A study of peginterferon-alfa intervention to achieve hepatitis B surface antigen loss in multi-drug resistant chronic hepatitis B participants under long-term viral suppression with tenofovir DF +/- lamivudine salvage therapy (TDF-109 cohort)

Hepatitis B virus is a major health issue worldwide and despite the advances in therapy, it is still the tenth leading cause of mortality. Currently there are two treatments available – peginterferon-alpha (pegIFNa) and nucleos(t)ide analogues (NA). PegIFNa is a drug which affects the immune system and is a finite treatment of 48 weeks, however majority end up on NA indefinitely, although not concurrently. NA are oral agents which are highly effective in controlling the virus, patients often flare once this medication is ceased. The ultimate goal of antiviral therapy is converting chronic hepatitis B (CHB) patients from surface antigen (HBsAg) positive to negative with development of surface antibodies (HBsAb) (HBsAg seroconversion). The TDF-109 study (Project No H2006/02552) evaluated the efficacy of tenofovir DF (TDF) +/- lamivudine (LMV) rescue therapy for LMV/ adefovir (ADV)-experienced Asian patients (Protocol No IN-AU-174-0109). The initial two year data was published by Patterson SJ, George J, Strasser SI, Lee AU, Sievert W, Nicoll AJ, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247-54. Most patients have now completed 5 years of treatment and TDF has resulted in significant viral suppression in the majority of patients. Significant declines of HBsAg titre were observed however no seroconversion. At this stage, majority of the patients will be on NA life-long. We believe that immunomodulation is required to achieve HBsAg loss, and that this explains the very low rates of HBsAg loss, and eventual plateau phase that have been observed during NA therapy. We hypothesize that in patients under long-term viral suppression with potent NA, add-on pegIFNa will reduce serum HBsAg levels and lead to HBsAg loss. We propose an investigator-initiated proof-of-concept study to evaluate the efficacy of add-on pegIFNa therapy (180mcg subcutaneously weekly) in patients who have been treated with TDF +/- LMV therapy for at least 5 years as part of the TDF-109 study. We will aim to recruit all the TF-109 patients into this study. Those suitable will be treated with 48 weeks of pegIFNa. Strategies used to monitor adherence includes taking a history from the patients as well as counting drug tablet return on their reviews.