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CD3(bright)CD56(+) T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients.

ABSTRACT: Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide, and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low, and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3(bright)CD56(+) T cells, a newly identified CD56(+) T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3(bright)CD56(+) T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3(bright)CD56(+) T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3(bright)CD56(+) T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3(bright)CD56(+) T cell population preferentially shown in CHB patients, and indicated that the presence of CD3(bright)CD56(+) T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment.

SUBMITTER: Guo C

PROVIDER: S-EPMC4865958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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CD3(bright)CD56(+) T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients.

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