studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 973A
ily was detected by Western blot, and the DNA binding level of
hepatocyte nuclear factor 4α(HNF4α) was detected by EMSA.
Summary: Luteolin decreased the levels of HBsAg and HBeAg
and the HBV DNA load both in the cultured medium and in
serum, and it also suppressed the HBV DNA RI and the expression
of HBsAg and HBcAg, which demonstrated that luteolin
can effectively inhibit HBV replication both in vitro and in vivo.
In addition, luteolin effectively downregulated the expression of
HNF4α and decreased its binding level with HBV preC/C promoter
in HepG2.2.15 cells. The extracellular signal-regulated
kinase(ERK) and c-Jun N-terminal kinase(JNK) signal pathways,
but not the p38 signal pathway in the MAPK family, were
activated by luteolin, which can be blocked by their inhibitors,
respectively. However, it was the ERK inhibitor(U0126) rather
than the JNK inhibitor(SP600125) can attenuate the down-regulation
of HNF4α by luteolin and restore the protein level of
HNF4α. In addition, blocking the ERK pathway with inhibitor
can cripple the inhibition of HBV replication by luteolin, while
blocking the JNK pathway do not affect the inhibitory effect
of luteolin on HBV replication. Conclusions: Luteolin inhibits
HBV replication through down-regulating HNF4α expressin via
activating ERK signal pathway. Keywords: luteolin; hepatitis B
virus; replication; hepatocyte nuclear factor 4α; extracellular
signal-regulated kinase
Disclosures:
The following authors have nothing to disclose: Yunhong Nong, Ying Shi, Miao
Liu, Libo Yan, Yong Lin, Lang Bai, Hong Tang
1563
Redefining the Natural History of Chronic Hepatitis B:
Using Viral Diversity to Classify Disease and Predict
Serological Response to Nucleos(t)ide Analogue (NA)
Therapy
Julianne Bayliss 1 , Gillian Rosenberg 1 , Lilly Yuen 1 , Anuj Gaggar 2 ,
Kathryn M. Kitrinos 2 , Mani Subramanian 2 , Edward J. Gane 3 ,
Henry Lik-Yuen Chan 4 , Rachel Hammond 1 , Scott Bowden 1 , Peter
A. Revill 1 , Stephen Locarnini 1 , Alex J. Thompson 5 ; 1 Molecular
R&D, VIDRL, Melbourne, VIC, Australia; 2 Gilead Sciences, Foster
City, CA; 3 New Zealand Liver Transplant Unit, Auckland City
Hospital, Auckland, New Zealand; 4 Medicine and Therapeutics,
Chinese University of Hong Kong, Hong Kong, Hong Kong; 5 Gastroenterology,
St Vincent’s Hospital, Melbourne, VIC, Australia
Background The presence of basal core promoter (BCP) and
precore (PC) mutations in immune tolerant (IT) patients with
chronic hepatitis B (CHB) suggests a transition between IT
and immune clearance (IC) disease. Here, next generation
sequencing (NGS) was used to analyse the impact of baseline
viral diversity on CHB natural history and its association
with baseline serology and response to NA treatment. Methods
GS-US-203-0101 and GS-US-174-0103 evaluated tenofovir
DF (TDF) containing regimens in IT and IC patients, respectively.
Only genotype B/C patients were included (B= 83;
C= 102). Patients were classified as True IT (ALT 20-40-80IU/mL). Viral diversity, defined as non-synonymous
(NS), genotype specific viral substitutions from wild
type (WT) and entropy scores across the whole genome (WG),
were calculated using Illumina MiSeq NGS and correlated
with baseline clinical and virological data and W192 serological
response. Results 185 patients were analysed (baseline:
median age 32yrs, 55% male; median ALT 29 IU/mL, HBV
DNA 8.38 log 10
IU/mL, HBsAg 51,590 IU/mL, HBeAg 3,358
PEIU/mL). Increased viral diversity was associated with lower
HBV DNA (p= 0.001), HBeAg (p< 0.0001) and HBsAg (p<
0.0001) titres and higher ALT levels (p< 0.0001). Although
HBV DNA, HBeAg and HBsAg titres did not differ significantly
between True IT and Late IT patients (Table 1), a significantly
higher percentage of Late IT patients had BCP and PC mutations
(p= 0.001 and p< 0.0001, respectively). Late IT patients
also had more NS substitutions (p= 0.001), higher entropy
scores (p= 0.002), and were more likely to achieve HBeAg
seroconversion by W192 compared to True IT patients (True
IT= 3%, Late IT= 14%, p< 0.0001). Discussion There is a subset
of IT CHB patients with a virological profile similar to IC
patients. This subset of patients may be transitioning between
IT and IC disease and are more likely to respond favourably
to TDF therapy.
Disclosures:
Julianne Bayliss - Grant/Research Support: Gilead Inc.
Gillian Rosenberg - Grant/Research Support: Gilead Sciences
Anuj Gaggar - Employment: Gilead Sciences, Inc.
Kathryn M. Kitrinos - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Mani Subramanian - Employment: Human Genome Sciences, Human Genome
Sciences, Human Genome Sciences, Human Genome Sciences; Stock Shareholder:
Human Genome Sciences, Human Genome Sciences, Human Genome
Sciences, Human Genome Sciences
Edward J. Gane - Advisory Committees or Review Panels: Novira, AbbVie, Janssen,
Gilead Sciences, Janssen Cilag, Achillion, Merck, Tekmira; Speaking and
Teaching: AbbVie, Gilead Sciences, Merck
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, MSD,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and
Teaching: Echosens
Peter A. Revill - Grant/Research Support: Gilead Sciences
Stephen Locarnini - Consulting: Gilead, Arrowhead; Employment: Melbourne
Health
Alex J. Thompson - Advisory Committees or Review Panels: Gilead, Abbvie,
BMS, Merck, Spring Bank Pharmaceuticals, Arrowhead, Roche; Grant/Research
Support: Gilead, Abbvie, BMS, Merck; Speaking and Teaching: Roche, Gilead,
Abbvie, BMS
The following authors have nothing to disclose: Lilly Yuen, Rachel Hammond,
Scott Bowden
1564
Angiopoetin-like protein 2 independently associated
with liver inflammation and fibrosis in patients chronically
infected with hepatitis B virus
Hong Zhao, Yong-Qiong Deng, Gui-Qiang Wang; Department of
infectious disease, Peking University First Hospital, Beijing, China
Background: Guidelines recommend antiviral therapy for
HBeAg(+)patients with HBV DNA >=20000IU/ml or HBeAg(-)
patients with HBVDNA >=2000IU/ml, and alanine aminotransferase
(ALT) levels more than 2 times of upper limit of normal
(ULN). For patients who don’t meet the criteria above, therapy
decision depends on hepatic histology, an invasive process.
The available non-invasive assessments could only predict the
stages of liver fibrosis. Therefore, a non-invasive method or
biomarker predicting moderate and more inflammation or significant
fibrosis is urgently needed. Angiopoetin-like protein 2
(Angptl2) is a mediator of chronic inflammation contributing to
extracellular matrix remodeling. Aim: The aim of the study was
to explore the predicting value of serum angptl2 for moderate