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Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

ABSTRACT: Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-? and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-?/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern before, during and after PegIFN-?/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-? production in therapy-naive chronic HCV patients was associated with higher HCV-RNA loads, which suggests that protective antiviral immunity is controlled by IL-10. In addition, as a consequence of PegIFN-?/ribavirin therapy, negative regulation of especially HCV-specific IFN-? production by TGF-? and IL-10 changed dramatically. Our findings emphasize the importance of negative regulation for the dysfunctional HCV-specific immunity, which should be considered in the design of future immunomodulatory therapies.

SUBMITTER: Claassen MA

PROVIDER: S-EPMC3493527 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

Claassen Mark A A MA de Knegt Robert J RJ Turgut Duygu D Groothuismink Zwier M A ZM Janssen Harry L A HL Boonstra André A

PloS one 20121108 11

Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-β and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-α/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern befo ...[more]

PMID: 23145169

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Project description:To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection.Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group?I?included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493).Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well.Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted.

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Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

Publications

Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.

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