Incidence and Risk Factor of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Receiving Long Term Entecavir-Exploring Hbv Pre-S Mutants and Combination Mutations of Pre-S/Core Promoter/Precore Regions

  • Lee, Chuan-mo (PI)
  • Chen, Chine Hung (CoPI)
  • Yen, Yi Hao (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and more than half of HCC cases are attributable to persistent hepatitis B virus (HBV) infection. Hepatitis B virus replication with subsequent immune-mediated liver injury is the main driver of disease progression. Previous studies found that pre-S/S and HBV core promoter complex mutation was associated with liver cirrhosis and HCC in chronic hepatitis B patients. Antiviral treatment can potentially reduce the risk of HCC since it suppresses viral replication, induces HBeAg seroconversion and improves liver histology. However, most evidence supporting a protective effect of antiviral treatment originates from non-randomized or retrospective studies and is limited to conventional interferon and lamivudine. Since viral load directly correlates with HCC risk, it is reasonable to hypothesize that the newer agents used in the management of CHB which are more effective at reducing HBV DNA and have a more favorable resistance profile such as entecavir will lower the risk of HCC. Previous study found that the large part of nucleoside-naive patients with CHB treated with entecavir in a long-term cohort had significant histological improvement and regression of fibrosis or cirrhosis. However, the number of patients was limited. Furthermore, studies exploring the effect of ETV treatment on HCC incidence are rare. Thus, studies investigating the effect of long-term ETV therapy on HCC risk in NA-naïve and NA-experienced patient groups are needed. Specific plan: 1. To study the long-term treatment response to entecavir and the incidence of HCC development in naïve patients and NA-experienced patient groups.. 2. To determine if risk factors of HCC development including basal core promoter, pre-S deletion and S mutation at baseline and during treatment are useful in predicting HCC development in chronic hepatitis B with entecavir therapy in naïve or NA-experienced patients and untreated controls 3. To determine whether these complex mutations of HBV associated with advanced liver disease identified by direct sequencing are co-located on the same HBV genome by molecular cloning and sequencing. Patients and Methods Approximately 140 cirrhotic and 160 non-cirrhotic CHB patients who received entecavir monotherapy at study entry will be included in this prospective study. Of 140 cirrhotic patients, 88 were naïve and 52 received other oral antiviral therapy. Of 160 CHB patients, 102 were naïve and 58 received other oral antiviral therapy. Based on a 1:1 case control design, 140 cirrhotic patients and 160 non-cirrhotic patients without anti-viral treatment before entry or during follow-up or evidence of HCC at entry and within 6 months follow-up who are age-, sex-, and HBeAg status- matched with patients with entecavir therapy will be included in this study. All patients will have a regular follow-up of at least 24 months and up to 60 months. HBV DNA levels, HBV genotypes, and the sequences of pre-S/S, precore/core promoter regions will be determined at study entry. Besides, we will test the pre-S/S/core promoter/precore sequences preceding the liver cirrhosis or HCC diagnoses or at the last follow-up examination for patients who had not developed liver cirrhosis if HBV DNA detectable. These viral factors and clinical factors e.g. age, sex, HBeAg status, ALT, total bilirubin, platelet etc. will be correlated with the development of HCC. Cloning sequencing of full-length HBV genomes of complex HBV mutations associated with advanced liver disease will be performed.

Project IDs

Project ID:PC10007-0389
External Project ID:NSC100-2314-B182-035
StatusFinished
Effective start/end date01/08/1131/07/12

Keywords

  • Entecavir
  • Pre-S mutation
  • Basal core promoter
  • Hepatocellular carcinoma
  • Drug resistant mutant
  • Liver cirrhosis

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