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HBV is a non-cytopathic virus and the progression of liver fibrosis is attributed to the host immune response. Complete suppression of viral replication using nucleotide or nucleoside analogues (NUCs) can prevent most complications related to chronic HBV infection. Unfortunately, antiviral treatment has to be administered lifelong to the majority of patients as HBV persists in the hepatocytes. However, although NUCs are very frequently administered in clinical practice, their effects on vital parts of the host immune response to HBV are not well established. In this review we summarize the currently available data gathered from longitudinal studies that investigated treatment-associated alterations of HBV-specific CD4+and CD8+T-cells, regulatory T-cells and natural killer (NK) cells. These observations are important, as they can guide the design of studies that investigate the efficacy of new immune therapeutic agents. Novel experimental compounds will likely be added to ongoing NUC treatment, which leads to a functional cure in only a small minority of patients.

Background Serum hepatitis B core-related antigen (HBcrAg) levels refect intrahepatic HBV replication activity. We aimed to study whether HBcrAg levels predict response to pegylated interferon (PEG-IFN) treatment in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. Methods We studied HBcrAg levels in 222 HBeAg-positive patients treated with PEG-IFN with or without lamivudine for 52 weeks in a global randomized trial and compared kinetics across treatment arms and types of response. Optimal HBcrAg cutoffs for stopping therapy were compared to and combined with the currently recommended hepatitis B surface antigen (HBsAg)-based stopping-rules. Results Baseline HBcrAg levels could not discriminate between responders and non-responders ( P=0.91). HBcrAg levels of patients responding to PEG-IFN therapy showed a more pronounced on-treatment decline (mean declines 3.4 versus 1.0 log U/ml; P8.35 log U/ml at week 24 identified 19 patients (19%) of whom 1 (negative predicitve value [NPV]=95%) achieved a response. The performance of this HBcrAg-based stopping rule alone was not superior to the one based on HBsAg >20,000 IU/ml. Among patients with an HBsAg 8.35, of whom 8 achieved no response (NPV 89%). Conclusions HBeAg-positive CHB patients with a response to PEG-IFN therapy achieve a more pronounced HBcrAg decline. HBcrAg levels at week 24 of therapy could be used to identify non-responders in combination with the established HBsAg-based stopping-rules.

BackgroundThe glycosphingolipid α-galactosylceramide (α-GalCer) is known to stimulate invariant natural killer T-cells (iNKTs) and is able to induce powerful antiviral immune responses. The present dose-escalating randomized placebo-controlled Phase I/II trial aimed to investigate antiviral activity and safety of α-GalCer as a novel class of treatment for chronic hepatitis B patients.MethodsPatients were randomly assigned to 0.1 μg/kg ( n=8), 1 μg/kg ( n=6) or 10 μg/kg ( n=6) α-GalCer or placebo ( n=7) treatment.ResultsAlmost all α-GalCer-treated patients showed a rapid and strong decrease in natural killer T-cell (NKT) numbers. Patients with high baseline NKT numbers showed immune activation, including natural killer cell activation, increased serum tumour necrosis factor-α and interleukin-6 levels, and development of fever. Three patients demonstrated a transient decrease in hepatitis B virus (HBV) DNA. Only one α-GalCer-treated patient had a sustained decrease in HBV DNA at the end of follow-up. Four patients discontinued therapy because of fever shortly after drug administration. No significant side effects were observed.Conclusionsα-GalCer (0.1–10 μg/kg) used as mono-therapy for chronic hepatitis B infection resulted in a strong decrease of NKTs, but did not clearly affect HBV DNA and alanine aminotransferase levels. α-GalCer was poorly tolerated and is unlikely to be suitable as an alternative monotherapy to the current treatment regimen.