title: Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.
abstract: OBJECTIVE
  HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control.
  
  
  METHODS
  HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models.
  
  
  RESULTS
  We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds.
  
  
  CONCLUSIONS
  Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.
authors.affiliation: Université Paris-Saclay, and Université Paris-Sud and Université de Versailles Saint-Quentin-en-Yvelines, and CESP, INSERM U1018, Kremlin-Bicêtre, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Chereau
authors.affiliation: Emerging Diseases Epidemiology Unit, Institut Pasteur, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Madec
authors.affiliation: Research Department of Infection and Population Health, UCL, Royal Free Campus, Rowland Hill Street, London, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sabin
authors.affiliation: Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Obel
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medecine, Institute of Biomedecine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Ruiz-Mateos
authors.affiliation: Department of Medicine, Infectious Disease Unit, Tzaneio General Hospital of Piraeus, Piraeus, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Chrysos
authors.affiliation: Imperial College, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fidler
authors.affiliation: Department of Internal Medicine I, University of Cologne and German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Lehmann
authors.affiliation: Department of Dermatology and Venereology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zangerle
authors.affiliation: University Bordeaux, ISPED, INSERM U1219-Bordeaux Population Health, INSERM, ISPED, Centre INSERM U1219-Bordeaux Population Health, CHU de Bordeaux, Pole de santé publique, Service d'information médicale, Bordeaux, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.affiliation: Stichting HIV Monitoring, Amsterdam, the Netherlands, and Department of Global Health, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.affiliation: Robert Koch Institute, Department for Infectious Disease Epidemiology, Berlin, Germany.
authors.forename: Osamah
authors.initials: O
authors.lastname: Hamouda
authors.affiliation: Hospital Clinico San Carlos, IdISSC/Universidad Complutense, Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Estrada Perez
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medecine, Institute of Biomedecine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal
authors.affiliation: Research Department of Infection and Population Health, UCL, Royal Free Campus, Rowland Hill Street, London, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mocroft
authors.affiliation: Epidemiology Service, Public Health Agency of Barcelona, Barcelona and CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Garcia De Olalla
authors.affiliation: Istituto Nazionale Malattie Infettive L. Spallanzani, IRCCS, Roma, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ammassari
authors.affiliation: Infectious Diseases Unit, Department of Health Sciences, ASST Santi Paolo e Carlo, University Hospital, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Arminio Monforte
authors.affiliation: Clinic of Infectious diseases, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mussini
authors.affiliation: Infectious Diseases Service, Parc Taulí Hospital Universitario and Universidad Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Segura
authors.affiliation: San Raffaele Vita Salute University, Milano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.affiliation: Infectious Diseases Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.affiliation: INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, and UPMC Université Paris 06, and Université Paris Descartes, Hôpital Cochin Hôtel-Dieu Paris, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Grabar
authors.affiliation: Service de médecine interne et maladies infectieuses, CHU de Bordeaux, Université de Bordeaux, Inserm U1219, Bordeaux, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Morlat
authors.affiliation: Department of Infectious Diseases, St Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Wit
authors.affiliation: Université Paris Sud, UMR 1184, Le Kremlin-Bicêtre, and CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, and INSERM, U1184, Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France and Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Médecine Interne et Immunologie clinique, Le Kremlin-Bicêtre, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambotte
authors.affiliation: Université Paris-Saclay, and Université Paris-Sud and Université de Versailles Saint-Quentin-en-Yvelines, and CESP, INSERM U1018, Kremlin-Bicêtre, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Meyer
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008297:Male; D019562:Viral Load / Q000187:drug effects / Q000276:immunology; D014766:Viremia / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents