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Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes

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      Abstract

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      Abstract

      Background:

      The failure to increase CD4 + T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4 + T-cell homeostasis and impacts clinical evolution.

      Methods:

      We evaluated different definitions of immunodiscordance based on CD4 + T-cell counts (cutoff) or CD4 + T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals.

      Results:

      Cutoff definition of CD4 + cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4 + T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4 + T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4 + T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4 + values were maintained in these participants over time.

      Conclusion:

      A cutoff value of CD4 + T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4 + T-cell recovery.

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      Most cited references 47

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      Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.

        (2008)
      Combination antiretroviral therapy has led to significant increases in survival and quality of life, but at a population-level the effect on life expectancy is not well understood. Our objective was to compare changes in mortality and life expectancy among HIV-positive individuals on combination antiretroviral therapy. The Antiretroviral Therapy Cohort Collaboration is a multinational collaboration of HIV cohort studies in Europe and North America. Patients were included in this analysis if they were aged 16 years or over and antiretroviral-naive when initiating combination therapy. We constructed abridged life tables to estimate life expectancies for individuals on combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, and stratified by sex, baseline CD4 cell count, and history of injecting drug use. The average number of years remaining to be lived by those treated with combination antiretroviral therapy at 20 and 35 years of age was estimated. Potential years of life lost from 20 to 64 years of age and crude mortality rates were also calculated. 18 587, 13 914, and 10 854 eligible patients initiated combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, respectively. 2056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1000 person-years in 1996-99 to 10.0 deaths per 1000 person-years in 2003-05. Potential years of life lost per 1000 person-years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003-05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per muL vs 50.4 [0.4] years for counts of 200 cells per muL or more). Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients. The average number of years remaining to be lived at age 20 years was about two-thirds of that in the general population in these countries.
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        Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease.

        Highly active antiretroviral therapy (HAART) increases CD4(+) cell numbers, but its ability to correct the human immunodeficiency virus (HIV)-induced immune deficiency remains unknown. A three-phase T cell reconstitution was demonstrated after HAART, with: (i) an early rise of memory CD4(+) cells, (ii) a reduction in T cell activation correlated to the decreasing retroviral activity together with an improved CD4(+) T cell reactivity to recall antigens, and (iii) a late rise of "naïve" CD4(+) lymphocytes while CD8(+) T cells declined, however, without complete normalization of these parameters. Thus, decreasing the HIV load can reverse HIV-driven activation and CD4(+) T cell defects in advanced HIV-infected patients.
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          HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects.

          Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.
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            Author and article information

            Affiliations
            [a ]University of California San Diego, La Jolla, California, USA
            [b ]Institut de Recerca de la Sida IrsiCaixa-HIVACAT, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, UAB, Badalona
            [c ]Universitat de Vic – Universitat Central de Catalunya, Barcelona
            [d ]Fundació Lluita contra la SIDA, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain
            [e ]Department of Microbiology, Infectiology and Immunology, Université de Montréal, Faculté de Médecine
            [f ]Centre de Recherche du CHUM, Montréal, Québec, Canada.
            Author notes
            Correspondence to Marta Massanella, PhD, Centre de Recherche du CHUM, Montréal, QC, Canada H2X 0A9. Tel: +1 514 890 8000/30238; e-mail: marta.massanella.luna@ 123456umontreal.ca
            Journal
            AIDS
            AIDS
            AIDS
            AIDS (London, England)
            Lippincott Williams & Wilkins
            0269-9370
            1473-5571
            24 September 2016
            07 September 2016
            : 30
            : 15
            : 2275-2287
            27427875 5017266 10.1097/QAD.0000000000001205 00004
            Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

            This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by/4.0

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