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Altered thymic function during interferon therapy in HCV-infected patients.

ABSTRACT: Interferon alpha (IFN?) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFN? therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFN? therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naïve T-cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFN? therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFN?-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFN? therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFN?-treated patients.

SUBMITTER: Beq S

PROVIDER: S-EPMC3328332 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Altered thymic function during interferon therapy in HCV-infected patients.

Beq Stephanie S Rozlan Sandra S Pelletier Sandy S Willems Bernard B Bruneau Julie J Lelievre Jean-Daniel JD Levy Yves Y Shoukry Naglaa H NH Cheynier Rémi R

PloS one 20120416 4

Interferon alpha (IFNα) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFNα therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic fu ...[more]

PMID: 22529911

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Project description:IntroductionAlmost 30 years ago, about 30% of Japanese hemophiliacs became infected with HIV-1 and hepatitis C virus (HCV) after receiving contaminated blood products. While several studies have reported the high efficacy and safety of direct acting antivirals (DAA) in HIV-1 co-infected patients, such data are limited in hemophiliacs.MethodsWe conducted a single-center, open-label study involving 27 Japanese patients (median age; 45 years) with inherited bleeding disorders who were co-infected with HCV/HIV-1. Patients with HCV genotype 1 (GT1) and GT4 received ledipasvir (90 mg) plus sofosbuvir (400 mg), those with HCV GT2 received sofosbuvir plus weight-based ribavirin, and those with HCV GT3 received daclatasvir (60 mg) plus sofosbuvir. Treatment was continued for 12 weeks in all patients. The primary endpoints were rate of sustained virologic response at 12 weeks after end of therapy (SVR12) and occurrence of adverse events during DAA therapy.ResultsEighteen (67%) patients had had received interferon-based therapy, and 11 (41%) had compensated cirrhosis. HCV genotypes were GT1a 4 (15%), GT1b 16 (59%), GT1 undetermined 2 (7%), GT2a 1 (4%), GT3a 3 (11%) and GT4a 1 (4%). All patients were on combination antiretroviral therapy (cART) and had undetectable HIV-1 viral load (<20 copies/μL) at baseline. All patients achieved SVR12. Serious adverse events were observed in 3 patients: arteritis of the leg, which resolved after completion of DAA therapy, asymptomatic QT prolongation and gastrointestinal hemorrhage. cART failure was noted in one patient due to emergence of raltegravir resistance during ledipasvir/sofosbuvir treatment. Although α-fetoprotein, Mac-2 binding protein glycosylation isomer (M2BPGi), and Fibro Scan (FS) scores decreased in most patients during DAA therapy, M2BPGi (>2.0 cutoff index) and FS scores (>15.0 kPa) were still high in 6 patients at week 36.ConclusionsDAA therapy is effective in all patients. However, adverse events and efficacy of cART should be monitored closely.

Project description:BackgroundImmune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response.MethodsFifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error.ResultsCompared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment.ConclusionsClear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.

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Altered thymic function during interferon therapy in HCV-infected patients.

Publications

Altered thymic function during interferon therapy in HCV-infected patients.

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