Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection

Lundgren JD 1 , Babiker AG 2 , Sharma S 3 , Grund B 4 , Phillips AN 5 , Matthews G 6 Show all authors , Kan VL 7 , Aagaard B 1 , Abo I 8 , Alston B 9 , Arenas-Pinto A 2 , Avihingsanon A 10 , Badal-Faesen S 11 , Brites C 12 , Carey C 6 , Casseb J 13 , Clarke A 14 , Collins S 15 , Corbelli GM 16 , Dao S 17 , Denning ET 3 , Emery S 18 , Eriobu N 19 , Florence E 20 , Furrer H 21 , Fätkenheuer G 22 , Gerstoft J 23 , Gisslén M 24 , Goodall K 2 , Henry K 25 , Horban A 26 , Hoy J 27 , Hudson F 2 , Azwa RISR 28 , Kedem E 29 , Kelleher A 6 , Kityo C 30 , Klingman K 9 , Rosa A 31 , Leturque N 32 , Lifson AR 33 , Losso M 34 , Lutaakome J 35 , Madero JS 36 , Mallon P 37 , Mansinho K 38 , Filali KME 39 , Molina JM 40 , Murray DD 1 , Nagalingeswaran K 41 , Nozza S 42 , Ormaasen V 43 , Paredes R 44 , Peireira LC 45 , Pillay S 46 , Polizzotto MN 47 , Raben D 1 , Rieger A 48 , Sanchez A 7 , Schechter M 49 , Sedlacek D 50 , Staub T 51 , Touloumi G 52 , Turner M 7 , Madruga JV 53 , Vjecha M 7 , Wolff M 54 , Wood R 55 , Zilmer K 56 , Lane HC 57 , Neaton JD 3 , INSIGHT Strategic Timing of AntiRetroviral Treatment (START) Study Group

Affiliations 

  • 1 CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen
  • 2 Medical Research Council Clinical Trials Unit, University College London, London
  • 3 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis
  • 4 School of Statistics, University of Minnesota, Minneapolis
  • 5 Institute for Global Health, University College London, London
  • 6 Kirby Institute, Sydney
  • 7 VA Medical Center, Washington, D.C
  • 8 Helsinki University Central Hospital, Helsinki
  • 9 Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD
  • 10 Thai Red Cross AIDS Research Centre, Bangkok, Thailand
  • 11 Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg
  • 12 Hospital Universitario Professor Edgard Santos, School of Medicine, Federal University of Bahia, Salvador, Brazil
  • 13 Laboratory of Medical Investigation - LIM56, Faculty of Medicine, Department of Dermatology, University of São Paulo, São Paulo
  • 14 Royal Sussex County Hospital, Brighton, United Kingdom
  • 15 HIV i-Base, London
  • 16 European AIDS Treatment Group, Brussels
  • 17 Mali-National Institute of Allergy and Infectious Diseases HIV Research Initiative, Bamako, Mali
  • 18 UNSW Medicine, Sydney
  • 19 Institute of Human Virology Nigeria, Abuja, Nigeria
  • 20 Institute of Tropical Medicine, Antwerp, Belgium
  • 21 Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
  • 22 Klinik I für Innere Medizin der Universität zu Köln, Cologne, Germany
  • 23 Rigshospitalet, Infektionsmedicinsk ambulatorium 8622, Copenhagen
  • 24 Sahlgrenska University Hospital, Gothenburg, Sweden
  • 25 Hennepin Health Research Institute, Minneapolis
  • 26 Wojewódzki Szpital Zakaźny, Warsaw, Poland
  • 27 Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, VIC, Australia
  • 28 University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 29 Rambam Medical Center, Haifa, Israel
  • 30 Joint Clinical Research Centre, Kampala, Uganda
  • 31 Asociación Civil IMPACTA Salud y Educación, Lima, Peru
  • 32 INSERM SC10-US19, Villejuif, Paris
  • 33 University of Minnesota, Minneapolis
  • 34 Hospital General de Agudos J.M. Ramos Mejia, Buenos Aires
  • 35 MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
  • 36 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City
  • 37 Centre for Experimental Pathogen Host Research, University College Dublin, Dublin
  • 38 Hospital de Egas Moniz, Lisbon, Portugal
  • 39 University Hospital Centre Ibn Rochd, Casablanca, Morocco
  • 40 Hôpital Saint-Louis, Paris
  • 41 Voluntary Health Services, Infectious Diseases Medical Centre, Chennai Antiviral Research and Treatment, Clinical Research Site, Chennai, India
  • 42 Ospedale San Raffaele S.r.l., Milan
  • 43 Oslo University Hospital, Ullevål, Oslo
  • 44 Hospital Universitari Germans Trias i Pujol, Barcelona
  • 45 Instituto de Infectologia Emílio Ribas, São Paulo
  • 46 Durban International Clinical Research Site, Durban, South Africa
  • 47 Clinical Hub for Interventional Research, College of Health and Medicine, The Australian National University, Canberra, ACT, Australia
  • 48 University Vienna General Hospital, Vienna
  • 49 Projeto Praça Onze, Rio de Janeiro
  • 50 University Hospital Plzen, Plzen, Czech Republic
  • 51 Centre Hospitalier de Luxembourg, Luxembourg
  • 52 Medical School, National and Kapodistrian University of Athens, Athens
  • 53 Centro de Referência e Treinamento em DST/AIDS, São Paulo
  • 54 Hospital Clínico San Borja Arriarán, Fundación Arriarán, Santiago, Chile
  • 55 Desmond Tutu Health Foundation, Cape Town, South Africa
  • 56 West Tallinn Central Hospital Infectious Diseases, Tallinn, Estonia
  • 57 National Institute of Allergy and Infectious Diseases, Bethesda, MD
NEJM Evid, 2023 Mar;2(3).
PMID: 37213438 DOI: 10.1056/evidoa2200302

Abstract

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain.

METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021.

RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference).

CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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