Hepatitis B Virus-Specific T–Cell Proliferation and Cytokine Secretion in Chronic Hepatitis B E Antibody-Positive Patients Treated With Ribavirin and Interferon Alfa

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Abstract
Immune elimination of hepatitis B virus (HBV) during antiviral therapy depends on the activation of T–cell responses, which are generally impaired in chronic hepatitis B. HBV–specific T helper (Th)–cell reactivity has been assessed post–treatment in liver and peripheral blood of 18 anti–HBe–positive patients with chronic hepatitis B administered combined ribavirin/interferon alfa (IFN–α) therapy. The results showed that patients with undetectable HBV DNA by quantitative polymerase chain reaction under combination therapy were able to mount an HBV–specific CD4+ Th–cell proliferative response and such T–cell reactivity is detectable 1 year after HBV DNA clearance. Hepatitis B virus core (HBcAg) and e (HBeAg) antigen–specific Th–cell proliferation was found more frequently in the liver and peripheral blood in those patients who sustained the alanine aminotransferase (ALT) normalization together with HBV DNA loss. However, HBV–specific IFN–γ production in vitro in peripheral blood mononuclear cells augmented in 4 of 5 sustained responders and all 13 nonresponders, interleukin 10 (IL–10) production decreased in all 5 sustained responders but increased in 7 of 13 nonresponders. Furthermore, intrahepatic HBcAg plus HBeAg–specific Th–cell proliferation only occurred in sustained responders (2 of 3, 67%, vs. 0 of 9; P = .045) whose cells showed in vitro significantly increased productions in HBcAg/HBeAg–specific IFN–γ and IL–12 compared with nonresponders in whom IFN–γ and IL–12 productions decreased together with increased IL–10 secretion. In conclusion this study indicates that combined therapy with ribavirin and IFN–α for chronic hepatitis B not only significantly reduces viremia levels but also induces lasting CD4+ T–cell proliferation and Th1 cytokine release at the site of infection, which may lead to sustained eradication of the HBV.

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