Abstract
Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.
Highlights
The Global Health Sector Strategy for the elimination of viral hepatitis by 2030 was approved at the 69th World HealthAssembly, approximately 250 million patients, from 120 countries, are currently living with hepatitis B virus (HBV) infection.[1,2] After the promising introduction of a highly effective treatment for hepatitis C virus (HCV) infections in 2013, hepatitis B was somewhat overshadowed by other public health priorities, and the possibility of a cure remained elusive
Our findings indicate with chronic hepatitis B (CHB) exhibited a serological response (SR) after therapy, with that IL-2 stimulation significantly promotes the activation of T cells no significant difference (P = 0.5010) between group 1 (Peg-IFN-α- and natural killer (NK) cells in NR (α-2b) patients ex vivo, without increasing the
We found that the proportion of To further investigate whether IL-2 directly promotes the effector CD25+CD4+ T cells was functions of lymphocytes in the liver, given the ethical significantly reduced in NR (α-2b) patients, but not in seroconversion response (SR) patients, considerations limiting such experimentation in patients, we after the administration of Peg-IFN-α-2b at week 72
Summary
The Global Health Sector Strategy for the elimination of viral hepatitis by 2030 was approved at the 69th World HealthAssembly, approximately 250 million patients, from 120 countries, are currently living with hepatitis B virus (HBV) infection.[1,2] After the promising introduction of a highly effective treatment for hepatitis C virus (HCV) infections in 2013, hepatitis B was somewhat overshadowed by other public health priorities, and the possibility of a cure remained elusive. Interferon alpha (IFN-α) represents the first-choice treatment for HBV infection.[3,4] IFN-α is considered to exert antiviral effects through the activation of a series of interferon-stimulated genes (ISGs) and the degradation of nuclear viral DNA, likely via the exosomes or the apolipoprotein B editing complex 3 (APOBEC3) DNA-editing enzyme. IFN-α augments the immune function of cytotoxic CD8+ T cells, and rescues the cytotoxic activities of natural killer (NK) cells, which are important component of the innate antiviral immunity, and could respond rapidly to virus-infected cells and kill them.[5,6] The quality and magnitude of cytotoxic CD8+ T-cell responses were important to overcome chronic virus infections;[7] recent studies evaluating the efficacy of IFN-α therapy have reported a rate of hepatitis B e antigen (HBeAg) seroconversion of only 30%, and a rate of hepatitis B surface antigen (HBsAg) loss of ~5%.8,9. Suppressive mechanisms, such as the activity of regulatory T cells (Tregs) and programmed cell death protein 1 (PD-1) expression, have been demonstrated to occur during HBV infection.[15,16,17,18] the modulation of these inhibitory pathways in vitro has led to effective functional
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