The START trial was designed and conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). A description of the contributions of the study members is provided in Section 2 in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Patients

HIV-positive patients who were 18 years of age or older and who had not yet initiated antiretroviral therapy, had no history of AIDS, and were in generally good health were eligible for the study if they had had two CD4+ counts of more than 500 cells per cubic millimeter at least 2 weeks apart within 60 days before enrollment. Women who were pregnant or breast-feeding at screening were not eligible; women who became pregnant during follow-up remained in the study. (For full details regarding the study design, see the study protocol, available at NEJM.org.) The study was approved by the institutional review board or ethics committee at each participating site, and written informed consent was obtained from all patients.

Study Design

We evaluated two strategies for initiating antiretroviral therapy: immediate initiation and deferred initiation until the CD4+ count declined to 350 cells per cubic millimeter or the development of an AIDS-related event or another condition that dictated the use of antiretroviral therapy (e.g., pregnancy).25,26 When the study was initiated in 2009, the deferral strategy was consistent with recommendations in most treatment guidelines.27-30 During the course of the study, some treatment guidelines changed. Because the evidence prompting these changes was limited, we did not revise the deferred-initiation strategy in our study.

The study protocol required the use of an approved drug combination derived from the guidelines of the Department of Health and Human Services as the first antiretroviral regimen in the two study groups (Section 3 in the Supplementary Appendix).27

Study End Points

The primary end point was a composite outcome that included two major components. The first was any serious AIDS-related event, which included death from AIDS or any AIDS-defining event (as outlined in the 1993 expanded surveillance document of the Centers for Disease Control and Prevention),31 with the exception of nonfatal herpes simplex virus infection and esophageal candidiasis, which were not counted because of their lesser severity. Hodgkin’s lymphoma was also counted as a serious AIDS-related event. The second component was any serious non–AIDS-related event, including death from causes other than AIDS. Serious non–AIDS-related events consisted of the following conditions: cardiovascular disease (myocardial infarction, stroke, or coronary revascularization) or death from cardiovascular disease, end-stage renal disease (initiation of dialysis or renal transplantation) or death from renal disease, liver disease (decompensated liver disease) or death from liver disease, non–AIDS-defining cancer (except for basal-cell or squamous-cell skin cancer) or death from cancer, and any death not attributable to AIDS.

An end-point review committee whose members were unaware of study-group assignments reviewed all reported serious AIDS-related and serious non–AIDS-related events and deaths using preestablished criteria.32 Events that the committee considered to be confirmed or probable were counted as end points.33,34

Secondary end points included serious AIDS-related events, serious non–AIDS-related events, death from any cause, grade 4 events, and unscheduled hospitalizations for reasons other than AIDS. Grade 4 events were defined as potentially life-threatening symptomatic events not attributable to AIDS that required a medical intervention.35 Grade 4 events and unscheduled hospitalizations (also referred to as “other serious clinical events”) were reported regardless of antiretroviral-therapy use or of any perceived association with antiretroviral therapy and were categorized according to codes used in the Medical Dictionary for Regulatory Activities, version 18.0.

The design and data collection plan for START have been reported previously.25 Key features, including a summary of a planned sample-size reestimation in February 2013, are provided in Section 4 in the Supplementary Appendix.

Interim Monitoring

Study investigators were unaware of interim summary results throughout the study. An independent data and safety monitoring board reviewed the results of interim analyses. An O’Brien–Fleming boundary and the Lan–DeMets spending function based on information time (fraction of primary events accrued) were used to adjust for a type I error in the analysis of the primary end point.36,37 The data and safety monitoring board was also asked to consider the consistency of findings for the two major components of the primary end point, serious AIDS-related and serious non–AIDS-related events, before making a recommendation to stop or modify the study. Consistency was specified as treatment hazard ratios for each component favoring the same treatment group, with a z statistic of more than 1.5.

On May 15, 2015, the board informed the National Institute of Allergy and Infectious Diseases (NIAID) and the study leadership that the primary question of the study had been answered and recommended that the findings be immediately disseminated. The board also recommended offering antiretroviral therapy to patients in the deferred-initiation group who were not receiving antiretroviral therapy and continuing to follow the study patients. By the time of this review, approximately 60% of the planned 213 primary events had occurred. On May 27, 2015, the study team leaders and NIAID notified investigators and patients of the findings.

Statistical Analysis

We compared the two study groups according to the intention-to-treat principle. We used time-to-event methods, including Kaplan–Meier survival curves and Cox proportional-hazards models, to compare the two groups for the primary end point, its two major components, death from any cause, and other serious clinical events. Follow-up was censored on May 26, 2015, or the date of last study contact.

For the primary end point, hazard ratios and 95% confidence intervals were estimated from a Cox model stratified according to six geographic regions (Africa, Europe and Israel, North America, South America and Mexico, Australia, and Asia) with a single binary indicator (immediate vs. deferred therapy). The proportional-hazards assumption was tested by including an interaction term between the randomized treatment indicator and log-transformed follow-up time.

We performed sensitivity analyses to assess the effects of the diagnostic certainty of events and of missing data (Section 5 in the Supplementary Appendix). The primary end point was also summarized for subgroups that were categorized according to eight predefined baseline characteristics. Heterogeneity of the treatment effect across subgroups was assessed by including terms for interactions between treatment and subgroup variables in expanded Cox models. Results of subgroup analyses should be interpreted with caution because there was no adjustment made for the type I error for the number of subgroups examined, and the statistical power was limited for subgroup analyses. Kaplan–Meier estimates were used to describe the time until the initiation of antiretroviral therapy. We compared the two study groups for changes in the CD4+ count from study entry through follow-up using longitudinal mixed models with random intercepts. Descriptive analyses (number and rate of primary end point) were performed for accumulated person-years within strata of specific, time-updated (latest) CD4+ counts during follow-up. Statistical analyses were performed with the use of SAS software, version 9.3 (SAS Institute). All P values are two-sided.