title: Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial.
abstract: BACKGROUND
  Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.
  
  
  METHODS
  The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581.
  
  
  RESULTS
  1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.
  
  
  CONCLUSIONS
  Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.
  
  
  BACKGROUND
  US National Institute of Allergy and Infectious Diseases.
authors.affiliation: Instituto de Pesquisa Clinica Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Beatriz
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authors.lastname: Grinsztejn
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA; UNC Project-Malawi, Lilongwe, Malawi.
authors.forename: Mina C
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authors.lastname: Hosseinipour
authors.affiliation: Harvard School of Public Health, Boston, MA, USA.
authors.forename: Heather J
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authors.lastname: Ribaudo
authors.affiliation: University of Nebraska Medical Center, Omaha, NE, USA.
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authors.lastname: Swindells
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Joseph
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authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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authors.affiliation: University of Zimbabwe, Harare, Zimbabwe.
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authors.affiliation: College of Medicine-Johns Hopkins Project, Lilongwe, Malawi.
authors.forename: Johnstone
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authors.affiliation: Hospital Geral de Nova Iguacu and Laboratorio de AIDS e Imunologia Molecular-IOC/Fiocruz, Rio de Janeiro, Brazil.
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authors.initials: JH
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authors.affiliation: National AIDS Research Institute (ICMR), Pune, India.
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authors.affiliation: Research Institute for Health Sciences, Chiang Mai University, Chaing Mai, Thailand.
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authors.affiliation: Hospital Nossa Senhora da Conceição, Porto Alegre RS, Brazil.
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authors.affiliation: Fenway Institute, Boston, MA, USA.
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authors.lastname: Mayer
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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authors.lastname: Eshleman
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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authors.affiliation: Botswana Harvard AIDS Institute, Gabarone, Botswana.
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authors.forename: Lisa A
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authors.affiliation: Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Ravindre
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authors.lastname: Panchia
authors.affiliation: Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Ian
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authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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authors.lastname: Gallant
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Irving
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authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Taha E
authors.initials: TE
authors.lastname: Taha
authors.affiliation: David Geffen UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Karin
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authors.lastname: Nielsen-Saines
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
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authors.lastname: Celentano
authors.affiliation: Harvard School of Public Health, Boston, MA, USA.
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mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000276:immunology; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D002318:Cardiovascular Diseases / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D015497:HIV-1; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000150:complications; D008107:Liver Diseases / Q000150:complications; D008297:Male; D009369:Neoplasms / Q000150:complications; D016016:Proportional Hazards Models; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis*; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents