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      Metabolic and anthropometric parameters contribute to ART-mediated CD4 + T cell recovery in HIV-1-infected individuals: an observational study

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          Abstract

          Background

          The degree of immune reconstitution achieved in response to suppressive ART is associated with baseline individual characteristics, such as pre-treatment CD4 count, levels of viral replication, cellular activation, choice of treatment regimen and gender. However, the combined effect of these variables on long-term CD4 recovery remains elusive, and no single variable predicts treatment response. We sought to determine if adiposity and molecules associated with lipid metabolism may affect the response to ART and the degree of subsequent immune reconstitution, and to assess their ability to predict CD4 recovery.

          Methods

          We studied a cohort of 69 (48 females and 21 males) HIV-infected, treatment-naïve South African subjects initiating antiretroviral treatment (d4T, 3Tc and lopinavir/ritonavir). We collected information at baseline and six months after viral suppression, assessing anthropometric parameters, dual energy X-ray absorptiometry and magnetic resonance imaging scans, serum-based clinical laboratory tests and whole blood-based flow cytometry, and determined their role in predicting the increase in CD4 count in response to ART.

          Results

          We present evidence that baseline CD4 + T cell count, viral load, CD8 + T cell activation (CD95 expression) and metabolic and anthropometric parameters linked to adiposity (LDL/HDL cholesterol ratio and waist/hip ratio) significantly contribute to variability in the extent of CD4 reconstitution (ΔCD4) after six months of continuous ART.

          Conclusions

          Our final model accounts for 44% of the variability in CD4 + T cell recovery in virally suppressed individuals, representing a workable predictive model of immune reconstitution.

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          Most cited references47

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          Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

          Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. We analysed data on 12,574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. FINDINGS During 24,310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/microL, adjusted hazard ratios were 0.74 (95% CI 0.62-0.89) for 50-99 cells/microL, 0.52 (0.44-0.63) for 100-199 cells/microL, 0.24 (0.20-0.30) for 200-349 cells/microL, and 0.18 (0.14-0.22) for 350 or more CD4 cells/microL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100,000 copies/microL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3.4% (2.8-4.1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43-58) in patients in the highest-risk strata. The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.
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            Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design.

            To determine rates, risk factors and causes of death among patients accessing a community-based antiretroviral treatment (ART) programme both prior to and following initiation of treatment. All in-programme deaths were ascertained between September 2002 and March 2005 among treatment-naive patients enrolled into a prospective community-based ART cohort in Cape Town, South Africa. Of 712 patients (median CD4 cell count, 94 cells/microl), 578 (81%) started triple ART a median of 29 days after enrollment. 68 (9.5%) patients died during 563 person-years of observation. The high pretreatment mortality rate of 35.6 deaths/100 person-years [95% confidence interval (CI), 23.0-55.1) decreased to 2.5/100 person-years (95% CI, 0.9-6.6) at 1 year among those who received ART. However, within the first 90 days from enrollment, 29 of 44 (66%) deaths occurred among patients awaiting ART; these would not be identified by an on-treatment analysis. Multivariate analysis showed that risk of death (both pre-treatment and on-treatment) was independently associated with baseline CD4 cell count and World Health Organization (WHO) clinical stage; stage 4 disease was the strongest risk factor. Major attributed causes of death were wasting syndrome, tuberculosis, acute bacterial infections, malignancy and immune reconstitution disease. Most early in-programme deaths occurred among patients with advanced immunodeficiency but who had not yet started ART. Programme evaluation using on-treatment analyses greatly underestimated early mortality. This mortality would be reduced by minimizing unnecessary in-programme delays in treatment initiation and by starting ART before development of WHO stage 4 disease.
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              Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection.

              Natural killer (NK) cells are critical in the first-line defense against viral infections. Chronic HIV-1 infection leads to a perturbation in the NK cell compartment, yet the kinetics of this deregulation and the functional consequences are unclear. Here, we characterized changes in the NK cell compartment longitudinally by multiparameter flow cytometry, starting in acute HIV-1 infection. Acute HIV-1 infection was associated with elevated NK cell numbers, with an expansion of CD3(neg)CD56(dim)CD16(pos) NK cells and an early depletion of CD3(neg)CD56(bright)CD16(neg) NK cells. Ongoing viral replication resulted in a depletion of CD3(neg)CD56(dim)CD16(pos) NK cells with a paralleled increase in functionally anergic CD3(neg)CD56(neg)CD16(pos) NK cells, accompanied by reduced functional activity, as measured by CD107a expression and cytokine secretion. Taken together, these studies demonstrate a sequential impairment of NK cell function with persistent viral replication resulting from a progressive deregulation of NK cell subsets with distinct functional properties.
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                Author and article information

                Journal
                J Int AIDS Soc
                Journal of the International AIDS Society
                BioMed Central
                1758-2652
                2011
                29 July 2011
                : 14
                : 37
                Affiliations
                [1 ]HIV-1 Immunopathogenesis Laboratory, the Wistar Institute, Philadelphia, PA, USA
                [2 ]School of Public Health and Health Sciences, University of Massachusetts, Amherst, USA
                [3 ]Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
                [4 ]Department of Chemical Pathology, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa
                [5 ]Department of Hematology and Molecular Medicine, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa
                Article
                1758-2652-14-37
                10.1186/1758-2652-14-37
                3163506
                21801351
                257fecc9-588d-434d-885f-7393d1f31432
                Copyright ©2011 Azzoni et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 December 2010
                : 29 July 2011
                Categories
                Research

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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