Objective: The Strategic Timing of AntiRetroviral Treatment (START) trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation. However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified. To supplement the published intention-to-treat (ITT) effect estimates, here we estimate the per-protocol effect of immediate versus deferred ART initiation in START. Design: The START trial randomized 4685 HIV-positive participants with CD4+ cell counts more than 500 cells/ml to start ART immediately after randomization (immediate initiation group) or to wait until the CD4+ cell count dropped below 350 cells/ml or an AIDS diagnosis (deferred initiation group). Methods: We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate initiation group, and deferred initiation groups had all the trial participants adhered to the protocol. Results: We estimated that the 5-year risk of the composite outcome would have been 3.2% under immediate ART initiation and 7.0% under deferred initiation. The difference of 3.8% (95% confidence interval 1.5, 6.5) was larger than the ITT effect estimate of 3.1%, corresponding to a difference in effect estimates of 0.72% (-0.35, 2.35). Conclusion: The ITT effect estimate may underestimate the benefit of immediate ART initiation by 23%. This estimate can be used by patients and policy-makers who need to understand the full extent of the benefit of changes in ART initiation policies.
Bibliographical noteFunding Information:
NIH R01 AI102634, PCORI ME-1503-28119, NIH grants UM1-AI068641 and UM1-AI120197, Y1-AI- 5072, and NIH R01 AI100654. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The views expressed are those of the author(s) and do not necessarily reflect the official views of the Uniformed Services University of the Health Sciences, the NIH, the Department of Defense, or the Departments of the Army, Navy, or Air Force.
Copyright © 2016 Wolters Kluwer Health, Inc.
- Antiretroviral treatment
- Per-protocol effect