Changes in serum hepatitis B surface and e antigen, interferon‐inducible protein 10, and aminotransferase levels during combination therapy of immune‐tolerant chronic hepatitis B

Abstract

Background and Aims Treatment of immune‐tolerant (IT) children and adults with combined peginterferon alfa‐2a and entecavir results in a decline in serum HBeAg and HBsAg concentrations but rarely results in loss of HBeAg or sustained off‐treatment response. Factors associated with declines in these viral antigens during treatment remain unexplored. Approach and Results We investigated the pattern of virologic and biochemical response in 86 participants (59 children, 27 adults) by serial quantitative measurement of HBsAg (qHBsAg), quantitative HBeAg (qHBeAg), HBV RNA, interferon‐inducible protein (IP‐10), IL‐18, and alanine aminotransferase (ALT). Each individual had previously been treated with 8 weeks of entecavir followed by 40 weeks of combined peginteferon and entecavir. We defined the interrelationships between these parameters and virologic response measured as nadir declines from baseline for HBeAg and HBsAg. The patterns of HBsAg and HBeAg decline were similar in pediatric and adult participants. Higher levels of IP‐10 were observed during treatment in participants with greater ALT elevations and greater reductions of qHBsAg and qHBeAg. Individuals with peak ALT values exceeding three times the upper limit of normal were significantly more likely to have >1 log10 decline in both viral antigens. HBV DNA became undetectable in 21 of 86 (24%) and HBV RNA in 4 of 77 (5%) during therapy, but both markers remained negative only in those who became HBsAg negative, all of whom also had ALT elevations. Conclusions Induction of IP‐10 during peginterferon treatment in adults and children in the IT phase of chronic HBV infection is associated with ALT elevations and decline in viral antigens, suggesting a degree of interferon‐inducible viral control.

Efficacy and Safety of Antiviral Therapy for Immune-tolerant Hepatitis B Viral Infection in Children: A Systematic Review and Meta-analysis

“…36 HBV clearance in IFN-treated patients is associated with IFN-responsive genotypes, relevant immune pathway genetic polymorphisms, and virologic factors such as HBV genotype. [37][38][39] Because the patients included in our study who had normal or nearnormal ALT levels were from different countries or races, whether the differences in treatment response were due to ethnicity requires further exploration in prospective studies.…”

Advances in Immunotherapy for Hepatitis B

“…In addition, the treatment of RO7020531 triggered obvious immune activation in patients with CHB [ 113 , 114 , 115 ]. Moreover, recently developed TLR-8 agonists may contribute to the activation of PRRs present in the liver, and GS-9688 has been shown to promote the production of IL-12 and IL-18 from monocytes or DCs [ 116 , 117 , 118 ]. Furthermore, as cytokines such as IL-12 also contribute to NK cell activation, which have been demonstrated to kill both HBV-infected hepatocytes and HBV-specific CD8 + T cells, it is necessary to comprehensively evaluate the function of activated innate immunity in the process of HBV eradication.…”

Making child’s play of tolerance: Defining the immune‐viral interplay during combination entecavir and pegylated interferon therapy for immune‐tolerant hepatitis B infection

“…In this context, Perrillo and colleagues have addressed a critical knowledge gap regarding immune responses during treatment in early hepatitis B infection by using the recent Hepatitis B Research Network Adult and Paediatric Cohort Study clinical trials of pegylated interferon and entecavir in people with hepatitis B who were classified as immune‐tolerant, defined in the study as HBV DNA levels > 7 log10 IU/ml and ALT < 1.5 times the upper limit of normal. [ 7 ] In these prospective single‐arm intervention studies, 86 adults and children (aged 2–17) from across the United States and Canada received an 8‐week entecavir lead‐in, then entecavir plus pegylated interferon for 40 weeks, followed by monitoring for a further 48 weeks. The primary composite endpoint was HBeAg loss and HBV DNA < 1000 IU/mL 48 weeks post–cessation of therapy.…”