Gastroenterology

Gastroenterology

Volume 143, Issue 4, October 2012, Pages 963-973.e9
Gastroenterology

Original Research
Clinical—Liver
Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues

https://doi.org/10.1053/j.gastro.2012.07.014Get rights and content

Background & Aims

In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control.

Methods

We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa–induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen–negative patients with chronic infections.

Results

Although HBV-specific T cells from nucleos(t)ide analogue–treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue–treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection.

Conclusions

In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.

Section snippets

Patient Populations

The categories of patients (most infected by genotype D HBV) (Table 1, Table 2 and Supplementary Table 1, Supplementary Table 2, Supplementary Table 3, Supplementary Table 4, Supplementary Table 5) enrolled at the Unit of Infectious Diseases and Hepatology in Parma, at the Viral Hepatitis Division in Naples, and at the 1st Division of Gastroenterology in Milan were as follows: NUC-treated HBeAg-negative patients with CHB who had persistent suppression of HBV replication, either HBsAg positive

In Vitro HBV-Specific CD4+ or CD8+ T-Cell Responses in Patients With Different Levels of HBV Control

Three different antiviral cytokines, IFN-γ, TNF-α, and IL-2, were simultaneously tested by intracellular cytokine staining (ICS) following 10 days of PBMC stimulation with overlapping peptides covering the overall X, core, polymerase, and envelope sequences of genotype D to define recovery level and kinetics of different antiviral T-cell functions.

Positive IFN-γ, IL-2, and TNF-α responses were consistently higher in patients who showed complete control of chronic infection following NUC therapy

Discussion

HBeAg-negative chronic hepatitis caused by genotype D HBV represents a difficult-to-treat form of infection that urgently needs additional therapeutic options. Available therapies are mostly based on the direct inhibition of HBV replication and also IFN-α therapy seems to act more by a direct antiviral effect rather than by a modulation of antiviral responses.1, 2, 10

A possible strategy to improve available therapeutic options is to exploit the protective effect of HBV-specific T cells by

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by a grant from Fondazione Cassa di Risparmio di Parma, Italy, and by an FIRB grant from the Italian Ministry of the University and Research, Protocol RBAP10TPXK.

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