studies

1200A AASLD ABSTRACTS HEPATOLOGY, October, 2015
antiHBs at the time of NUCs discontinuation. No HBsAg seroreversion
occurred during a median of 12 months follow-up
(range, 2-55 months). No patient developed hepatic complications
or hepatocellular carcinoma. A new 24 months-follow-up
analysis is currently on-going to evaluate previous outcomes.
Those results will be presented during AASLD congress. Conclusions:
These data suggest the time between the diagnosis
of CHB and HBsAg loss is longer in HBeAg negative than
in HBeAg positive patients. In addition, HBsAg loss occurred
faster with TDF/ETV than with LAM/ADV. HBsAg loss was
maintained in all patients after discontinuation of NUCs.
Disclosures:
Emilio Suarez - Advisory Committees or Review Panels: Gilead; Speaking and
Teaching: Gilead, Bristol Myers Squibb
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, MSD;
Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead,
Janssen, BMS
Martin Prieto - Advisory Committees or Review Panels: Bristol, Gilead
Rafael Gómez Rodríguez - Consulting: Gilead
Moisés Diago - Grant/Research Support: MSD, JANSSEN; Speaking and Teaching:
BMS, ABBVIE, GILEAD
Rosa María Morillas - Advisory Committees or Review Panels: BRISTOL, GILEAD,
Abvvie; Speaking and Teaching: ROCHE, JANSSEN, MSD
The following authors have nothing to disclose: Miguel A. Simon, Juan Manuel
Pascasio, Manuel Rodriguez, Teresa Casanovas, Javier Crespo, Juan I. Arenas,
Blanca Figueruela, Jose M. Zozaya, José Luís Calleja, Marta Casado, Esther
Molina, Javier Fuentes
2033
Prolongation of interferon therapy increases maintained
virological response rates and improves the natural
course of chronic delta hepatitis
Onur Keskin, Ali Tuzun, Fatih Karakaya, Cagdas Kalkan, Aysun
Caliskan Kartal, Ersin Karatayli, Senem C. Karatayli, A.Mithat
Bozdayi, Ramazan Idilman, Cihan Yurdaydin; Gastroenterology,
Ankara University School of Medicine, Ankara, Turkey
Introduction and Aim: Chronic delta hepatitis (CDH) is the
most severe form of chronic viral hepatitis. Interferons are the
only approved therapy in CDH. HDV RNA 6 months post-treatment
is an unreliable surrogate of treatment efficacy. Hence
maintained virologic response (MVR) is important. Aim of
this study was to assess effect of prolonged interferon therapy
on MVR and on natural course of CDH. Patients and
Methods: We searched our CDH database for patients who
received interferon treatment. 99 CDH patients (70M/29F;
mean age:49.8±11.3 years, 21 cirrhotic/78 non-cirrhotic at
baseline) who received at least 6 months of conventional or
pegylated interferon were identified and included in the analysis.
MVR was defined as durable negative HDV RNA after
2 years of post-treatment follow-up. HDV RNA was assessed
by in-house PCR. Median treatment duration was 24 months
(6-126) and median number of treatment episodes was 2 (1-8).
Duration of IFN therapies were classified as 6-12 (n:32),13-
24 (n:26), 25-36 (n:11), 37-48 (n:15), 49-60 (n:7) and >60
months (n:8), respectively. Median follow up time after treatment
discontinuation was 118 (24-255) months. Overall, 35
patients had a MVR and 64 did not have MVR . Development
of hepatocellular cancer (HCC), hepatic decompansation, liver
related mortality, liver transplantation and HBsAg loss were
considered as clinical end-points. Results: Only 16 patients
(16%) had MVR with 12 months of IFN therapy. With prolongation
of IFN treatment, 19 new patients (6, 2, 4, 3 and 4
patients after 24, 36, 48, 60 and > 60 months of IFN treatment,
respectively) achieved MVR. Cumulative probability of
MVR was 16%, 24%, 26%, 30%, 33% and 38% at end of
6-12, 24, 36, 48, and > 60 months of interferon treatment,
respectively. Development of HCC (p: 0.05), decompansation
(p:0.013), liver-related mortality (p:0.03) and transplantation
(p:0.012) were more common in non-responders and HBsAg
clearance occurred more often in patients with MVR (p:0.002).
By multivariate analysis, low platelet count and no response
to therapy were independent factors for development of any
clinical endpoint (p=0.014 and 0.021, respectively). Conclusion:
Longer duration of IFN therapy increases MVR rates (from
16.1% to 38%) in CDH. Low platelet count at baseline and
no response to treatment were independent predictors for the
development of a clinical endpoint. These results suggest that
treatment with pegylated interferon should be started early in
CDH and that prolonged periods of treatment may be needed.
Further, the results underline the urgent need for new drug
development in CDH.
Disclosures:
Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche,
Merck, Gilead, AbbVie; Speaking and Teaching: BMS
The following authors have nothing to disclose: Onur Keskin, Ali Tuzun, Fatih
Karakaya, Cagdas Kalkan, Aysun Caliskan Kartal, Ersin Karatayli, Senem C.
Karatayli, A.Mithat Bozdayi, Ramazan Idilman
2034
TKM-HBV, a Novel RNA Interference Treatment for
Chronic Hepatitis B, has a Complementary Mode of
Action to Current Standard of Care Nucleos(t)ide Analogs
Emily P. Thi, Ammen P. Dhillon, Amy C. Lee; Tekmira Pharmaceuticals,
Burnaby, BC, Canada
Current approved nucleos(t)ide analog (NA) drugs for hepatitis
B virus (HBV) are highly effective at inhibiting viral replication
but do not cure the chronic infection and are largely ineffective
in preventing viral protein production. HBV proteins are understood
to play a variety of roles in contributing to suppression
of host immune responses and viral persistence. Quantitative
changes in peripheral HBV surface antigen (HBsAg) in particular
have been correlated with differences in clinical outcomes.
TKM-HBV is a novel RNA interference HBV therapeutic
intervention currently in Phase 1 clinical development. It is a
mixture of three different oligonucleotide duplexes, encapsulated
within a lipid nanoparticle delivery system, that cleaves
all forms of HBV RNAs thus preventing the synthesis of viral
proteins. Because TKM-HBV is understood to act on a separate
viral target and in a different cellular compartment than that
of NAs (in the cytoplasm versus the viral capsid), there is little
basis to expect drug:drug interference in a co-treatment setting.
TKM-HBV combination treatment with NA drugs (including the
current frontline compounds, entecavir and tenofovir) was studied
in two HBV infection models: primary human hepatocytes
(PHH) and humanized mice. To mimic a potential clinical study
setting, TKM-HBV was administered after onset of NA treatment.
Reductions in HBV DNA and HBsAg were observed in
PHH cultures co-treated with TKM-HBV and either entecavir,
tenofovir or lamivudine. No antagonism of either drug activity
was detected and most often additive effects were observed.
A second PHH study examining performance against different
viral genotypes also did not detect any drug:drug interference
in the ability of entecavir to inhibit viral replication or TKM-HBV
to reduce viral antigen load when applied against gt A, B, C
or D. Interestingly, the magnitude of TKM-HBV activity was
more consistent than that of entecavir across the four genotypes
examined. The combination approach was also demonstrated
to be effective in the uPA/SCID humanized mouse model of
chronic HBV, resulting in simultaneous control of both HBV
DNA titre and peripheral HBsAg (3 log and 1 log reductions,
respectively). In summary, these results show that TKM-HBV
and NA modes of action are complementary, and combination