Treatment Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: An Update

On April 8, 2015, HSS released updated HIV treatment guidelines. ¹ The original 1998 guidelines for the use of antiretroviral agents for treating adults and adolescents infected with HIV emphasized the benefit of potent combination antiretroviral therapies (ARTs) that included protease inhibitors (PIs). ^2,3 Since then there have been more than 25 HSS guidelines focusing primarily on when to initiate ART and which ART to prescribe. The question of when to start ART had been controversial, but the most recently issued guidelines have addressed this question. For the first time, HSS recommends ART for all individuals infected with HIV regardless of CD4+ T-cell count. ¹ The timely initiation of effective ART with an associated reduction in HIV viremia benefits patients infected with HIV and substantially decreases transmission of HIV to uninfected sexual partners. ³

Three large, international randomized placebo-controlled studies conducted between 2002 and 2015 provide evidence that the benefits of ART outweigh the potential deleterious effects of long-term ART. The Strategies for Management of Antiretroviral Therapy (SMART) was the first published study in this trifecta. ^4,5 Given concern about the adverse effects (AEs) of ART, particularly PIs, this study was designed to investigate whether long-term ART was associated with more toxicities than was deferred therapy, determined by CD4+ cell counts. The study was halted prematurely, because the risk of death or grade-4 toxicity was statistically greater among those receiving episodic ART than among those on continuous therapy. The SMART trial demonstrated that ART therapy was beneficial, but it did not determine when to initiate ART, particularly in asymptomatic persons. ⁵

It was thought that the risk of transmission of HIV through sexual contact or shared drug paraphernalia was significantly lower for patients on ART who achieve viral suppression compared with those with uncontrolled viremia. The HIV Prevention Trials Network study enrolled HIV-serodiscordant couples to examine transmission of HIV. The trial compared HIV-positive patients who initiated ART when their CD4+ cell count was between 350 to 550 cells/mm3 with patients who began therapy when their CD4+ cell count was < 250 cells/mm3 or when an AIDS-defining illness was diagnosed. The difference in the rate of transmission to a HIV-negative partner was dramatic. The rate was 96% less among those in the early-therapy group vs those in the deferred-therapy group. In addition, there was a 40% reduction in the progression of HIV-related disease in the participants randomized to the early-therapy group. ⁶

In March 2011, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), which conducted SMART, initiated the Strategic Timing of AntiRetroviral Treatment (START) study to define the optimal time to begin ART among asymptomatic patients with a CD4+ count of > 350 cells/mm3. Patients with a CD4+ cell count of > 500 cells/mm3 were randomized to either initiate ART, or defer ART until the CD4+ cell count fell to < 350 cells/mm3 or until an AIDS-defining illness occurred ^.7 On May 15, 2015, the study was terminated early. Based on an interim analysis, the data safety and monitoring board announced that the risk for a serious AIDS-related event, serious non-AIDS-related event, or death from any cause was 57% less in the early treatment group. When compared with patients who delayed ART, for those on ART, serious AIDS-related events were reduced 72%, and serious non-AIDS events were reduced 39%. ⁸ A similar study conducted in the Ivory Coast from March 2008 to January 2015 also favored early rather than deferred ART ^.9