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
External Project ID:NSC100-2314-B182-035
Status | Finished |
---|---|
Effective start/end date | 01/08/11 → 31/07/12 |
Keywords
- Entecavir
- Pre-S mutation
- Basal core promoter
- Hepatocellular carcinoma
- Drug resistant mutant
- Liver cirrhosis
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