title: The impact of the 2013 WHO antiretroviral therapy guidelines on the feasibility of HIV population prevention trials.
abstract: BACKGROUND
  Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization (WHO) guidelines raising the ART initiation threshold to CD4 <500/µL could attenuate these trials' effect size by increasing ART usage in control clusters.
  
  
  METHODS
  We used a computational model to simulate strategies from a hypothetical cluster-randomized HIV prevention trial. The primary model outcome was the relative reduction in 24-month HIV incidence between control (ART offered with CD4 below threshold) and intervention (ART offered to all) strategies. We assessed this incidence reduction using the revised (CD4 <500/µL) and prior (CD4 <350/µL) control ART initiation thresholds. Additionally, we evaluated changes to trial characteristics that could bolster the incidence reduction.
  
  
  RESULTS
  With a control ART initiation threshold of CD4 <350/µL, 24-month HIV incidence under control and intervention strategies was 2.46/100 person-years (PY) and 1.96/100 PY, a 21% reduction. Raising the threshold to CD4 <500/µL decreased the incidence reduction by more than one-third, to 12%. Using this higher threshold, moving to a 36-month horizon (vs 24-month), yearly control-strategy HIV screening (vs bian-nual), and intervention-strategy screening every 2 months (vs biannual), resulted in a 31% incidence reduction that was similar to effect size projections for ongoing trials. Alternate assumptions regarding cross-cluster contamination had the greatest influence on the incidence reduction.
  
  
  CONCLUSIONS
  Implementing the 2013 WHO HIV treatment threshold could substantially diminish the incidence reduction in HIV population prevention trials. Alternative HIV testing frequencies and trial horizons can bolster this incidence reduction, but they could be logistically and ethically challenging. The feasibility of HIV population prevention trials should be reassessed as the implementation of treatment guidelines evolves.
authors.affiliation: Medical Practice Evaluation Center, Department of General Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Ross
authors.affiliation: Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Frank
authors.initials: F
authors.lastname: Tanser
authors.affiliation: Medical Practice Evaluation Center, Department of General Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Pamela
authors.initials: P
authors.lastname: Pei
authors.affiliation: Faculty of Medicine and Faculty of Social and Human Sciences, University of Southampton, Southampton, England.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Newell
authors.affiliation: Medical Practice Evaluation Center, Department of General Medicine, Massachusetts General Hospital, Boston, Massachusetts Department of Orthopedics, Brigham and Women's Hospital, Boston, Massachusetts Harvard University Center for AIDS Research, Cambridge, Massachusetts Harvard Medical School, Boston, Massachusetts.
authors.forename: Elena
authors.initials: E
authors.lastname: Losina
authors.affiliation: Centre INSERM U897 for Epidemiology and Biostatistics, Bordeaux, France Institut de Santé Publique, d'Épidémiologie, et de Développement (ISPED), University of Bordeaux, Bordeaux, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiebaut
authors.affiliation: Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Milton
authors.initials: M
authors.lastname: Weinstein
authors.affiliation: Medical Practice Evaluation Center, Department of General Medicine, Massachusetts General Hospital, Boston, Massachusetts Harvard University Center for AIDS Research, Cambridge, Massachusetts Harvard Medical School, Boston, Massachusetts Department of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Freedberg
authors.affiliation: Centre INSERM U897 for Epidemiology and Biostatistics, Bordeaux, France Institut de Santé Publique, d'Épidémiologie, et de Développement (ISPED), University of Bordeaux, Bordeaux, France Programme PAC-CI/ANRS, Abidjan, Côte d'Ivoire.
authors.forename: Xavier
authors.initials: X
authors.lastname: Anglaret
authors.affiliation: Medical Practice Evaluation Center, Department of General Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Callie
authors.initials: C
authors.lastname: Scott
authors.affiliation: Centre INSERM U897 for Epidemiology and Biostatistics, Bordeaux, France Institut de Santé Publique, d'Épidémiologie, et de Développement (ISPED), University of Bordeaux, Bordeaux, France Programme PAC-CI/ANRS, Abidjan, Côte d'Ivoire Institut National de la Santé et de la Recherche Médicale, University of Bordeaux, Bordeaux, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Dabis
authors.affiliation: Medical Practice Evaluation Center, Department of General Medicine, Massachusetts General Hospital, Boston, Massachusetts Harvard University Center for AIDS Research, Cambridge, Massachusetts Harvard Medical School, Boston, Massachusetts Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Walensky
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D008954:Models, Biological; D012680:Sensitivity and Specificity; D013997:Time Factors; D014944:World Health Organization
chemical_list: D019380:Anti-HIV Agents
keywords: HIV; highly active antiretroviral therapy; prevention; randomized controlled trials