title: Extended follow-up confirms early vaccine-enhanced risk of HIV acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus HIV vaccine (Step Study).
abstract: BACKGROUND
  The Step Study tested whether an adenovirus serotype 5 (Ad5)-vectored human immunodeficiency virus (HIV) vaccine could prevent HIV acquisition and/or reduce viral load set-point after infection. At the first interim analysis, nonefficacy criteria were met. Vaccinations were halted; participants were unblinded. In post hoc analyses, more HIV infections occurred in vaccinees vs placebo recipients in men who had Ad5-neutralizing antibodies and/or were uncircumcised. Follow-up was extended to assess relative risk of HIV acquisition in vaccinees vs placebo recipients over time.
  
  
  METHODS
  We used Cox proportional hazard models for analyses of vaccine effect on HIV acquisition and vaccine effect modifiers, and nonparametric and semiparametric methods for analysis of constancy of relative risk over time.
  
  
  RESULTS
  One hundred seventy-two of 1836 men were infected. The adjusted vaccinees vs placebo recipients hazard ratio (HR) for all follow-up time was 1.40 (95% confidence interval [CI], 1.03-1.92; P= .03). Vaccine effect differed by baseline Ad5 or circumcision status during first 18 months, but neither was significant for all follow-up time. The HR among uncircumcised and/or Ad5-seropositive men waned with time since vaccination. No significant vaccine-associated risk was seen among circumcised, Ad5-negative men (HR, 0.97; P=1.0) over all follow-up time.
  
  
  CONCLUSIONS
  The vaccine-associated risk seen in interim analysis was confirmed but waned with time from vaccination.
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington 98109-1024, USA. aduerr@hvtn.org
authors.forename: Ann
authors.initials: A
authors.lastname: Duerr
authors.forename: Yunda
authors.initials: Y
authors.lastname: Huang
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coombs
authors.forename: Jorge
authors.initials: J
authors.lastname: Sanchez
authors.forename: Carlos
authors.initials: C
authors.lastname: del Rio
authors.forename: Martin
authors.initials: M
authors.lastname: Casapia
authors.forename: Steven
authors.initials: S
authors.lastname: Santiago
authors.forename: Peter
authors.initials: P
authors.lastname: Gilbert
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000257:Adenoviridae Infections / Q000150:complications; D000328:Adult; D002944:Circumcision, Male; D005260:Female; D005822:Genetic Vectors; D015658:HIV Infections / Q000209:etiology / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D016016:Proportional Hazards Models; D012307:Risk Factors; D012725:Sexual Behavior; D013997:Time Factors; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000276:immunology; D019562:Viral Load
chemical_list: D016915:AIDS Vaccines; D014614:Vaccines, Synthetic