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When to start antiretroviral therapy (ART) has kindled passionate debate since the early years of treatment, with the pendulum swinging from “hit early and hard” to “hold therapy until AIDS develops.” Today, better-tolerated drugs, evidence that uncontrolled viral replication leads to long-term complications, data from cohort studies, and realization that virologic suppression impedes HIV transmission have led to current U.S. treatment guidelines recommending that ART be offered at the time of HIV diagnosis, regardless of CD4-cell count. Until now, however, the strength of this recommendation has varied, ranging from AI (strong, based on results of randomized controlled trials) at <350 cells/mm3 to BIII (moderate, based on expert opinion) at >500 cells/mm3.
To more clearly define the optimal timing of ART initiation, the NIH funded the START trial. Launched in March 2011, this trial compared potential benefits and risks (e.g., developing AIDS or other serious conditions, including cardiovascular disease, cancer, kidney failure, and liver disease, or death) between early and deferred treatment (ART initiation at CD4 counts >500 cells/mm3 vs. counts <350 cells/mm3). The study involved 4685 HIV-infected, treatment-naive adults (median age, 36) at 215 sites in 35 countries with an average follow-up of 3 years. On May 27, 2015, the NIH released the study results early after an interim analysis revealed that, although the overall event rate was low (<3% over 3 years), the risk for serious illness or death was reduced by 53% in the early-treatment group. The reduction was greater for AIDS-related events than for non-AIDS events (70% and 33%, respectively).
Starting antiretroviral treatment early improves outcomes for HIV-infected individuals [press release]. Bethesda, MD: National Institutes of Health; May 27, 2015. (http://www.nih.gov/news/health/may2015/niaid-27.htm)
Comment
The study findings are reassuring and strengthen the belief that most of us have held and followed for many years: HIV irreparably damages the immune system, and therapy should be started at diagnosis. Guidelines will likely change rapidly in wealthier countries such as the U.K., where treatment has not been recommended for all, but not much will change in the guidelines or practice in the U.S.
In most countries, however, the implications are enormous. Recently updated WHO Treatment Guidelines recommend starting therapy regardless of CD4-cell count for serodiscordant couples, patients with tuberculosis or severe hepatitis B coinfection, pregnant women, and children aged <5 years, and at counts <500 cells/mm3 for all others. At that level, >25 million people globally would require treatment, yet only approximately 13 million are currently receiving it. If the WHO guidelines change as a result of the START trial, approximately 32 million people will be in need of ART — about 2.5 times as many as we are currently treating.
Implementation poses a second challenge. Worldwide, diagnosis frequently occurs late, and retention in care thereafter is often suboptimal. In the U.S., the median CD4 count at diagnosis is slightly over 300 cells/mm3, and nearly 50% of HIV-infected individuals are not retained in care. We need to step up efforts to improve the HIV care continuum and begin therapy regardless of CD4-cell count. It is the right thing to do.