title: Evaluation of rapid progressors in HIV infection as an extreme phenotype.
abstract: METHODS
  Rapid CD4 cell loss represents an HIV phenotype used to identify causal variants of accelerated disease progression. The optimal rate and threshold for identifying this extreme phenotype in recently infected individuals is unclear.
  
  
  METHODS
  Using a cohort of patients with known dates of HIV-1 seroconversion (SC), CASCADE (Concerted Action on SeroConversion on AIDS and Death in Europe), we identified proportions experiencing nadir CD4 cell levels within 1 year of SC, and assessed their mean AIDS-free survival time at 10-year follow-up and hazard of AIDS/death, compared with those whose CD4 remained >500 cells per cubic millimeter. Follow-up was censored at December 31, 1996 to avoid bias due to combination antiretroviral therapy initiation.
  
  
  RESULTS
  Of 4876 individuals, 2.8%, 7.3%, and 24.9% experienced ≥1 CD4 <100, 200, and 350 cells per cubic millimeter, respectively, within 1 year of SC. Minimum CD4 levels of 30, 166, 231, and 506 cells per cubic millimeter were experienced during this period by 1%, 5%, 10%, and 50% of individuals, respectively. Mean (95% confidence interval) AIDS-free survival at 10 years follow-up was 2.9 (2.3 to 3.6), 5.5 (5.0 to 6.1), 6.7 (6.5 to 7.0), 7.4 (7.2 to 7.6), and 8.1 (7.9 to 8.3), for those with minimum counts ≤100, 100-200, 200-350, 350-500, >500 cells per cubic millimeter, respectively. Using counts of >500 cells per cubic millimeter as reference, the hazard ratios (95% confidence interval) of AIDS/death were 15.0 (11.9 to 18.9), 3.6 (2.9 to 4.5), 2.1 (1.8 to 2.4), and 1.5 (1.3 to 1.7), respectively. The hazard ratio increased to 37.5 (26.5 to 53.1) when a minimum CD4 count <100 was confirmed within 1 year of SC.
  
  
  CONCLUSIONS
  At least 1 CD4 ≤100 cells per cubic millimeter within the first year of SC identifies a rare group of individuals at high risk of disease progression and could form the basis for defining the rapid progressor phenotype.
authors.affiliation: *Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; †INSERM U943, Paris, France; ‡UPMC, Paris, France; §Innsbruck Medical University, Innsbruck, Austria; ‖University of Calgary, Calgary, Alberta, Canada; ¶Vall d'Hebrón Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; #Instituto de Salud Carlos III, Madrid, Spain; **Service de Médecine Interne et Maladies Infectieuses, CHU Bicêtre, Paris, France; ††Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy; ‡‡Institute of Epidemiology and Health Care, University College London, London, United Kingdom; §§Ulleval University Hospital, Oslo, Norway; and ‖‖Hospital Universitário Ramón y Cajal, Madrid, Spain.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Olson
authors.forename: Marguerite
authors.initials: M
authors.lastname: Guiguet
authors.forename: Robert
authors.initials: R
authors.lastname: Zangerle
authors.forename: John
authors.initials: J
authors.lastname: Gill
authors.forename: Santiago
authors.initials: S
authors.lastname: Perez-Hoyos
authors.forename: Sara
authors.initials: S
authors.lastname: Lodi
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.forename: Maria
authors.initials: M
authors.lastname: Dorrucci
authors.forename: Anne
authors.initials: A
authors.lastname: Johnson
authors.forename: Mette
authors.initials: M
authors.lastname: Sannes
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.forename: Kholoud
authors.initials: K
authors.lastname: Porter
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015331:Cohort Studies; D016001:Confidence Intervals; D018450:Disease Progression; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D015497:HIV-1; D006801:Humans; D008297:Male; D016016:Proportional Hazards Models