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The Liver Meeting |
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October 29 - November 2 |
Poster
19
PRODUCTION
OF IMMUNOGENIC HBSAG-PULSED HUMAN DENDRITIC CELLS (DCS): EVALUATION OF SAFETY
AND EFFICACY OF HBSAG-PULSED DCS IN NORMAL VOLUNTEERS, HB VACCINE NONRESPONDERS
AND PATIENTS WITH CHRONIC HEPATITIS B
Sk. Md. Fazle Akbar, Shinya Furukawa, Norio Horiike, Morikazu Onji, Ehime University School of Medicine, Shitukawa, Japan.
Background:
Antigen
loaded on antigen-presenting dendritic cell (DC) [antigen-pulsed DC] has shown
potent therapeutic efficacy in animal models of human diseases.
Aims:
Indeed,
administration of hepatitis B surface antigen (HBsAg)-pulsed DCs to hepatitis B
virus (HBV) transgenic mouse led to the production of antibody to HBsAg
(anti-HBs) in the sera. However, the immune modulatory potential of
HBsAg-pulsed DCs has not been evaluated in human due to two major factors: (1)
the methodology of production of immunogenic HBsAg-pulsed human DCs has not
been optimized and (2) there are major concerns about the safety of
HBsAg-pulsed human DCs in human. The aim of this study was: (1) to prepare
immunogenic HBsAg-pulsed human DCs, (2) to assess their safety in human and (3)
to evaluate their immunogenicity in vivo.
Methods:
Human
DCs were obtained by culturing an adherent population of peripheral blood
mononuclear cells with granulocyte-macrophages colony stimulating factor and
interleukin-4 for 7 days. DCs were incubated with a commercial vaccine
containing 5-10 microgram of HBsAg (subtype, adw) for 8-24 hours. After washing
for 5 times in media, the expressions of HLA DR and CD86 of HBsAg-pulsed DCs
were assessed by flow cytometry. Five million HBsAg-pulsed DCs were
administered, interdermally, once to two anti-HBs-positive normal subjects,
five HB vaccine nonresponders and one patient with chronic hepatitis B (CHB).
Results:
HBsAg-pulsed
DCs did not contain any free HBsAg, endotoxin, toxoplasma and mycoplasma.
HBsAg-pulsed DCs expressed higher levels of HLA DR and CD86 compared to
unpulsed DCs. No volunteers exhibited any physical or biochemical evidences of
inflammation, autoimmunity, liver or kidney dysfunction (at day 1, 3, 7, 14, 28
and 56 after administrations of HBsAg-pulsed DCs). Patient with CHB only showed
slight elevation of serum alanine aminotransferase. The levels of serum
anti-HBs increased 5-20 times due to a single injection of HBsAg-pulsed DCs in
two anti-HBs-positive normal volunteers. To our surprise, all HB vaccine
nonresponders developed detectable levels of anti-HBs within 2 weeks of a
single injection of HBsAg-pulsed DCs. Anti-HBs was detected in the sera within
2 weeks of administration of HBsAg-pulsed DCs in one patient with CHB in the
sera.
Conclusions:
This
is the first report about the preparation of antigen-pulsed DCs for human usage
in which antigen pulsing resulted in upregulation of HLA DR and CD86 on DCs.
HBsAg-pulsed DCs were completely safe and induced anti-HBs in vivo in all
subjects. HBsAg-pulsed human DCs represent a new and noble prophylactic vaccine
for HB vaccine nonresponders. HBsAg-pulsed DCs could also be used as a
therapeutic tool for patients with CHB.
Poster
20
PEGINTERFERON
ALFA-2A (40KD) (PEGASYS(r)) MONOTHERAPY AND IN COMBINATION WITH LAMIVUDINE IS
MORE EFFECTIVE THAN LAMIVUDINE MONOTHERAPY IN HBEAG-POSITIVE CHRONIC HEPATITIS
B: RESULTS FROM A LARGE, MULTINATIONAL STUDY
George Lau, Queen Mary Hospital, Hong Kong, Hong Kong Special Administrative Region of China; Teerha Piratvisuth, Songklanakarin Hospital, Songkla, Thailand; Kang Xian Luo, Nangfang Hospital, Guangzhou, China; Patrick Marcellin, Hôpital Beaujon, Clichy, France; Satawat Thongasawat, Chiang Mai University, Chiang Mai, Thailand; Graham Cooksley, Royal Brisbane Hospital, Herston, Australia; Edward Gane, Middlemore Hospital, Otahuhu, New Zealand; Michael Fried, University of North Carolina, Chapel Hill, NC; Wan Cheng Chow, Singapore General Hospital, Singapore, Singapore; Seung Woon Paik, Samsung Medical Centre, Seoul, Republic of Korea; Wen Yu Chang, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Republic of China; Thomas Berg, Charité Humboldt Universität zu Berlin, Berlin, Germany; Robert Flisiak, University of Bialystok, Bialystok, Poland; Friederike Zahm, Roche, Basel, Switzerland; Nigel Pluck, Roche, Welwyn, United Kingdom.
Background:
Recent
data show that peginterferon alfa-2a (40KD) (PEGASYS(r)) gives significantly
higher post-therapy response rates than lamivudine in HBeAg-negative chronic
hepatitis B (CHB). Combining peginterferon alfa-2a and lamivudine did not
improve response rates over peginterferon alfa-2a alone [Marcellin et al, J
Hepatol 2004].
Aims:
In
this study, the efficacy and safety of peginterferon alfa-2a with and without
lamivudine vs lamivudine alone has been evaluated in HBeAg-positive CHB.
Methods:
Randomized,
partially double-blind multinational study. Patients with HBeAg-positive CHB (n=814)
received (1:1:1):
1)
Peginterferon alfa-2a (40KD) (PEGASYS(r)) 180 µg once weekly (qw) + placebo
once daily (qd)
2)
Peginterferon alfa-2a (40KD) (PEGASYS(r)) 180 µg qw + lamivudine 100 mg qd
3)
Lamivudine 100 mg qd.
Patients
were treated for 48 weeks and assessed after 24 weeks of treatment-free
follow-up.
Results:
Baseline characteristics were comparable in
all treatment groups. The overall patient population was predominantly Asian
(85-87%). After 24 weeks follow-up (week 72), the proportion of patients
achieving predefined co-primary endpoints (HBeAg seroconversion or HBV DNA
<100,000 copies/ml), and secondary endpoints (HBeAg loss and ALT
normalization), was significantly higher with peginterferon alfa-2a monotherapy
or combination therapy than with lamivudine monotherapy (see table).
HBsAg
seroconversion at week 72 was reported in 16 patients receiving peginterferon
alfa-2a (± lamivudine) compared with none receiving lamivudine monotherapy.
Withdrawals
from treatment for safety reasons were low across all groups (<=3%). The
majority of adverse events were mild in nature and incidence of serious adverse
events was low in all treatment groups (2-6%). Adverse events were comparable
between peginterferon alfa-2a monotherapy and the combination therapy.
Conclusions:
Significantly
higher post-therapy response rates were achieved with peginterferon alfa-2a
(40KD) (PEGASYS(r)) monotherapy or combination therapy than with lamivudine
monotherapy in patients with HBeAg-positive CHB. Combining peginterferon
alfa-2a and lamivudine did not improve response rates over peginterferon
alfa-2a alone. No unexpected adverse events were reported for peginterferon
alfa-2a and the addition of lamivudine did not significantly alter the
peginterferon alfa-2a safety profile.
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Poster
21
INDUCTION
OF HBS-SPECIFIC T CELL RESPONSES IN HBV CHRONIC CARRIERS BY AN HEPATITIS B
VIRUS DNA VACCINE
Marie-Louise Michel, Maryline Bourgine, Institut Pasteur, Paris, France; Hélène Fontaine, Hôpital Necker, Paris, France; Daniel Scott-Algara, Institut Pasteur, Paris, France; Christian Brechot, Stanislas Pol, Hôpital Necker, Paris, France.
Background:
In
the 370 millions HBs Ag chronic carriers, the viral persistence is thought to
be related to poor HBV-specific T-cell responses.
Aim:
To
investigate, in a phase I clinical trial, whether specific HBV DNA vaccination
could restore T-cell responsiveness.
Methods:
Ten
patients with chronic active hepatitis B nonresponder to approved treatments
for HBV infection were given 4 intramuscular injections of 1 mg of a DNA
vaccine encoding HBV envelope proteins. HBV-specific T-cell responses were
assessed by proliferation, ELISPOT assays and tetramer staining. Secondary end
points included safety and the monitoring of HBV viremia and serological markers.
Results:
Proliferative
responses to hepatitis B surface antigen were detected in two patients after
DNA injections. Few HBV-specific interferon-g secreting T-cells were
detectable before immunization, but the frequency of such responses was
significantly increased by three DNA injections. Immunization was well
tolerated. The mean viremia decreased from 2384 ± 4725 to 1483 ± 1906 pg/ml,
with a level lower than 2.5 pg/ml in 2. HBe Ab appeared in 2 patients with an
HBe seroconversion in one.
Conclusion:
This
study provides evidence that HBV DNA vaccination is safe and immunologically
effective and demonstrates that DNA vaccination can specifically activate
T-cell responses in chronic HBV carriers.
Poster
22
A
DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF EMTRICITABINE (FTC, EMTRIVA)
ADMINISTERED ONCE-DAILY FOR TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV)
INFECTION
Mitchell L. Shiffman, Virginia Commonwealth University Health System, Richmond, VA; T. M. Ng, Changi General Hospital, Singapore, Singapore; Z. Krastev, Medical University, Sofia, Bulgaria; I. A. Kotzev, Medical University, Varna, Bulgaria; G. Mechkov, Medical University, Sofia, Bulgaria; N. N. S. Kung, United Christian Hospital, Kowloon, Hong Kong Special Administrative Region of China; S. Chan, New York Hospital at Queens, Flushing, NY; F. Rousseau, J. Anderson, E. Mondou, Gilead Sciences, Inc., Durham, NC; J. Sorbel, Gilead Sciences, Durham, NC; S. G. Lim, National University Hospital, Singapore, Singapore.
Aims:
The
current study was a randomized, double blind, placebo controlled trial to
assess the safety and efficacy of FTC in the treatment of chronic HBV.
Emtricitabine (FTC) is a cytidine analog that selectively inhibits the HBV DNA
polymerase.
Methods:
All
patients were HBsAg positive, HBeAg positive or negative and HBV DNA positive,
had elevated serum ALT within 3 months of enrollment and a necroinflammatory
score of >3 (Knodell HAI) on liver biopsy (LBX). Patients were randomized
(2:1) to receive either FTC 200 mg QD or placebo for 48 weeks at which time the
LBX was repeated. HBV DNA was assessed by the Digene assay (lower limit of
detection (LLD) 4700 copies/mL). Patients with detectable HBV DNA at week 48
were typed for presence of YMDD mutation. The primary efficacy parameter was
histological response; defined as a reduction of at least two points in the
Knodell necroinflammatory score and lack of fibrosis progression. The primary
safety parameter was failure to tolerate study medication. Secondary endpoints
included virologic, serologic and, biochemical responses and emergence of drug
resistant mutations.
Results:
The
study population consisted of 248 patients with mean age of 40 yrs, 71% male,
59% Asian and 38% Caucasian; 63% were HBeAg positive. After 48 weeks of
treatment, serum ALT was normal in 65% vs 25% of FTC and placebo treated
patients (p<0.001) and HBV DNA was undetectable in 56% vs 7% (p<0.001)
respectively. 43% of patients treated with FTC had both normal ALT and
undetectable HBV DNA vs 4% in the placebo group (p<0.001). Similar results
were observed in both HBeAg positive and negative patients. 12% of HBeAg
positive patients seroconverted and became HBeAg negative and anti-HBe
positive. This was similar in both FTC and placebo groups. After 48 weeks,
12.6% of FTC treated patients developed YMDD mutation. Histologic response was
observed in 62% vs 25% of FTC and placebo patients respectively (p<0.001).
When analyzed by ranked assessment FTC treated patients had a greater
improvement in both necroinflammatory activity (p<0.001) and fibrosis
(p<0.009) compared to patients treated with placebo. 3% percent of patients
discontinued study drug due to adverse events. The most common AEs observed
were upper respiratory infection, abdominal pain, fatigue, influenza and
headache. These were observed in similar frequency in both the FTC and placebo
treatment groups.
Conclusions:
FTC
at a dose of 200 mg QD produced significant histologic improvement, with both a
reduction of inflammation and fibrosis when compared to placebo after 48 weeks
of treatment in both HBeAg positive and HBeAg negative chronic HBV patients.
FTC demonstrated potent antiviral activity and had a safety and tolerability
profile similar to placebo during treatment.
Poster
23
PHASE
I/II DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF THE NOVEL ANTI-HBV
AGENT LB80380/ANA380 IN PATIENTS WITH CHRONIC HBV INFECTION
M.F. Yuen, The University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China; J. Kim, LG Life Sciences, Seoul, Republic of Korea; D. Averett, Anadys Pharmaceuticals Inc, San Diego, CA; D.K.H. Wong, The University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China; C.R. Kim, LG Life Sciences, Seoul, Republic of Korea; B. Kerr, Anadys Pharmaceuticals Inc, San Diego, CA; V.W.S. Ngai, Y.C.H. Yuen, Ching-Lung Lai, The University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China.
Background:
LB80380/ANA380
is an orally available drug that is converted after dosing to LB80331 and
subsequently to LB80317, a novel guanosine phosphonate nucleotide analogue that
exhibits activity against HBV in vitro, including HBV variants resistant to
lamivudine. The compound has a favourable toxicity profile in vitro, including
low potential for renal toxicity. Animal toxicology studies confirmed the
favourable tolerability of LB80380/ANA380, and studies in woodchucks showed
reductions in serum viral titre greater than six log after four weeks of
dosing. Phase I studies in healthy volunteers demonstrated good safety,
tolerability, and pharmacokinetics consistent with once daily dosing.
Aims:
We
report the final study results of a Phase I/II study designed to assess the
safety, pharmacokinetics, and antiviral activity of LB80380/ANA380 in HBeAg
positive, HBV DNA positive patients.
Methods:
This
study was a double-blind, randomized, placebo-controlled, multiple ascending
dose evaluation of LB80380/ANA380 dosed once daily for 28 days at 30mg, 60mg,
120mg, and 240 mg. Cohorts of seven patients were randomized (6:1 active:
placebo) at each dose level, and safety was established at each dose prior to
dose escalation. Patients were followed for 12 weeks after completing the
dosing phase.
Results:
The
median age and male: female ratio was 27.5 years and 20:8 respectively. Serum
HBV levels at screening ranged from 1x107 to 5x109. LB80380 was well tolerated,
with no serious or moderate adverse events attributed to treatment. Systemic
exposure to LB80331 and LB80317 was proportional to LB80380/ANA380 dose. HBV
DNA reductions were observed during treatment in all patients receiving
LB80380/ANA380, and returned to pre-treatment levels during follow-up. Median
log serum HBV reductions on day 28 of treatment were 3 to 4 log.
Conclusions:
Treatment
with LB80380/ANA380 for 28 days at doses up to 240mg was well tolerated and
safe in this study population. Substantial anti-HBV effects were observed at
all doses of LB80380/ANA380. These results encourage additional investigation
for longer duration and in other study populations.
Poster 24
VALTORCITABINE
PROVIDES POTENT SUPPRESSION OF HEPATITIS B VIRUS IN PATIENTS WITH CHRONIC
HEPATITIS B: RESULTS OF A PHASE I/II CLINICAL TRIAL
Ching Lung Lai, University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China; Nathaniel A. Brown, Maureen Myers, Idenix Pharmaceuticals, Cambridge, MA; Man Fung Yuen, University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region of China; Chun Tao Wai, National University Hospital, Singapore, Singapore; Deborah Lloyd, Keith Pietropaolo, Xiao Jian Zhou, George Chao, Idenix Pharmaceuticals, Cambridge, MA; Seng Gee Lim, National University Hospital, Singapore, Singapore.
Background:
Development
of more effective monotherapies or combination therapies for chronic hepatitis
B (CHB) remains a priority. The L-nucleosides L-deoxycytidine (LdC) and
L-thymidine (telbivudine; LdT) are potent inhibitors of hepatitis B virus (HBV)
replication in vitro. Telbivudine demonstrated significantly greater viral
suppression and serum ALT normalization, compared with lamivudine, in a
one-year phase IIb clinical trial in patients with CHB (Lai et al., AASLD
2003). Valtorcitabine is a well-absorbed pro-drug of LdC, and is synergistic
with telbivudine for inhibiting HBV replication in vitro and in the woodchuck
hepadnavirus model.
Aims:
Evaluation
of valtorcitabine in patients with CHB has been undertaken as the initial step
toward a goal of potentially developing an effective and safe combination
therapy with telbivudine.
Methods:
A
phase I/II dose escalation trial evaluated the antiviral efficacy, safety, and
pharmacokinetics of two valyl ester prodrugs of LdC. Initially, a 3',5'-divalyl
form was investigated in sequential dose cohorts of 50, 100, 200, and 400
mg/day. The study then switched to a more stable 3'-monovalyl form of
valtorcitabine for subsequent cohorts of 300, 600, 900, and 1200 mg/day; dosing
with the monovalyl form was initiated at a dosing level (300 mg/day) that
approximated the LdC exposure afforded by the last divalyl dose tested (400
mg/day). Each cohort comprised 7 HBeAg+ patients with chronic hepatitis B,
randomized 6:1 (drug vs. placebo). Patients were evaluated weekly during 28
days of treatment, with 12 weeks of follow-up.
Results:
Seven of the eight dose cohorts have completed treatment. Consistent,
dose-related HBV DNA reductions have been observed, ranging from a mean 1.63
log10 for the 50 mg/day group at Day 28, to 3.04 log10 copies/mL at the highest
completed dose, 900 mg/day. The final dose cohort, 1200 mg/day, is ongoing and
results will be reported. Emax modeling of the dose-response data indicate that
maximal antiviral effects are achieved with the LdC exposure offered by
valtorcitabine doses of 900 mg/day and above. Safety appears comparable to
placebo, with no treatment-related pattern of adverse events or laboratory
abnormalities.
Conclusions:
Valtorcitabine
exhibits substantial anti-HBV activity and excellent safety in patients with
chronic hepatitis B. Clinical investigation of the efficacy and safety of
telbivudine + valtorcitabine in combination is planned.
Poster
61
VACCINATION
WITH AN EXPERIMENTAL ANTI-HBV VACCINE YIELDS HIGH RESPONSE RATES IN LIVER
TRANSPLANT PATIENTS AND ALLOWS SAFE DISCONTINUATION OF HEPATITIS B
IMMUNOGLOBULINS PROPHYLAXIS
Peter Starkel, Anne Bouvier, St. Luc University Hospital, Brussels, Belgium; Michel Stoffel, Glaxo-Smith-Kline, Rixenart, Belgium; Jan Lerut, Yves Horsmans, St. Luc University Hospital, Brussels, Belgium.
Background:
Efficient
protection against HBV is rarely obtained in liver transplant candidates and
transplanted patients with currently available vaccines. Strategies using
lamivudine and hepatitis B immunoglobulins (HBIG) for prevention of hepatitis B
re-infection after liver transplantation (LT) are expensive since life long
treatment is needed.
Aim:
To
evaluate the possibility to obtain protective anti-HBs titers after LT and to
discontinue HBIG prophylaxis after a reinforced course of hepatitis B
vaccination using an experimental adjuvanted HbsAg/AS04 vaccine (GSK,
Rixensart) in patients transplanted for hepatitis B.
Methods:
Fifteen
patients on stable low immunosuppression (tacrolimus, cyclosporine monotherapy)
were vaccinated with a double dose of the vaccine at 0,1,2,6 and 12 months: 5
patients transplanted for non-viral diseases and 10 consecutive patients
transplanted for HBV on HBIG monotherapy. HBIG were continued during baseline
vaccination (0,1,2) and then when anti-HBs titres determined every 6 weeks
dropped below 150 IU/ml. Follow-up consisted of serum transaminases before and
4 weeks after each injection of the vaccine, anti-HBs titres every 6 weeks, HBs
antigen every three months and HBV-DNA at 0,3,6,12 and 18 months. Follow-up
period was 18 months. Response to the vaccine was defined as anti-HBs titres
> 500 IU/ml 6 weeks after vaccination without prior administration of HBIG
in the HBV group. Sustained long-term response was defined as anti-HBs titres
> 500 IU/ml during a follow-up period of at least 12 months without further
need for HBIG administration in the HBV group.
Results:
Overall
sustained response to vaccination was 53 % (8/15 patients). 80% (4/5 patients) in
the non-viral disease group and 40% (4/10 patients) in the HBV group developed
a sustained long-term response (anti-HBs > 1000 IU/ml) and were free of HBIG
at the end of the 18 months' follow-up. Three patients had their HBIG
requirements reduced by almost 40% during vaccination without meeting the
criteria for a sustained long-term response. One patient in the non-viral
disease group and 3 patients in the HBV group did not respond to vaccination.
No HBV recurrence, rejection or side effects were seen in any of the patients
during the 18 months of follow-up.
Conclusions:
Protective
anti-HBs titers were obtained in a substantial number of LT patients following
a reinforced course of HBV vaccination with a vaccine containing a new
immuno-stimulating adjuvant. It was possible to withdraw HBIG immunoprophylaxis
in almost half of the patients in the HBV group, an interesting and cost
effective alternative in prophylactic regimens in the future. Furthermore,
vaccination with this vaccine seems well tolerated and safe in LT patients.
Poster
62
LIVING
DONOR LIVER TRANSPLANTATION FROM HEPATITIS B CORE ANTIBODY POSITIVE DONORS
Arzu Celebi, Zeki Karasu, Murat Kilic, Tijen Ozacar, Fatih Tekin, Fulya Gunsar, Galip Ersoz, Yildiray Yuzer, Yaman Tokat, Ege University School of Medicine, Izmir, Turkey.
Background:
Liver
allografts from donors previously exposed to hepatitis B virus (HBV) carries
the risk of transmission of HBV infection to the immunosuppressed recipient.
However, exclusion of the donor candidates with the serologic evidence of
resolved hepatitis B - HBV surface antigen (HBsAg) negative and HBV core
antibody (anti-HBc) positive - is not feasible in countries endemic for HBV
virus.
Aim:
Our
aim was to assess the safety and outcome of living donor liver transplantation
from anti-HBc positive donors.
Methods:
152
consecutive living donor liver transplantations were performed in our
institution between June 1999 and April 2003. Among these 152 living donors, 56
(37%) were anti-HBc positive. All of the anti-HBc positive donors had normal
liver function tests and liver biopsies. Among 56 recipients, 36 were
transplanted for HBV related cirrhosis while 20 of the recipients were
transplanted for reasons other than HBV. The recipients who were HBsAg
negative, recieved prophylaxis with lamivudine (100 mg/day) alone while those
transplanted for HBV cirrhosis received low dose hepatitis B immune globulin
combined with lamivudine.
Results:
The
mean follow-up time for the 56 recipients was 17 (1-56) months. None of the
HbsAg negative recipients developed de novo HBV infection under lamivudine
monoprophylaxis and only 1 of the recipients transplanted for HBV cirrhosis
developed recurrent HBV infection.
Conclusion:
The
use of liver allografts from anti-HBc positive living donors is reasonably safe
even in HbsAg-negative recipients under prophylaxis of lamivudine. These
allografts may help to increase the number of available organs in countries
with limited number of cadaveric organ donation and high prevalence of HBV. There
is no need to administer HBIG in addition to in addition to lamivudine prophylaxis for the liver
recipients who receive anti-HBc positive donor organs.
Poster
63
THE
EFFECT OF HEPATITIS B REPLICATION STATUS ON HEPATITIS B IMMUNOGLOBULIN DOSE REQUIREMENTS
AND PHARMACOKINETICS IN LIVER TRANSPLANTATION FOR HEPATITIS B VIRUS
RC
Dickson, Mayo Clinic, Jacksonville, FL; Nora Terrault, U. of California, San
Francisco, CA; Michael Ishitani, Mayo Clinic, Rochester, MN; Rajender Reddy, U.
of Pennsylvania, Philadelphia, PA; Patricia Sheiner, Westchester Med Center,
Hawthorn, NY; Consuelo Soldevila-Pico, U. of Florida, Gainesville, FL; Velimir
Luketic, Virginia Commonwealth U., Richmond, VA; Richard Brundage, U. of
Minnesota, Minneapolis, MN; Donald Jensen, Rush Univ., Chicago, IL; Michael
Fried, UNC, Chapel Hill, NC; Robert S. Brown Jr., Columbia, NY, NY; Larry
Muenz, Gary Horwith, Nabi, Rockville, MD; Anna Lok, U. of Michigan, Ann Arbor,
MI.
Background:
Lamivudine
combined with Hepatitis B Immune Globulin(HBIG) successfully prevents post
liver transplant (LT) HBV recurrence. However, the effect of lamivudine
suppression of HBV on the dose requirements and pharmacokinetics (PK) of HBIG
is not well understood.
Aim:
To
assess effect of replication status on the PK, antibody titers and dosage
requirements of an intravenous 5% hepatitis B immune globulin (Nabi HBVIg) in
the first 36 weeks post LT. We report the final results of our prospective,
multicenter trial.
Methods:
Adults
undergoing LT for chronic HBV received Lamivudine prior to or at time of LT and
IV Nabi HBVIg 10,000 IU on day 0 x 2, on days 1-7, weeks 4 and 8, and then
5,000 IU every 4 weeks. Anti-HBs titers were obtained at peak and trough with
each dose and at scheduled time points between doses. Additional HBVIg 5,000
IU/L IV was to be given if projected levels were below 500 IU in the first 12
weeks or below 250 IU in weeks 12-36. Replicative status based on serum HBV DNA
> or < 5 pg/ml (replicator =R, nonreplicator =N) was determined first at time
of Lamivudine initiation (R or N), then at time of LT (r or n), resulting in 3
groups: Nn, Rn, Rr.
Results:
30
patients (10 Nn, 13 Rn, 6 Rr, 1 unknown) mean age of 52 years underwent LT from
12/99 to 5/01. 23patientscompleted the 36 week trial and 7 did not due to death
in 4 (day 3 to week 8), consent withdrawn in 3 (week 4 to 30). 2patientswere
excluded: anti-HBs at time of LT (1), replication status unknown (1). 1 pt had
data censored for the first 12 weeks due to reLT on day 2, and 1 pt had data censored
post reLT at week 28. Patient and graft survival was 87% and 80% respectively.
Analysis of paired serum HBsAg and anti-HBs revealed: HBsAg was present during
week 1 in 9/11 with anti-HBs < 300 IU/L vs 1/44 with anti-HBs > 300 IU/L;
during weeks 2-12, in 4/7 with anti-HBs < 200 IU/L vs 2/112 with anti-HBs
> 200 IU/L; and during weeks 12-36 in 0/4 with anti-HBs <100 and 0/127
with anti-HBs >100 IU/L. No pt had HBsAg present at the end of follow up.
The number ofpatientswith trough anti-HBs titers below the target levels and
T1/2 of HBVIg for the different replicative groups are listed in the table. a =
CMH test, b = One way ANOVA.
Conclusions:
Patients
with active replication at LT have increased anti-HBs requirements for
neutralization of HBsAg during weeks 1-12. However, preLT suppression of HBV
replication (Rn) leads to PK similar to native nonreplicators (Nn) within 1
week after LT. This trial provides rational for the use of lower dose HBVIg in
Nonreplicators (Nn, Rn) after week 1.
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Poster
64
TREATMENT
OF LAMIVUDINE RESISTANCE HEPATITIS B PATIENTS AFTER LIVER TRANSPLANT: RESULTS
OF A SINGLE CENTER EXPERIENCE
Kamran Safdar, Guy Neff, Hideo Yoshida, Jose Nery, Caio Nery, Seigo Nishida, Juan Madariaga, Andreas Tzakis, Eugene Schiff, University of Miami, Miami, FL.
Background:
The
development of therapeutic agents against HBV adefovir dipivoxil and tenofovir
disoproxil fumarate, has improved post transplant survival in patients
suffering from LAM resistance.
Aim:
To
analyze the time to HBV DNA suppression and normalization of ALT following the
administration of ADV or TNF in liver transplant recipients with HBV suffering
from lamivudine resistance.
Methods:
We
retrospectively analyzed data form our center July 1992-November 2003. During
that time 16 patients were found who were HBV DNA positive at the time of
surgery. All the patients in post liver transplant period received HBIG and or lamivudine
whenever they became available. All patients were closely monitored clinically
and biochemically.
Results:
The
median time to develop LAM resistance was 1,254 days. The evidence of HBV
resistance to LAM was documented by rise in ALT and appearance of HBV DNA. None
of the patients at that time had acute cellular rejection. Seven patients were
started on tenofovir and all but one was maintained on standard lamivudine
therapy. Nine patients were given adefovir and all but two were continued with lamivudine.
Patients were then monitored for normalization of ALT and disappearance of HBV
DNA. Median time for ALT to normalize was 111 days in tenofovir group and 252
days in adefovir group (p value=0.090). The median time for HBV DNA to
disappear was 214 days in tenofovir group and 595 in adefovir arm (p
value=0.020). Two patients on adefovir never became HBV DNA negative and in
addition three broke through with appearance of HBV DNA and was rescued with
addition of tenofovir. In contrast one out of seven patients on tenofovir arm
had HBV break through and remainder remained HBV negative. The sole patient
with tenofovir resistance was started on adefovir. There was no statistical
difference in the numbers of viral break through in adefovir and tenofovir arms(p=0.102).
Conclusion:
The
above data demonstrates the effectiveness of HBV DNA suppression when
administering TNF. More importantly is that the period of time to HBV DNA
suppression is decrease in the group of patients receiving TNF. Further
prospective studies are needed to validate this finding.
Poster
65
LAMIVUDINE
PROPHYLAXIS WITH ADEFOVIR SALVAGE IN HEPATITIS B PATIENTS UNDERGOING LIVER
TRANSPLANT IS MORE COST EFFECTIVE THAN COMBINATION LAMIVUDINE/HBIG THERAPY
Yock
Young Dan, Seng Gee Lim, National University Hospital, Singapore, Singapore.
Background:
Combination
high dose Hepatitis B immunoglobulin with lamivudine prophylaxis (Lam/HBIG) is
highly effective in preventing Hepatitis B (Hep B) recurrence post-transplant
but is expensive and inconvenient. Lamivudine resistant Hepatitis B, which has
limited the usefulness of lamivudine monoprophylaxis in the transplant setting,
can now be effectively controlled with adefovir dipivoxil.
Aims:
We
performed a decision and cost-effectiveness analysis comparing the strategies
of lamivudine prophylaxis with adefovir salvage after development of lamivudine
resistance (lam/adv), and standard combination Lamivudine/HBIG prophylaxis.
Methods:
Markov
modeling was performed with TreeAge Pro 2004 software with analysis performed
from societal perspective up to 5 years post transplant. Probability rates were
derived from systematic review of the literature and cost taken from actual
Medicare database. Payoffs were discounted 3% annually. Outcome measures were
cost effectiveness ratio (CER) per quality adjusted life year (QALY),
incremental cost effectiveness ratio and cost, per incidence of hepatitis B
recurrence. All projections and estimates were widely varied in sensitivity
analysis to determine validity as well as to study the impact of variables on
cost-effectiveness.
Results:
Combination
Lam/HBIG cost USD $330,000 per patient over 5 years with 8% hepatitis B
recurrence and 5% mortality. This translates to USD $109,000/ QALY saved.
Lamivudine/adefovir therapy cost USD $27,000 and has 19% recurrence but only
slightly higher mortality of 9%. The cost effectiveness ratio using lam/adv is
only USD $10,070/ QALY saved. As the incremental benefit of lam/HBIG is
marginal, the incremental cost effectiveness of lam/HBIG over lam/adv treatment
is a staggering USD2 million per QALY. Cost to prevent each Hep B recurrence is
USD $3 million using Lam/HBIG compared to USD $145,000 for lam/adv.
Cost-effectiveness is most sensitive to cost of HBIG. If the price of HBIG were
to drop to USD $40,000 per year, CER will go below USD $50,000 per QALY. Hep B
recurrence rate and mortality rate post liver transplant has minimal impact on
cost effectiveness.
Conclusion:
Adefovir
dipivoxil in the post-transplant setting, has been shown to retard disease
progression due to Hepatitis B recurrence and has fairly good outcome.
Lamivudine prophylaxis followed by adefovir salvage after the emergence of
lamivudine resistance appears to offer a far cheaper option for Hep B patients
undergoing liver transplant compared to Lam/HBIG prophylaxis. Long term data
and prospective trials are needed to define the optimal treatment strategy.
Poster
66
RELATION
BETWEEN HBV GENOTYPES AND HBV VARIANTS AND INDICATIONS FOR LIVER TRANSPLANT (LT)
IN HEPATITIS B PATIENTS IN THE U.S.*
Anna S. Lok, University of Michigan, Ann Arbor, MI; A. Regev, University of Miami, Miami, FL; E. B. Keeffe, Stanford University, Palo Alto, CA; S. H. Han, UCLA, Los Angeles, CA; S. Emre, Mount Sinai Medical Center, New York, NY; M. Ishitani, Mayo Clinic, Rochester, MN; V. Luketic, Virginia Commonwealth University, Richmond, VA; R. Brown, Columbia University, New York, NY; Scott K. Fung, M. Hussain, HBV-OLT Study Group, University of Michigan, Ann Arbor, MI.
Background:
HBV
genotype C and core promoter variants have been reported to be associated with
an increased risk of hepatocellular carcinoma [HCC], but the data remain
controversial and most of the studies were conducted in Asia.
Aims:
To
determine the relation between HBV genotypes, core promoter [CP] (A1762T and
G1764A) and precore [PC] (G1896A) variants and indications for LT in a cohort
of hepatitis B patients in the U.S.
Methods:
Sera
from patients enrolled in the U.S. HBV-OLT Study with detectable HBV DNA by PCR
were tested for HBV genotype, CP and PC variants using InnoLipa assay.
Results:
82
patients, mean age 50.4± 10.0 years, 58 M/24 F were included; 33 were Asians,
30 whites, 4 blacks, 7 Hispanics, and 8 others. Indications for LT were
cirrhosis (n=54), HCC (n=22) and acute liver failure (n=6). Distribution of HBV
genotypes was: A 31%, B 15%, C 35%, D 17% and F 2%. CP variant was detected in
67 (82%) patients and PC variant in 34 (41%) patients. Compared to patients
listed for cirrhosis, patients listed for HCC were more likely to be Asians
(p=0.04) and had a slightly higher prevalence of genotype C (50% vs. 32%) but
there was no difference in prevalence of PC or CP variants. Asian patients were
younger than non-Asians (mean age 46.8 years vs. 52.7 years, p=0.008) and more
likely to have HCC as indication for LT (42% vs. 16%, p=0.02). Distribution of
HBV genotypes among Asians was: A 3%, B 21%, C 73% and D 3%; and among
non-Asians: A 50%, B 10%, C 8%, D 27% and F 4%. HCC was the indication for LT
in 43% of Asians with genotype B and 42% of those with genotype C; and in 21%
of non-Asians with genotype A and 15% of those with genotype D. All 6 patients
listed for acute liver failure were non-Asians, 5 had genotype A, 3 had CP and
2 had PC variants.
Conclusions:
Asians
comprised 40% of hepatitis B patients listed for LT in the U.S. Asian patients
were younger and more likely to have HCC. There was no association between HBV
genotype, PC and CP variants and HCC as an indication for LT among Asians as
well as non-Asians. Patients with acute liver failure were non-Asians, younger,
and more likely to be female and to be infected with genotype A. Further
studies are required to confirm the relationship of genotype on the clinical
outcome of HBV infection.
*This
study was supported by NIDDK, NIH.
|
|
|
|
|
|
Mean
Age ± SD (yrs) |
51.9 ±
8.2 |
49.8 ±
11.1 |
0.4 |
|
%
Asians |
35 |
64 |
0.04 |
|
%
Genotype A |
26 |
27 |
0.8 |
|
%
Genotype B |
17 |
14 |
0.9 |
|
%
Genotype C |
32 |
50 |
0.2 |
|
%
Genotype D |
21 |
9 |
0.4 |
|
%
Genotype F |
4 |
0 |
0.9 |
|
% PC
variant |
42 |
41 |
0.8 |
|
% CP
variant |
85 |
82 |
0.9 |
Poster
70
ENTECAVIR
IS SUPERIOR TO LAMIVUDINE FOR THE TREATMENT OF HBEAG(+) CHRONIC HEPATITIS B: RESULTS
OF PHASE III STUDY ETV-022 IN NUCLEOSIDE-NAïVE PATIENTS
TT Chang, National Cheng Kung University Hospital, Tainan, Taiwan Republic of China; R Gish, California Pacific Medical Center, San Francisco, CA; R de Man, Erasmus University Hospital, Rotterdam, Netherlands; A Gadano, Hospital Italiano, Buenos Aires, Argentina; J Sollano, University of Santo Tomas, Manila, Philippines; KH Han, Severance Hospital, Yonsei University College of Medicine, Seoul, Democratic People's Republic of Korea; Z Goodman, Armed Forces Institute of Pathology, Washington, WA; J Zhu, A Cross, D DeHertogh, D Apelian, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT; the BEHoLD Study Group.
Background:
Entecavir
(ETV) is a potent and selective inhibitor of hepatitis B virus (HBV)
polymerase.
Aim:
This
Phase III trial compared the efficacy and safety of treatment with ETV 0.5 mg
QD to treatment with lamivudine (LVD) 100 mg QD for 48 weeks in
nucleoside-naïve (< 12 weeks of prior nucleoside therapy), HBeAg(+) chronic
hepatitis B patients.
Methods:
ETV-022
is a multinational, double-blind, comparative Phase III trial in which 715
patients were randomized 1:1 to receive ETV 0.5 mg QD or LVD 100 mg QD.
Eligible patients were HBeAg(+) and had HBV DNA > 3 MEq/mL by bDNA assay,
ALT 1.3 -10 x ULN, and compensated liver function. The primary endpoint,
Histologic Improvement, was the proportion of patients having a > 2-point
decrease in the Knodell necroinflammatory score and no worsening of fibrosis
(worsening: > 1-point increase in Knodell fibrosis score). Results: Mean
baseline viral loads by PCR were ETV: 9.61 log10 c/mL; LVD: 9.69 log10 c/mL.
Mean baseline ALTs were ETV: 141 U/L; LVD: 146 U/L. Results of primary and
major secondary endpoints are listed below:
|
Primary
and Major Secondary Endpoints, Week 48 (non-completer = failure) |
|||
|
Endpoint |
ETV
0.5 mg |
LVD
100 mg N=355 (treated) |
p-value |
|
*Histologic Improvement (%) |
72% |
62% |
0.0085 |
|
†HBV
DNA |
−
6.98 |
−
5.46 |
<0.0001 |
|
HBV
bDNA |
91% |
65% |
<0.0001 |
|
HBV DNA |
69% |
38% |
<0.0001 |
|
ALT
Normalization (<1.25 x ULN) (%) |
78% |
70% |
0.0136 |
|
*n = 314 with evaluable histology in each treatment group |
|||
At
Week 48, HBeAg seroconversion (loss of HBeAg and gain of HBeAb) occurred in 21%
of ETV and 18% of LVD patients. A greater proportion of LVD than ETV patients
were observed to have virologic non-response (HBV DNA > 0.7 MEq/mL) at Week
48, and met protocol criteria to discontinue study treatment. No mutations
associated with resistance to ETV were detected. Safety was comparable between
the two groups: 7% of patients in both groups had serious adverse events.
Conclusion:
Entecavir
achieves superior histologic, virologic, and biochemical improvement in
HBeAg(+) chronic hepatitis B patients, with a comparable safety profile to LVD.
Primary treatment with entecavir provided superior benefit over LVD in
nucleoside-naïve, HBeAg(+) chronic hepatitis B patients.
Poster
181
IN
VITRO CROSS-RESISTANCE TESTING OF ADEFOVIR, LAMIVUDINE, TELBIVUDINE (L-DT),
ENTECAVIR AND OTHER ANTI-HBV COMPOUNDS AGAINST FOUR MAJOR MUTATIONAL PATTERNS
OF LAMIVUDINE-RESISTANT HBV
William Delaney IV, Huiling Yang, Xiaoping Qi, A Sabogal, Michael Miller, Shelly Xiong, Gilead Sciences, Inc., Foster City, CA.
Background: