studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1201A
therapy allows effective disease targeting at multiple critical
nodes of the viral life cycle.
Disclosures:
Emily P. Thi - Employment: Tekmira Pharmaceuticals
Amy C. Lee - Employment: Tekmira
The following authors have nothing to disclose: Ammen P. Dhillon
2035
The New Cyclophilin Inhibitor STG-175 Efficiently Inhibits
Mono- as well as Co-Infections of HIV-1, HCV and
HBV
Philippe Gallay 1 , Michael Bobardt 1 , Udayan Chatterji 1 , Zhengyu
Long 2 , Shengli Zhang 2 , Zhuang Su 2 ; 1 The Scripps Research Institute,
La Jolla, CA; 2 S & T Global, Inc., Woburn, MA
BACKGROUND: Human immunodeficiency virus type-1 (HIV-
1), hepatitis B virus (HBV) and hepatitis C virus (HCV) share
a common route of transmission. HBV and HCV mono-infection
represent the major causes of chronic liver disease globally.
HIV-1 co-infection with HBV or HCV is associated with
accelerated progression to severe liver disease, increased risk
of hepatotoxicity from antiretroviral therapy and reduced survival.
Co-infected patients are often refractory to most therapies
and develop liver fibrosis, cirrhosis and liver cancer more
often than mono-infected patients. Since a growing body of
evidence suggests that HIV-1, HCV and HBV, all exploit the
host protein cyclophilin A (CypA) to optimally infect and replicate
in human cells, we tested a new cyclophilin inhibitor
STG-175 for its capacity to inhibit mono- as well as co-infections
of these three prime viral human threats. MATERIAL AND
METHODS: For mono-infections: i) human PBMCs were infected
with HIV-1 (JR-CSF) and viral replication was quantified by
HIV-1 capsid/p24 ELISA; ii) hepatoma Huh7.5.1 cells were
infected with HCV (JFH-1) and viral replication was quantified
by HCV core ELISA; and iii) NTCP-positive Huh7 cells were
infected with HBV AD38 and viral replication was quantified
by HBV HBeAg ELISA. For dual and triple infections: target
cell populations were mixed prior to virus exposure. For drug
treatments, STG-175 was added to cells either i) together with
viruses or ii) 3 days post-infection and then every 3 days for
a period of 12 days. RESULTS: In this in vitro co-culture infection
system, we found that STG-175 inhibits in a dose-dependent
manner mono-infections, dual co-infections as well as the
triple HIV-1/HCV/HBV co-infection. The degree of STG-175
antiviral efficacy was HCV > HIV-1 > HBV. The addition of
STG-175 together with virus totally blocked HCV and HIV-1
infection and greatly attenuated HBV infection. When added
3 days post-infection and then every 3 days, STG-175 totally
eradicated the pre-established HCV infection, almost totally
aborted the established HIV-1 infection and prevented the viral
expansion of the pre-established HBV infection. Similar results
were observed during the triple HIV-1/HCV/HBV co-infection.
STG-175 was found to be constantly more efficacious than
the well-characterized cyclophilin inhibitor alisporivir in both
mono- and co-infections. CONCLUSIONS: By demonstrating a
potent and broad spectrum of antiviral activity, the new cyclophilin
inhibitor STG-175 represents an attractive drug partner
for an IFN-free regimen for the treatment of HIV-1/HCV/HBV
co-infections.
Disclosures:
The following authors have nothing to disclose: Philippe Gallay, Michael Bobardt,
Udayan Chatterji, Zhengyu Long, Shengli Zhang, Zhuang Su
2036
Association of Interferon-gamma Inducible Protein 10
Polymorphism with Treatment Response to Pegylated
Interferon in HBeAg-Positive Chronic Hepatitis B
Pisit Tangkijvanich 1 , Umaporn Limothai 1 , Natthaya Chuaypen 1 ,
Apichaya Khlaiphuengsin 1 , Rujipat Wasitthankasem 2 , Yong Poovorawan
3 ; 1 Biochemistry, Chulalongkorn University, Bangkok, Thailand;
2 Chulalongkorn University, Bangkok, Thailand; 3 Pediatrics,
Chulalongkorn University, Bangkok, Thailand
Background: Interferon-gamma inducible protein 10 (IP-10)
plays an important role in the natural history and treatment
outcome of patients with chronic hepatitis B (CHB). The aim of
this study was to investigate the association of single nucleotide
polymorphism (SNP) G-201A in the promoter region of the IP-10
gene and treatment response to pegylated interferon (PEG-IFN)
in patients with HBeAg-positive CHB. The potential effect of
SNP rs12979860 in the interferon lambda-3 (IFNL3) gene was
also examined. Method: We retrospectively analyzed data of
Thai patients with HBeAg-positive CHB treated with PEG-IFN
for 48 weeks. Virological response (VR) was defined as HBeAg
clearance and HBV DNA < 2,000 IU/mL at 24 weeks post
treatment. The SNPs G-201A and rs12979860 were identified
by PCR–RFLP method. HBV genotype was performed by direct
sequencing. Baseline serum IP-10 levels were measured by a
commercially available assay. Results: Among 107 patients
enrolled (72 male, mean age 34.3 years), VR was achieved
in 45 (42.1%) patients. HBsAg clearance and HBsAg decline
(< 100 IU/mL) at 24 weeks post treatment were achieved in
10 (9.3%) and 22 (20.6%) patients, respectively. The distribution
of HBV genotypes B and C was 12.1% and 81.3%,
respectively. The overall distribution of GG, GA and AA genotypes
of G-201A was 76.6%, 19.6% and 3.7%, respectively.
Patients with GG genotype, compared to those with non-GG
genotype, achieved significantly higher rated of VR (48.8% vs.
19.2%; P=0.011), HBsAg decline (25.6% vs. 4.0%, P=0.019),
and a trend of HBsAg clearance (11.0% vs. 4%, P=0.294).
Patients with GG-genotype had more pronounced decline of
serum HBsAg during and after therapy (weeks 0, 4, 12, 24,
48 and 72) and had higher baseline IP-10 levels than those
with non-GG genotype (432.2±339.0 vs. 257.3±145.7 pg/
mL, P=0.028). Patients achieving VR had significantly higher
pretreatment IP-10 levels than non-responders (496.0±394.6
vs. 328.0±232.2, P=0.013). The distribution of CC, CT and
TT genotypes of rs12979860 was 89.7%, 10.3% and 0%,
respectively. Patients with CC and CT genotypes achieved
VR in 41.7% and 45.5%, respectively (P=0.810). In logistic
regression analysis, SNP G-201A was an independent factor
associated with VR (odds ratio 3.81, 95% confidence interval:
1.31-11.12, P=0.014). Conclusions: These data demonstrated
that IP-10 polymorphism, but not IFNL3 polymorphism, was
independently associated with response to PEG-IFN therapy in
Thai patients with HBeAg-positive CHB.
Disclosures:
The following authors have nothing to disclose: Pisit Tangkijvanich, Umaporn Limothai,
Natthaya Chuaypen, Apichaya Khlaiphuengsin, Rujipat Wasitthankasem,
Yong Poovorawan