title: The per-protocol effect of immediate versus deferred antiretroviral therapy initiation.
abstract: 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.
  
  
  
  The START trial randomized 4685 HIV-positive participants with CD4 cell counts more than 500 cells/μl to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 cell count dropped below 350 cells/μl or an AIDS diagnosis (deferred initiation group).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors: aDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts bDivision of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA cDepartment of Infectious Diseases, Rigshospitalet, University of Copenhagen, København, Denmark dResearch Department of Infection & Population Health, University College London, London, United Kingdom eDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina fInfectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences gHenry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA hMedical Research Council, Clinical Trials Unit in University College London, London, United Kingdom iUniversity of Wuerzburg Medical Center, Würzburg, Germany jThe Kirby Institute, Sydney, Australia kDepartment of Biostatistics, Harvard T.H. Chan School of Public Health lHarvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.
authors: Sara
authors: S
authors: Lodi
authors: Shweta
authors: S
authors: Sharma
authors: Jens D
authors: JD
authors: Lundgren
authors: Andrew N
authors: AN
authors: Phillips
authors: Stephen R
authors: SR
authors: Cole
authors: Roger
authors: R
authors: Logan
authors: Brian K
authors: BK
authors: Agan
authors: Abdel
authors: A
authors: Babiker
authors: Hartwig
authors: H
authors: Klinker
authors: Haitao
authors: H
authors: Chu
authors: Matthew
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authors: Law
authors: James D
authors: JD
authors: Neaton
authors: Miguel A
authors: MA
authors: Hernán
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D044966:Anti-Retroviral Agents
keywords: antiretroviral treatment; g-formula; HIV; per-protocol effect