Nucleos(t)ide withdrawal in HBeAg negative hepatitis B virus infection to promote HBsAg clearance. (NUC-B)

Chronic infection with hepatitis B virus causes death through decompensated cirrhosis or hepatocellular carcinoma in over a million people per year. Treatment is available to prevent progression to end stage liver disease either by induction of immune responses during finite therapy with type I interferon or by suppressing viral replication using nucleos(t)ide` analogues (1,2). The majority of patients in the UK have the HBeAg negative form of infection and are treated with nucleos(t)ide analogues but cure of the infection, indicated by loss of HBV surface antigen (HBsAg), occurs in less than 2% of cases so the majority remain indefinitely on treatment (3). A study in HBeAg negative patients investigated the effect of treatment withdrawal after 4-5 years of nucelos(t)ide analogues and found that 30% of patients lost HBsAg during 4 years of follow up and a further 30% remained stable with low viral load and normal liver function off treatment (7). The primary aim of the proposed study is to demonstrate that this outcome can be replicated in a larger and more diverse group of HBV infected patients. Loss of HBsAg in patients with chronic HBV infection requires immune-mediated clearance of the HBV minichromosome (cccDNA) from infected hepatocytes. Innate and adaptive immune responses are impaired in chronic HBV infection. High level viral replication and an attenuated endogenous interferon response have been implicated in the HBV-specific immune paresis but partial restoration of immune responses have been observed after long term viral suppression (9, 10). Interferon is used clinically to promote innate and adaptive immune responses against HBV. Although combining pegylated interferon with nucleos(t)ide analogues as initial treatment does not improve clinical outcomes, there is a strong immunological rationale for using interferon as sequential therapy after viral replication has been suppressed and some adaptive immunity restored. This has been validated in HBeAg positive patients(15). Unlike nucleos(t)ide analogues interferons activate intracellular cytadine deaminases which promote cccDNA degradation (12). The second aim of the proposed study is therefore to explore whether adding a short course of pegylated interferon therapy prior to complete treatment cessation would increase the proportion of patients achieving HBsAg loss. It is clearly important to understand the mechanisms associated with HBsAg loss so the third aim of the study will be to measure HBV specific immune responses and NK cell responses at multiple timepoints during the trial to identify correlates of viral elimination. In a subset of patients who consent to repeated fine needle aspirates of the liver we will explore immune response in more detail by analysing the phenotype and function of intrahepatic lymphocytes using state-of-the-art FACS techniques. Finally we will try to identify from baseline parameters which patients are most likely to achieve HBsAg loss. Serum HBsAg concentrations, intrahepatic cccDNA levels, viral genotype, immunological parameters and demographic variables will be explored as predictors of successful clinical outcomes. HBsAg loss is important to the NHS as it allows patients to be discharged from clinic without requirement for indefinite antiviral therapy.