions, treatment adherence, and cost. Recommendations for initiation of ART in asymptomatic adults are generally based on CD4 T-cell counts; the level needed to start therapy has been progressively raised over the last decade and favors earlier treatment (N Engl J Med 2013 Mar 7;368(10):886). While treatment guidelines in the United States recommend antiretroviral therapy for all HIV-infected patients, the evidence to support this recommendation was strongest for starting therapy when CD4 T-cell counts are < 500 cells/mcL. To address this evidence gap, two recent randomized trials compared immediate initiation of ART vs. delaying ART until specific clinical criteria have been met in asymptomatic, treatment naïve patients with HIV infection.

The START trial included 4,685 adults (mean age 36 years, 73% male) from 35 countries with CD4 T-cell counts > 500 cells/mcL who were randomized to immediate vs. delayed ART. The protocol for delayed ART initiation included starting therapy when the patient had a CD4 T-cell count ≤ 350 cells/mcL, or the patient developed AIDS or another condition requiring the initiation of ART (such as pregnancy). This trial was terminated early at the recommendation of the data and safety monitoring board after the immediate ART group demonstrated superior outcomes. At a mean follow-up of 3 years, 1.8% of patients in the immediate therapy group and 4.1% of patients in the delayed therapy group experienced at least one of the composite outcomes of serious AIDS-related events, serious non-AIDS-related events, or death (p < 0.001, NNT 44). Serious AIDS-related events, serious non-AIDS-related events, tuberculosis, and Kaposi’s sarcoma were all significantly reduced in the immediate initiation group. Of note, the majority of adverse events observed in this trial occurred when the CD4 count was above 500/mcL. There were no significant differences between groups in all-cause mortality, grade 4 adverse events (defined as potentially life-threatening events requiring medical intervention not attributable to AIDS), or unscheduled hospitalizations.

The TEMPRANO trial included 2,056 patients (median age 35 years, 75% female) from Ivory Coast with CD4 T-cell counts < 800 cells/mcL, and randomized patients using a 2 by 2 factorial design to immediate vs. delayed ART initiation and isoniazid preventative therapy for 6 months vs. no isoniazid preventative therapy. In this trial, delayed ART initiation was defined by the current WHO criteria at the time of enrollment, and patients were followed for 30 months. Comparing immediate vs. delayed initiation of ART, death or severe HIV-related illness occurred in 6.2% vs. 10.9%, respectively (p < 0.05, NNT 22). AIDS, tuberculosis, and invasive bacterial disease were all significantly less common in patients immediately treated with ART compared to those with delayed treatment initiation. Grade 3-4 adverse events were significantly increased in the immediate ART group compared to the delayed ART group during the first 6 months after randomization. However, this trend was reversed in the 6-30 month post-randomization and immediate ART was associated with a significantly reduced risk of serious adverse events compared with delayed ART in this time period.

These two randomized trials demonstrate mortality and morbidity benefits to ART initiation in HIV-infected patients with CD4 T-cell counts > 500 cells/mcL. Although both trials were unblinded and the event rates were relatively low, they show a clear benefit to early initiation of ART in asymptomatic patients with HIV infection. This benefit was also observed without an increase in the rate of serious adverse events. Together, the results of these trials provide clear evidence that immediate initiation of ART reduces the development of AIDS, AIDS-related complications, and death in HIV-infected patients regardless of CD4 T-cell counts. Based on these results, the United States Department of Health and Human Services has now issued a strong recommendation for initiation of ART in all adults with HIV infection, including those with CD4 T-cell counts > 500 cells/mcL (AIDSinfo 2015 July 28).

For more information, see the Initiating therapy in patients with HIV infection topic in DynaMed Plus. DynaMed users click here.