Written by The INSIGHT START Study Group

This article originally appeared on the New England Journal of Medicine website.

The immune compromise caused by the human immunodeficiency virus (HIV) is characterized by a loss of CD4+ T cells. Rates of HIV-associated complications and death increase as the number of these cells in peripheral blood (CD4+ count) declines. It has been general practice to defer the initiation of antiretroviral therapy in asymptomatic patients with a CD4+ count above a certain threshold level. The applicable threshold has changed over time, and recommendations remain inconsistent across various guidelines.

Randomized studies that have assessed the benefits and risks of treating patients with HIV infection sooner rather than later have largely enrolled patients with a CD4+ count of less than 500 cells per cubic millimeter. In such studies, “later” has been defined as a CD4+ count of 200 or 250 cells per cubic millimeter. These data, along with observational studies, provide strong evidence for the initiation of antiretroviral therapy in patients with a CD4+ count of 350 cells per cubic millimeter.

Evidence for initiating antiretroviral therapy in patients with a CD4+ count of more than 350 cells per cubic millimeter comes mainly from the results of observational studies. However, the findings of these studies are inconsistent and are subject to residual confounding. Furthermore, most studies have focused only on the risks of the acquired immunodeficiency syndrome (AIDS) and death and have not fully addressed the risks and benefits of initiating antiretroviral therapy in patients with a high CD4+ count, in whom complications and death are largely attributed to non–AIDS-related events. Some studies have raised concern about the adverse effects of antiretroviral therapy on cardiovascular and renal disease, particularly in an aging HIV-positive population. However, in an earlier large, randomized study, the continuous use of antiretroviral therapy, as compared with intermittent therapy, reduced these risks.

Given the small absolute risk of AIDS among patients with a high CD4+ count, it is important to establish whether it is safe and beneficial to initiate antiretroviral therapy in asymptomatic patients who have a CD4+ count that is much higher than 350 cells per cubic millimeter. This information is particularly important given the known benefits of antiretroviral therapy in reducing infectivity.

In response to this gap in evidence, we designed a multicontinental randomized study, Strategic Timing of Antiretroviral Therapy (START), to determine the risks and benefits of the immediate initiation of antiretroviral therapy in asymptomatic HIV-positive patients who have a CD4+ count of more than 500 cells per cubic millimeter, as compared with deferring initiation until the CD4+ count is 350 cells per cubic millimeter.

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