Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1-Positive Individuals with Sustained Virological Suppression on Antiretroviral Therapy

• Type of Material: Article
• Authors: Luuk Gras, Stichting HIV Monitoring; Margaret May, University of Bristol; Lars Peter Ryder, Copenhagen University Hospital; Adam Trickey, University of Bristol; Marie Helleberg, Copenhagen University Hospital; Niels Obel, Copenhagen University Hospital; Rodolphe Thiebaut, Bordeaux Population Health; Jodie L. Guest, Emory University; John Gill, University of Calgary; Heidi Crane, University of Washington; Viviane Dias Lima, St. Paul's Hospital; Antonella D'Arminio Monforte, Università degli Studi di Milano; Timothy R. Sterling, Vanderbilt University; Jose Miro, Universitat de Barcelona; Santiago Moreno, Hospital Ramon y Cajal; Christoph Stephan, Klinikum und Fachbereich Medizin Johann Wolfgang Goethe-Universität Frankfurt am Main; Colette Smith, University College London; Janet Tate, Yale University School of Medicine; Leah Shepherd, University College London; Mike Saag, University of Alabama
• Language: English
• Date: 2019-03-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Wolters Kluwer Health, Inc.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/QAI.0000000000001913
• Title of Journal or Parent Work: Journal of Acquired Immune Deficiency Syndromes
• ISSN: 1525-4135
• Volume: 80
• Issue: 3
• Start Page: 292
• End Page: 300
• Grant/Funding Information: J.M.M. received a personal 80:20 research grant from the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–2019.; COHERE receives funding from the European Union Seventh Framework Programme (FP7/2007-2013) under EuroCoord grant agreement no 260694.; Jonathan Sterne is funded by National Institute for Health Research Senior Investigator award NF-SI-0611-10168.; Sources of funding of individual cohorts include the Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the French, Italian, and Spanish Ministries of Health, the Swiss National Science Foundation (Grant 33CS30_134277), the Ministry of Science and Innovation and the “Spanish Network for AIDS Research” (RIS; ISCIII-RETIC RD06/006), the Stichting HIV Monitoring, which is supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, the European Commission (EuroCoord Grant 260694), the British Columbia and Alberta Health Services, the National Institutes of Health (NIH) [UW Center for AIDS Research (CFAR) (NIH Grant P30 AI027757), UAB CFAR (NIH Grant P30-AI027767), The Tennessee CFAR (NIH Grant P30 AI110527)], National Institute on Alcohol Abuse and Alcoholism (U10-AA13566, U24-AA020794), the US Department of Veterans Affairs, the Michael Smith Foundation for Health Research, the Canadian Institutes of Health Research, the VHA Office of Research and Development, and unrestricted grants from Abbott, Gilead, Tibotec-Upjohn, ViiV Healthcare, MSD, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, Roche, and Boehringer-Ingelheim.; Supported by the UK Medical Research Council (MRC) (Grant number MR/J002380/1) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.; R.G. was supported by the Wellcome Trust (Grant number 106680/Z/14/Z).; The Danish HIV Cohort Study is founded by Preben and Anne Simonsens Foundation.; M.H. received funding from the Danish National Research Foundation (Grant number 715).
• Keywords: HIV; CD4 cell count; CD4:CD8 ratio; CD8 cell count; antiretroviral therapy; age
• Research Categories: Health Sciences, Public Health

Abstract

Background:An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics.Methods:We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models.Results:When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm 3 . Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm 3 .Discussion:Starting ART with a CD4 cell count of ≥500 cells/mm 3 makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.