title: Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study.
abstract: BACKGROUND
  Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL.
  
  
  METHODS
  We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55,826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders.
  
  
  RESULTS
  Median CD4 count at diagnosis of HIV infection was 376 cells per μL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per μL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per μL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per μL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per μL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9).
  
  
  CONCLUSIONS
  The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART.
  
  
  BACKGROUND
  National Institutes of Health.
authors.affiliation: Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA. Electronic address: slodi@hsph.harvard.edu.
authors.forename: Sara
authors.initials: S
authors.lastname: Lodi
authors.affiliation: University College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Phillips
authors.affiliation: Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Logan
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Olson
authors.affiliation: Sorbonne Universités, University Pierre et Marie Curie (UPMC), UMR S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Costagliola
authors.affiliation: Sorbonne Universités, University Pierre et Marie Curie (UPMC), UMR S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Antoine Béclère, Service de Médecine Interne, Clamart, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Abgrall
authors.affiliation: Stichting HIV Monitoring, Amsterdam, Netherlands.
authors.forename: Ard
authors.initials: A
authors.lastname: van Sighem
authors.affiliation: Stichting HIV Monitoring, Amsterdam, Netherlands; Academic Medical Center, Department of Global Health and Division of Infectious Diseases, University of Amsterdam, and Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.affiliation: Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Miró
authors.affiliation: Bellvitge University Hospital, L'Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, L'Hospitalet de Llobregat, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Ferrer
authors.affiliation: Yale University School of Medicine, New Haven, and VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Justice
authors.affiliation: Departments of Epidemiology, Global Health, and Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Neel
authors.initials: N
authors.lastname: Gandhi
authors.affiliation: Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland.
authors.forename: Heiner C
authors.initials: HC
authors.lastname: Bucher
authors.affiliation: Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.affiliation: Ramón y Cajal Hospital, Madrid, Spain; University of Alcalá de Henares, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.affiliation: University of Alcalá de Henares, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Monge
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Giota
authors.initials: G
authors.lastname: Touloumi
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pantazis
authors.affiliation: Bristol University, Bristol, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sterne
authors.affiliation: Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Young
authors.affiliation: Université Paris Sud, UMR 1018, and AP-HP, Hôpital de Bicêtre, Service de Santé Publique, le Kremlin Bicêtre, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Meyer
authors.affiliation: Université Paris Sud, UMR 1018, and AP-HP, Hôpital de Bicêtre, Service de Santé Publique, le Kremlin Bicêtre, France.
authors.forename: Rémonie
authors.initials: R
authors.lastname: Seng
authors.affiliation: INSERM U897, Centre Inserm Epidémiologie et Biostatistique, Université de Bordeaux, and Bordeaux University Hospital, Department of Internal Medicine, Bordeaux, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Dabis
authors.affiliation: INSERM U897, Centre Inserm Epidémiologie et Biostatistique, Université de Bordeaux, and Bordeaux University Hospital, Department of Internal Medicine, Bordeaux, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Vandehende
authors.affiliation: Consorcio de Investigación Biomédica de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Pérez-Hoyos
authors.affiliation: Consorcio de Investigación Biomédica de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Centro Nacional de Epidemiologia, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Inma
authors.initials: I
authors.lastname: Jarrín
authors.affiliation: University College London, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Jose
authors.affiliation: University College London, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sabin
authors.affiliation: Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T H Chan School of Public Health, and Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Boston, MA, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Hernán
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D057186:Comparative Effectiveness Research; D019049:Developed Countries; D005060:Europe; D005260:Female; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D057766:Policy; D015996:Survival Rate; D013997:Time Factors; D014481:United States; D019562:Viral Load; D055815:Young Adult