title: Temporal trends in prognostic markers of HIV-1 virulence and transmissibility: an observational cohort study.
abstract: BACKGROUND
  Measures of CD4 T-cell count and HIV-1 plasma viral load before antiretroviral therapy are proxies for virulence. Whether these proxies are changing over time has implications for prevention and treatment. The aim of this study was to investigate those trends.
  
  
  METHODS
  Data were derived from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration of mainly European seroconverter cohorts. Longitudinal CD4 cell counts and plasma viral load measurements before the initiation of antiretroviral therapy or AIDS onset were analysed by use of linear or fractional polynomials mixed models adjusting for all available potential confounders. Calendar time effects were modelled through natural cubic splines.
  
  
  RESULTS
  15 875 individuals seroconverting from 1979 to 2008 fulfilled the inclusion criteria; 3215 (20·3%) were women; median follow-up was 31 months (IQR 14-62); dropout before starting antiretroviral therapy or AIDS onset was 8·1%. Estimated CD4 counts at seroconversion for a typical individual declined from about 770 cells per μL (95% CI 750-800) in the early 1980s to a plateau of about 570 cells per μL (555-585) after 2002. CD4 cell rate of loss increased up to 2002. Estimated set-point plasma viral loads increased from 4·05 log10 copies per mL (95% CI 3·98-4·12) in 1980 to 4·50 log10 copies per mL (4·45-4·54) in 2002 with a tendency of returning to lower loads thereafter. Results were similar when we restricted analyses to various subsets, including adjusting for plasma viral load assay, censored follow-up at 3 years, or used variations of the main statistical approach.
  
  
  CONCLUSIONS
  Our results provide strong indications of increased HIV-1 virulence and transmissibility during the course of the epidemic and a potential plateau effect after about 2002.
  
  
  BACKGROUND
  European Union Seventh Framework Programme.
authors.affiliation: Athens University Medical School, Athens, Greece. Electronic address: npantaz@med.uoa.gr.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pantazis
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Kholoud
authors.initials: K
authors.lastname: Porter
authors.affiliation: INSERM, U1136, Paris, France; UPMC Université Paris 06, UMR S1136, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Service des maladies infectieuses et tropicales, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Costagliola
authors.affiliation: Clinic of Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy; Unit of Infectious Diseases, Siena University Hospital, Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.affiliation: AP-HP, Hôpital Bicêtre, Service de médecine interne, Le Kremlin-Bicêtre, Paris, France; Faculté de Médecine site Necker, Université Paris Descartes, EA 3620, Paris, France.
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.affiliation: INSERM, U1136, Paris, France; UPMC Université Paris 06, UMR S1136, Paris, France.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Guiguet
authors.affiliation: Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Johnson
authors.affiliation: Kirby Institute, UNSW, Sydney, NSW, Australia.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.affiliation: FHI 360, Durham, NC, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Morrison
authors.affiliation: INSERM U897 Centre of Epidemiology and Biostatistics, ISPED Bordeaux School of Public Health, University Bordeaux Segalen, Bordeaux, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiebaut
authors.affiliation: INSERM U897 Centre of Epidemiology and Biostatistics, ISPED Bordeaux School of Public Health, University Bordeaux Segalen, Bordeaux, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.affiliation: Athens University Medical School, Athens, Greece.
authors.forename: Giota
authors.initials: G
authors.lastname: Touloumi