Dataset Information

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+?: ?CD8+ ratio.

ABSTRACT: OBJECTIVE:Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+?:?CD8+ ratio. DESIGN:Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data. METHODS:We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4+?:?CD8+ ratio trend from this model. We assessed whether CD4+ and CD8+ cell count trends and the CD4+?:?CD8+ ratio trend varied according to CD4+ cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. RESULTS:A total of 39?979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/?l, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+?:?CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+?:?CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/?l. A higher baseline CD4+ cell count predicted a shorter time to normalization. CONCLUSION:Declines in CD8+ cell count and increases in CD4+?:?CD8+ ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4+?:?CD8+ ratio is strongly related to baseline CD4+ cell count.

SUBMITTER: Hughes RA

PROVIDER: S-EPMC5991182 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+ : CD8+ ratio.

Hughes Rachael A RA May Margaret T MT Tilling Kate K Taylor Ninon N Wittkop Linda L Reiss Peter P Gill John J Schommers Philipp P Costagliola Dominique D Guest Jodie L JL Lima Viviane D VD d'Arminio Monforte Antonella A Smith Colette C Cavassini Matthias M Saag Michael M Castilho Jessica L JL Sterne Jonathan A C JAC

AIDS (London, England) 20180601 10

<h4>Objective</h4>Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+ : CD8+ ratio.<h4>Design</h4>Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data.<h4>Methods</h4>We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, w ...[more]

PMID: 29851663

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Project description:IntroductionRituximab (RTX) is a B cell-depleting agent approved for the treatment of granulomatosis with polyangiitis (GPA). RTX reduces antibody producing precursor plasma cells and inhibits B and T cells interaction. Infections related to T cell immunodeficiency are not infrequent during RTX treatment. Our study investigated CD4 cell count and CD4/CD8 ratio in GPA patients during the first two years of long-term RTX treatment.MethodsA single centre cohort study of 35 patients who received median total cumulative dose of cyclophosphamide (CYC) of 15 g and were treated with RTX 2 g followed by retreatment with either 2 g once annually or 1 g biannually. Serum levels of total immunoglobulin (Ig) and lymphocytes subsets were recorded at RTX initiation and at 3, 6, 12, 18 and 24 months. Low CD4 count and inverted CD4/CD8 ratio were defined as CD4 < 0.3 × 10(9)/l and ratio < 1.ResultsThe CD4 cell count and CD4/CD8 ratio decreased slightly following the initial RTX treatment and then increased gradually during maintenance treatment. While the proportion of patients with low CD4 cell count decreased from 43% at baseline to 18% at 24 months, the ratio remained inverted in 40%. Oral daily prednisolone dose at baseline, CYC exposure and the maintenance regimen did not influence the CD4 cell count and ratio. Being older (p = 0.012) and having a higher CRP (p = 0.044) and ESR (p = 0.024) at baseline significantly increased the risk of inverted CD4/CD8 ratio at 24 months. Inverted ratio at baseline associated with lower total Ig levels during the study.ConclusionsOverall, the CD4 and CD4/CD8 ratio increased during maintenance RTX therapy in GPA with no discernible impact of other immunosuppressive therapy. However the increase in CD4 was not followed by an increase in the CD4/CD8 ratio, especially in older patients. Inverted CD4/CD8 ratio associated with lower Ig levels, suggesting a more profound B cell depleting effect of RTX with a relative increase in CD8+ lymphocytes.

Project description:HIV infection provokes a myriad of pathological effects on the immune system where many markers of CD4+ T cell dysfunction have been identified. However, most studies to date have focused on single/double measurements of immune dysfunction, while the identification of pathological CD4+ T cell clusters that is highly associated to a specific biomarker for HIV disease remain less studied. Here, multi-parametric flow cytometry was used to investigate immune activation, exhaustion, and senescence of diverse maturation phenotypes of CD4+ T cells. The traditional method of manual data analysis was compared to a multidimensional clustering tool, FLOw Clustering with K (FLOCK) in two cohorts of 47 untreated HIV-infected individuals and 21 age and sex matched healthy controls. In order to reduce the subjectivity of FLOCK, we developed an "artificial reference", using 2% of all CD4+ gated T cells from each of the HIV-infected individuals. Principle component analyses demonstrated that using an artificial reference lead to a better separation of the HIV-infected individuals from the healthy controls as compared to using a single HIV-infected subject as a reference or analyzing data manually. Multiple correlation analyses between laboratory parameters and pathological CD4+ clusters revealed that the CD4/CD8 ratio was the preeminent surrogate marker of CD4+ T cells dysfunction using all three methods. Increased frequencies of an early-differentiated CD4+ T cell cluster with high CD38, HLA-DR and PD-1 expression were best correlated (Rho = -0.80, P value = 1.96×10-11) with HIV disease progression as measured by the CD4/CD8 ratio. The novel approach described here can be used to identify cell clusters that distinguish healthy from HIV infected subjects and is biologically relevant for HIV disease progression. These results further emphasize that a simple measurement of the CD4/CD8 ratio is a useful biomarker for assessment of combined CD4+ T cell dysfunction in chronic HIV disease.

Dataset Information

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+?: ?CD8+ ratio.

Publications

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+ : CD8+ ratio.

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