Restoration of HBV-specific CD8+ T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy

Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-alpha-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-naive; 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-alpha-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-alpha 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-alpha-26 therapy were non-responders, we observed a decrease in CD25 expression on their CD4(+) T cells, suggesting that IFN-alpha 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.

Automated summary

Patients with chronic hepatitis B often do not respond well to IFN-alpha therapy. However, sequential IL-2 therapy has shown efficacy in increasing the frequency and function of HBV-specific CD8(+) T cells, leading to improved clinical outcomes for non-responder CHB patients. This suggests a potential new therapeutic approach for refractory CHB patients.