Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection

Abstract

Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.

Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.

Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.

Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).

Figure 1. Antiretroviral Therapy, HIV RNA Suppression, and CD4+ Count

Shown are the percentages of patients who were receiving antiretroviral therapy (ART) and the percentages of patients who had an HIV RNA level of less than 200 copies per milliliter (Panel A) and the mean CD4+ count (Panel B) in the immediate-initiation group and the deferred-initiation group over a 5-year period. The vertical lines around the data points in Panel B indi cate 95% confidence intervals. Once ART was initiated, appropriate changes in regimens were mandated in cases of treatment-limiting adverse drug reactions or if the existing regimen did not fully suppress viral replication. Additional details regarding study-specified initial regimens of antiretroviral therapy and the frequency of specific antiretroviral drugs that were used in the initial regimens are provided in Section 3 and Table S2 in the Supplementary Appendix.

Figure 2. Primary and Secondary End Points

Shown are Kaplan–Meier estimates of the cumulative percentages of patients with the composite primary end point (a serious AIDS-related or serious non–AIDS-related event, including death) in the two study groups (Panel A). Secondary end points included serious AIDS-related events (Panel B), serious non–AIDS-related events (Panel C), death from any cause (Panel D), and grade 4 events (Panel E). Grade 4 events were defined as potentially life-threatening symptomatic events that were not attributable to AIDS and that required medical intervention.

Figure 3. Subgroup Analyses for the Primary End Point

For subgroups that were defined according to age, CD4+ count, HIV RNA level, and risk of coronary heart disease (CHD), the continuous variables were used for interaction tests. For 71 patients (1.5%), the Framingham Heart Study risk of CHD could not be calculated because of missing data. Of the patients with missing data, the primary end point occurred in 2 in the deferred-initiation group.