Hepatitis B Treatment
11/14/2005 8:00 AM - 6:30 PM
Poster
960
Abstract
ID: 66805
Category:
J1O: Hepatitis B: Treatment
One-year treatment of entecavir results in reduction in intrahepatic covalently closed circular DNA level.
D. K.
Wong, The University of Hong Kong, Hong Kong, Hong Kong, M. Yuen, The
University of Hong Kong, Hong Kong, Hong Kong, V. Ngai, The University of Hong
Kong, Hong Kong, Hong Kong, C. Kwok, The University of Hong Kong, Hong Kong,
Hong Kong, C. Lai, The University of Hong Kong, Hong Kong, Hong Kong
Background:
Two phase 3, multicenter, double-blind trials on
HBeAg-positive and HBeAg-negative patients demonstrate that, compared with
lamivudine, entecavir is superior in inducing histologic improvement, serum HBV
DNA suppression and transaminase normalization. Since intrahepatic HBV DNA and
covalently closed circular (ccc) DNA are important for control of viral
replication, the efficacy of entecavir vs. lamivudine in achieving suppression
of these entities should be studied.
Methods and
Patients:
The patients involved in this study were recruited
from patients
participating in the two phase 3 entecavir trials at our
center in Hong Kong. Forty chronic hepatitis B patients (14 HBeAg-positive and
26 anti-HBe-positive) were randomized to receive either entecavir (0.5 mg once
daily) or lamivudine (100 mg once daily). Paired liver biopsy and serum samples
were collected both at baseline and week 48 of treatment. Total intrahepatic
HBV DNA and cccDNA were measured by the Invader® assay.i Serum HBV DNA was
measured by the COBAS Amplicor HBV Monitor Test.
Results:
This is an interim report for the 14 HBeAg-positive
patients. (The findings of the 26 anti-HBe-positive patients will be analyzed
later.) For the 14 HBeAg-positive patients, 7 were randomized to receive
entecavir, while the rest received lamivudine.
Conclusion:
The preliminary results of this study showed that 1
year of entecavir was
superior to lamivudine in suppression of total
intrahepatic and ccc DNA in liver biopsies. The addition of the data from the
26 anti-HBe patients may confirm these results.
i Wong et al, Hepatology (2004) 40:727-737.
Poster
961
Abstract
ID: 61589
Category:
J1O: Hepatitis B: Treatment
High prevalence of significant fibrosis in patients with immunotolerance to chronichepatitis B infection.
C.
Wang, University of Washington, Seattle, WA, H. Deubner, University of
Washington, Seattle, WA, M. Shuhart, University of Washington, Seattle, WA, J.
N. Manansala, University of Washington, Seattle, WA, L. Corey, University of
Washington, Seattle, WA, K. V. Kowdley, University of Washington, Seattle, WA
OBJECTIVE:
To determine the extent of liver disease in patients
with chronic hepatitis
B and normal serum ALT.
METHODS:
Patients were eligible with HBeAg positive CHB, serum
HBV DNA > 106
copies/mL, and 2 ALT measurements within normal limits
in the 2 years prior to liver biopsy. The mean value of the 2 ALT measurements
was calculated. Liver biopsies were scored using the Batts and Ludwig scoring
method with a 4-point scoring scale for inflammation and fibrosis.
RESULTS:
9 men and 4 women were enrolled. Median age was 26
(range 19-46). All
had endemically-acquired infection by history. Nine
patients were born in China, 2 in Vietnam, 1 in Korea, and 1 in Cambodia.
Median ALT was 28 U/L (range 13-77) and median serum HBV DNA was 5.1 x 107
(range 4.5 x 104 – 3.4 x108). On biopsy, 10 of 13 (77%) had evidence of
fibrosis: None had cirrhosis or septal fibrosis; 6 of 13 (46%) had periportal
fibrosis or rare portal-portal septa, resulting in fibrosis scores of 2, and 4
of 13 (31%) patients had portal fibrosis with at most mild periportal fibrosis,
yielding fibrosis scores of 1 or 1-2. Mean liver biopsy grade was 1.23 (range
1-2) and mean stage was 1.30 (range 0-2). The R-square coefficient for a
correlation between ALT and liver biopsy stage was .07, indicating that ALT was
poorly correlated with liver biopsy fibrosis score (see graph). Four of 5
patients with a liver fibrosis stage of 2 had serum ALT < 30 IU/L.
CONCLUSIONS:
A high proportion of Asian immunotolerant HBeAg
positive patients
have hepatic fibrosis on biopsy. Serum ALT level may
not accurately predict histologic stage in these patients. These preliminary
findings support recent recommendations to perform liver biopsy to guide
treatment decisions in HBeAg positive patients even if serum ALT is normal.
Supported by a research grant from Gilead Sciences (Wang) and by K24 DK02957
(Kowdley).
Poster
962
Abstract
ID: 67445
Category:
J1O: Hepatitis B: Treatment
Entecavir Two Year Resistance Update: No Resistance Observed in Nucleoside Naïve Patients and Low Frequency Resistance Emergence in Lamivudine Refractory Patients.
R.
Colonno, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford,
CT, R. Rose, Bristol-Myers Squibb Pharmaceutical Research Institute,
Wallingford, CT, S. Levine, Bristol-Myers Squibb Pharmaceutical Research Institute,
Wallingford, CT, J. Baldick, Bristol-Myers Squibb Pharmaceutical Research
Institute, Wallingford, CT, K. Pokornowski, Bristol-Myers Squibb Pharmaceutical
Research Institute, Wallingford, CT, M. Plym, Bristol-Myers Squibb
Pharmaceutical Research Institute, Wallingford, CT, C. Yu, Bristol-Myers Squibb
Pharmaceutical Research Institute, Wallingford, CT, C. Mazzucco, Bristol-Myers
Squibb Pharmaceutical Research Institute, Wallingford, CT, J. Fang,
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, M.
Hsu, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT,
A. Walsh, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford,
CT, B. Eggers, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford,
CO, A. Thiry, Bristol-Myers Squibb Pharmaceutical Research Institute,
Wallingford, CT, D. Tenney, Bristol-Myers Squibb Pharmaceutical Research
Institute, Wallingford, CT
Background:
Entecavir (ETV) is a potent inhibitor of hepatitis B
virus (HBV) with proven
clinical efficacy. High level ETV resistance (ETVr)
requires pre-existing lamivudine (LVD)- resistance (LVDr) substitutions and
additional changes at HBV RT residues rtT184, rtS202 or rtM250. Patients
receiving ETV for 1 year showed no evidence of emerging ETVr in nucleoside
naïve patients and virologic rebounds due to ETVr in only 1% of LVD refractory
patients.
Methods:
Virologic rebounds (confirmed ³1 log increase from
nadir by PCR) observed in patients from studies AI463-022 & AI463-027
(nucleoside naïve), AI463-014 & AI463-026 (LVD refractory), and AI463-901
(extended treatment) were analyzed for emerging ETVr. Genotypic analysis
compared patient HBV RT sequences with those at study entry and with WT HBV.
Phenotypes of emerging substitutions were determined using antiviral assays
measuring HBV DNA yields from HepG2 cells transfected with plasmids expressing
patient RT sequences.
Results:
Among >650 nucleoside naïve, HBeAg pos & HBeAg
neg patients completing at least 24 wk of ETV therapy, 93% achieved HBV DNA
reductions to <300 copies/ml. Over 200 patients completed ≥ 90 wks of
therapy. Genotypic analysis of the 18 observed virologic rebounds (2 year
treatment period) failed to show any evidence of emerging ETVr substitutions,
with population phenotypes at the time of rebound essentially unchanged from
baseline or WT. Four additional patients failing to achieve HBV DNA reductions
<100,000 copies/ml on ETV also had HBV fully susceptible to ETV. Therefore,
there is no evidence of ETVr emerging in nucleoside naïve patients treated with
ETV. Virologic rebounds due to resistance were observed in 10% of LVD
refractory patients treated with ETV for 2 years. In all cases, ETVr variants
had pre-existing LVDr substitutions and emerging changes at residues rtT184
and/or rtS202. Of the 12 patients exhibiting a rebound, 2 had been on
suboptimal ETV therapy (0.5 mg) and 3 others received ETV/LVD combination
therapy. Subsequent analysis of baseline viral samples demonstrated selection
of ETVr substitutions during prior LVD treatment.
Summary:
There was no evidence of emerging ETVr in nucleoside
treatment naïve subjects undergoing 2 years of ETV therapy, coinciding with
substantial suppression of viral DNA levels. Among LVD refractory patients,
10% experienced virologic rebounds due to emerging
ETVr by the 2nd yr of therapy. Phenotypic ETVr required the presence of
pre-existing LVDr substitutions, which can be selected with exposure to LVD.
Therefore, LVD treatment results in frequent emergence of LVDr and may
negatively impact future HBV treatment options.
Poster
963
Abstract
ID: 61542
Category:
J1O: Hepatitis B: Treatment
REAPPEARANCE OF WILD-TYPE HEPATITIS B VIRUS DURING ADEFOVIR MONOTHERAPY FOR PATIENTS WITH LAMIVUDINE RESISTANCE.
H. Hann, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, J. L. Platt, Questdiagnostics Nichols Institute, San Juan Capistrano, CA Disclosures: Hie-Won Hann - Speakers Bureau(s):GlaxoSmtihkline Gilead Sciences,Inc., Consultant for: GlaxoSmtihkline Gilead Sciences,Inc., Grant / Research Support by: GlaxoSmtihkline Gilead Sciences,Inc.; Jamie Platt
Background?:
No
relationships to disclose Adefovir Dipivoxil (ADV) is effective for both wild
type (WT) and YMDD variant (YMDDv) HBV which is resistant to Lamivudine (LAM).
While the majority of LAM resistant patients respond well to ADV, some patients
show slow/poor antiviral responses and even have an increase in HBV DNA levels
while on ADV therapy. We investigated if this poor/worsening response was the
result of ADV resistance.
Materials
and Methods:
133
patients after LAM resistance, were treated with ADV for varying periods. Good
responses to ADV were seen in 87/133 patients while 46 showed slow /poor
virologic responses although biochemical improvement was noted. Pre-ADV and
on-ADV therapy serum samples were available from 13/46 patients. For the
remaining 33, Pre-ADV and on-ADV specimens were unavailable since HBV DNA
levels were measured elsewhere. To understand the nature of slow/poor
responses, HBV polymerase genotypes were investigated using an YMDD PCR-RFLP
assay and sequencing of the HBV pol gene. The PCR-RFLP assay examined the
presence of mutations at 2 sites (rtL180 and rtM204)). The sequencing assay
assessed mutations at codons, rt180, rt181, rt204, and rt236. Analytes of the
sequencing assay included genotype and PMUL and PMUA, polymerase mutants for
LAM and for ADV espectively. These 13 patients were Asian Americans, aged 19-67
years, 9 males and 4 females. Treatment with LAM lasted 12-60 months until
viral breakthroughs were noted. Median pre-ADV HBV DNA levels were 5 x 106
copies/mL (range 1.2 x 106-2.5 x 108) while median on-ADV HBV DNA levels were 9
x 106 (range 1.7x 104 - 8 x 106). The median duration of ADV therapy for 13
patients was 13 months (range 6-30).
Results:
Polymerase
genotypes were examined on 10 pre-ADV and 13 on-ADV samples, all of HBV
genotype C. Among 10 pre-ADV samples, 8 contained YMDDv HBV and 5/8 also
contained a small portion of mixed population; surprisingly 2/10 had mostly
WT-HBV although they had viral breakthrough. Following ADV therapy (6-30
months), 10/13 patients had a return of WT-HBV; 3 of these10 contained a small
portion of YMDD and 3/13 had YMDDv-HBV. One patient with 18months on ADV, showed
WTHBV return mixed with ADV resistant HBV (N236T). It appeared that YMDDv-HBV
were suppressed by ADV but in some WT-HBV was strong enough to return even
under ADV effect.
Conclusion:
These
results suggest that in patients with LAM resistance who did not
respond
well to ADV, the majority of poor responses were due to the return of WT HBV
and not due to ADV resistance. Continuation of LAM in combination with ADV, at
least for a period of time, may therefore be the preferred management in
patients with LAM
resistance.
Poster
964
Abstract
ID: 63945
Category:
J1O: Hepatitis B: Treatment
First line combination therapy of chronic hepatitis B with tenofovir plus lamivudine versus sequential therapy with tenofovir monotherapy after lamivudine failure.
S. Mauss,
Center for HIV and Hepatogastroenterology, Duesseldorf, AE, Germany, M. Nelson,
Kobler Clinic, Chelsea, AE, United Kingdom (Great Britain), T. Lutz,
HIVPractice,Frankfurt, AE, Germany, J. Sheldon, Hospital Carlos III, Madrid,
AE, Spain, R. Bruno, San Matteo Hospital, Pavia, AE, Italy, F. van Boemmel,
Charite, Berlin, AE, Germany, J. Rockstroh, Med. Klinik I, Bonn, AE, Germany,
E. Wolf, MUC Research, Muenchen, AE, Germany, A. Stoehr,
Infektiologie, Hamburg, AE, Germany, V. Soriano,
Hospital Carlos III, Madrid, AE, Spain, F. Berger, Center for HIV and
Hepatogastroenterology, Duesseldorf, AE, Germany, T. Berg, Charite, Berlin, AE,
Germany, A. Carlebach, HIV-practice, Frankfurt, AE, Germany, C.
Schwarze-Zander, Med. Klinik I, Bonn, AE, Germany, T. Wunsche, Charite, Berlin,
AE, Germany, H. Jaeger, MUC Research, Muenchen, AE, Germany, G. Schmutz, Center
for HIV and Hepatogastroenterology, Duesseldorf, AE,
Therapy with HBV-polymerase inhibitors is based on long
term suppression of viral replication. At present sequential monotherapy is
standard of care, however combination therapy with at least two HBV-polymerase
inhibitors is considered a promising alternative approach. It is unknown to
date whether combination therapy with lamivudine plus tenofovir could be
superior to sequential therapy with tenofovir after the occurrence of
lamivudine resistance for chronic hepatitis B treatment in coinfected patients.
We conducted a multicenter, 1:2 matched pair analysis
comparing patients with HBV/HIV-coinfection starting an antiretroviral regimen
including tenofovir plus lamivudine with patients who had highly replicative,
lamivudine resistant hepatitis B (> 100,000 copies/mL) and started therapy
with tenofovir as the only active HBV-polymerase inhibitor. Resistance to
lamivudine was demonstrated by HBVgenotyping. The lower limit of detection of
HBV-DNA was 1000 copies/mL. At baseline patients starting with tenofovir plus
lamivudine (n=23) had a median HBV-DNA of 59,000,000 copies/mL compared to
120,000,000 copies/mL in the tenofovir arm (n=46) (p=0.75). After 3 months on
treatment, median HBV-DNA decreased to 138,450 copies/mL in the tenofovir plus
lamivudine group compared to 27,950 copies/mL in the tenofovir group (p=0.26).
After 12 months and 24 months median HBV-DNA was <1000 copies/mL in patients
taking either tenofovir plus lamivudine or tenofovir alone (p=0.46, p=0.24). A
sustained undetectable HBV-DNA <1000 copies/mL was achieved in 19/23 (83%)
patients on tenofovir plus lamivudine and in 38/46 (83%) patients on tenofovir
(p = 1.00). A loss of HBe-antigen was observed in 7/22 HBe-antigen positive
patients on tenofovir plus lamivudine and in 11/44 patients on tenofovir
(p=0.57). HBsantigen loss was found in 1/23 and 2/46 patients, respectively.
In conclusion in this cohort of HBV/HIV-coinfected
individuals, full virologic HBVDNA suppression was achieved in the majority of
patients independent of treatment allocation. In addition loss of HBe- and
HBs-antigen was not different in both arms. Over a median observational period
of 24 months tenofovir alone was as effective as tenofovir plus lamivudine in
HBV/HIV-coinfected patients with highly replicative chronic hepatitis B.
Poster
965
Abstract
ID: 64736
Category:
J1O: Hepatitis B: Treatment
Hepatitis B Virus with rtL80V/I Mutation Associates with Poor Response to Adefovir Dipivoxil Therapy.
Y.
Lee, University of Ulsan College of Medicine, Asan Medical Center, Seoul,
Korea,Republic of, Y. Chung, University of Ulsan College of Medicine, Asan
Medical Center, Seoul, Korea, Republic of, S. Ryu, University of Inje College
of Medicine, Seoul Paik Hospital, Seoul, Korea, Republic of, J. A. Kim,
University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea,
Republic of, M. Choi, University of Ulsan College of Medicine, Asan Medical
Center, Seoul, Korea, Republic of, S. Jung, University of Ulsan College of
Medicine, Asan Medical Center, Seoul, Korea, Republic of, S. Kim, Korea
Veterans' Hospital, Seoul, Korea, Republic of, J. Shin, University of Ulsan
College of Medicine, Ulsan University Hospital, Ulsan, Korea, Republic of, N.
Park, University of Ulsan College of Medicine, Ulsan University Hospital,
Ulsan, Korea, Republic of, K. Kim, University of Ulsan College of Medicine,
Seoul, Korea, Republic of, Y. Lim,
University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea,
Republic of, Y. Lee, University of Ulsan College of Medicine, Asan Medical
Center, Seoul, Korea, Republic of, D. Suh, University of Ulsan College of
Medicine, Asan Medical Center, Seoul, Korea, Republic of
Background/Aims:
Resistance occurs frequently during long-term
lamivudine (LAM)
therapy, mostly associated with YMDD mutants
(rtM204V/I). Besides rtM204V/I mutation, rtL80V/I and rtL180M mutations have
been reported to be associated commonly in patients with LAM resistance. In
this study, we intended to examine the effects of a certain type of mutations
at polymerase domain of Hepatitis B Virus (HBV) on the antiviral efficacy
following adefovir dipivoxil (ADV) therapy in patients with LAM-resistant
chronic hepatitis B (CHB).
Methods:
One hundred and nineteen patients with LAM-resistant
CHB were treated with ADV at a dose of 10mg daily for >12 weeks. The entire
polymerase domain of HBV in the sera obtained just before ADV therapy was
sequenced using direct sequencing method. Genotypes of HBV were determined by
restriction fragment length polymorphism (RFLP) following polymerase chain
reaction (PCR). Serum HBV-DNA levels were quantified by real-time PCR method.
The antiviral responses, which were evaluated by the change of serum alanine
aminotransferase (ALT) and HBV-DNA levels at 12 weeks following ADV therapy,
were compared in relation to the preexisting mutations at HBV polymerase domain.
Results:
All of 119 subjects revealed to have HBV of genotype
C. Out of them, 105 patients (88%) had YMDD mutations; 70 (67%) rtM204I, 28
(27%) rtM204V variant and 7 (6%) both. In addition to mutations at YMDD motif,
rtL80V/I mutation was found in 70 (59%) and rtL180M in 72 (61%). The rtM204I
variant was accompanied by rtL80V/I (p<0.001) and rtM204V was associated
with rtL180M mutation more frequently (p<0.005). Median serum HBV DNA level
at baseline was 7.82 log(10) copies/mL and the median change of serum HBV DNA
levels from baseline were -2.40 log(10) copies/mL at week 12. The rate of serum
ALT normalization was 42% following 12 weeks of ADV therapy. The rate of serum
ALT normalization (45% vs. 35%; p>0.05) and the changes of serum HBV DNA
level (median, -2.43 vs. -2.93 log(10) copies/mL; p>0.05) at 12 weeks
following ADV therapy were not significantly different between patients with
rtM204I and those with rtM204V variant. Very interestingly, the change of serum
HBV-DNA levels was significantly greater in patients with rtL80V/I mutation
compared with those without it. (Median, -2.10 vs. -2.83 log(10) copies/mL;
p<0.05) However, the presence of rtL180M mutation did not affect the change
of serum HBV-DNA level following ADV therapy. (Median, -2.53 vs. -2.20 log(10)
copies/mL; p>0.05)
Conclusions:
It is suggested that rtL80V/I variants of HBV may
associate with poor antiviral response to ADV therapy.
Poster
966
Abstract
ID: 67006
Category:
J1O: Hepatitis B: Treatment
Delayed viral decline is associated with highest sustained response rate during PEGinterferon treatment for HBeAg-positive chronic hepatitis B.
M. J.
ter Borg, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
Netherlands, H. J. Flink, Erasmus MC, University Medical Center Rotterdam,
Rotterdam, Netherlands, H. L. Janssen, Erasmus MC, University Medical Center
Rotterdam, Rotterdam, Netherlands, B. E. Hansen, Erasmus MC, University Medical
Center Rotterdam, Rotterdam, Netherlands, R. A. de Man, Erasmus MC, University
Medical Center Rotterdam, Rotterdam, Netherlands, S. W. Schalm, Erasmus MC,
University Medical Center Rotterdam,
Little is known about the patterns of HBV-DNA decline
and their relation to response for chronic hepatitis B patients treated with
alpha-interferon. To investigate different patterns in viral decline during
treatment and follow-up, we analyzed 254 HBeAg-positive chronic hepatitis B
patients treated with pegylated interferon alpha-2b (PEG-IFN) 100 μg/week
for 52 weeks with or without lamivudine 100 mg/day. PEG-IFN dose was reduced to
50 μg/week after 32 weeks of treatment. Endpoints were HBeAg-negativity,
HBV-DNA < 400 copies/ml and HBsAg negativity 26 weeks after therapy.
The total trial population consisted of 266 patients.
From 12 patients, insufficient HBV-DNA measurements were available to assess
HBV-DNA patterns.
In the patients treated with PEG-IFN monotherapy
(n=124), 5 different patterns of viral decline could be recognized: a. early
decline of at least 1 log during week 0-4 of therapy; b. delayed decline of at
least 2 log from baseline HBV-DNA during week 4-32; c. late decline of at least
2 log between week 32 and 52; d. post-treatment decline of 2 log from baseline
HBV-DNA after week 52; e. no substantial decline at any time point. Endpoints
for these different patterns are shown in the table. A delayed rather than
early viral decline was associated with highest response rates at the end of
follow-up (HBeAg response 63% vs. 52%, respectively).
Patients with a late or post treatment decline pattern
had lower response rates (HBeAg response 31% and 27%, respectively).
Interestingly, 7 out of 8 patients (88%) with HBsAg
loss and all patients with HBV-DNA <400 copies/ml at the end of follow-up
exhibited a delayed HBV-DNA decline. In the patients treated with combination
therapy (n=130), a similar biphasic pattern of decline in HBV-DNA was seen in
nearly all patients with a fast decline in the first four weeks and a slower
decline thereafter.
In conclusion, different patterns in HBV-DNA decline
were found during PEG-IFN monotherapy. A delayed rather than early viral
decline was associated with the highest response rate. This underlines the
important immunomodulatory effect of PEG-IFN and the limited predictive value
of early viral kinetics in PEG-IFN therapy for HBeAg-positive chronic hepatitis
B.
PEG Monotherapy
Poster
967
Abstract
ID: 67180
Category:
J1O: Hepatitis B: Treatment
Effect of ethnicity, genotype, gender, age and bodyweight on sustained response in a large, randomised study of peginterferon alfa-2a (40KD) (PEGASYS®) +/- lamivudine versus lamivudine alone for HBeAg-positive chronic hepatitis B.
W.
Chow, Singapore General Hospital, Singapore, Singapore, M. Manns, Medizinischen
Hochschule, Hannover, Germany, S. Paik, Samsung Medical Center, Seoul, Korea,
Republic of, T. Berg, Charité Universitätsmedizin Berlin, Berlin, Germany, T.
Piratvisuth, Songklanakarin Hospital, Songkla, Thailand, W. Chang, Kaohsiung
Medical University Hospital, Kaohsiung, Taiwan, G. K. Lau, Queen Mary Hospital,
Hong Kong, China, P. Marcellin, Hôpital Beaujon, Clichy, France, E. Gane,
Middlemore Hospital, Otahuhu, New Zealand, N. Pluck, Roche, Welwyn, United
Kingdom (Great Britain)
Background:
Recent data have shown that baseline ALT, HBV DNA and
HBeAg levels are strongly associated with sustained HBeAg seroconversion in
patients treated with peginterferon alfa-2a and/or lamivudine for chronic
hepatitis B (CHB).
Objective:
To investigate the effect of ethnicity, genotype,
gender, age and bodyweight on response in patients receiving peginterferon
alfa-2a ± lamivudine or lamivudine alone for CHB.
Methods:
HBeAg-positive patients (n=814) received 48 weeks of
180mg peginterferon alfa-2a (PEGASYS®) once-weekly (qw) + placebo daily (qd),
180mg peginterferon alfa-2a qw + 100mg lamivudine qd, or 100mg lamivudine qd.
For this analysis, response was defined as HBeAg seroconversion 24 weeks
post-treatment (week 72). Baseline variables included in multivariate (MV) analysis:
ethnicity, genotype, gender, age, bodyweight, ALT, HBV DNA and HBeAg.
Results:
Most patients were of Asian origin (87%) and infected
with HBV genotype C (59%) or B (28%). Response in Asian patients closely
reflected overall results. Among Caucasians (n=79), the highest response rates
were seen with peginterferon alfa-2a alone (50% [12/24]). Response rates were
also high in patients with genotype A receiving peginterferon alfa-2a alone
(52% [12/23]). Patients infected with genotype C or B had the same response to
peginterferon alfa-2a alone (31% vs 30%). Response rates were higher in females
than males in all treatment arms; 35% vs 31%, 37% vs 25%, and 26% vs 17% with
peginterferon alfa-2a alone, combination therapy, and lamivudine alone. There
was no clear relationship between patient age and response, regardless of
treatment. In the two peginterferon alfa-2a arms, response rates were
comparable in patients weighing ≤ 65 kg and >65 kg. Response rates in
lamivudine-treated patients weighing ≤ 65 kg were slightly higher than in
those >65 kg (22% vs16%). In MV analyses across all treatment arms,
ethnicity, genotype, age and bodyweight were not significant predictors of
response (P=0.757, ≥ 0.21, 0.716 and 0.790); gender was of borderline
significance (P=0.077).
Conclusion:
Genotype was not a significant predictor of response
by MV analysis. The rate of response was the same for patients with genotype B
or C, the predominant genotypes in the study. This contrasts with previous
studies of interferon-based therapy. Genotype A patients, who represented a
minority of patients in our study, treated with peginterferon alfa-2a alone had
the
highest rate of HBeAg seroconversion at week 72.
Gender had a marginal effect on response and this was mostly seen with combination
therapy and lamivudine alone. Patient bodyweight had no effect on response to
peginterferon alfa-2a.
Poster
969
Abstract
ID: 62802
Category:
J1O: Hepatitis B: Treatment
A sensitive line probe assay to simultaneously detect Lamivudine and Adefovir resistant mutations.
M. T.
Hussain, University of Michigan, Ann Arbor, MI, S. Fung, University of
Michigan, Ann Arbor, MI, J. Doutreloigne, Innogenetics, Inc, Ghent, Belgium, E.
Sablon, Innogenetics, Inc, Ghent, Belgium, A. S. Lok, University of Michigan,
Ann Arbor, MI
Background:
Antiviral-resistant hepatitis B virus (HBV) mutations
have become an increasing problem in the treatment of chronic hepatitis B.
Development of rapid, simple, and sensitive assays that can detect
antiviral-resistant HBV as they emerge may help improve patient management.
Aim:
To assess the accuracy of a line probe assay, INNOLiPA
HBV DRv2 (Innogenetics NV, Ghent, Belgium), by comparing results of this assay
with those of direct sequencing and to determine if DRv2 can detect antiviral-resistant
HBV earlier.
Patients and
Methods:
A total of 101 serum samples from 56 chronic HBV
patients receiving Lamivudine and/or Adefovir were analyzed for the presence of
antiviral-resistant mutations using both DRv2 and sequencing. The DRv2 involves
reverse hybridization of PCR products onto strips coated with oligonucleotide
probes. These probes can differentiate wild type vs. mutant sequences at codons
80, 173, 180 and 204 and at codons 181 and 236 of the HBV reverse
transcriptase/polymerase, that are known to be associated with lamivudine and
adefovir resistance, respectively.
Results:
Complete concordance was observed for 573 (95%) of 606
analyzed codons (95% of samples analyzed for codon 80, 98% for codon 173, 87%
for codon 180, 100% for codon 181, 90% for codon 204 and 97% for codon 236).
Among the 33 discordant cases, DRv2 detected mutants while sequencing revealed
wild type virus in 31 cases; sequencing of follow-up samples confirmed the
presence of mutant sequences in all 27 cases with follow-up samples. In these
27 cases, DRv2 detected mutants earlier than sequencing by a mean of 6 months
(range 2-11). In only 1 case sequencing detected mutant while DRv2 detected
wild type virus; DRv2 of follow-up samples confirmed the presence of mutant
sequence. Complete discordance was observed in only 1 case, where DRv2 showed
wild type at position 80, whereas sequencing showed a STOP codon. The DRv2
assay is more rapid and amenable to high throughput compared to sequencing but
it can only detect the presence of known drug-resistant mutations.
Conclusions:
Our study demonstrates that the INNO-LiPA HBV DRv2 can simultaneously detect the presence of Lamivudine and Adefovir-resistant mutations. The results of DRv2 show a high degree of concordance with sequencing and can detect mutants earlier, thus permitting prompt initiation of additional therapy.
Poster
970
Abstract
ID: 64162
Category:
J1O: Hepatitis B: Treatment
RECOGNITION OF MUTATED (G145R) HBsAg BY HEPEX-B (2 HUMAN MONOCLONAL ANTIBODIES) OFFERS A POTENTIAL TREATMENT FOR HBV IMMUNE ESCAPE PATIENTS.
R.
Eren, XTL Biopharmaceuticals Ltd., Rehovot, Israel, D. Landstein, XTL
Biopharmaceuticals Ltd., Rehovot, Israel, R. Kovjazin, XTL Biopharmaceuticals
Ltd., Rehovot, Israel, O. Nussbaum, XTL Biopharmaceuticals Ltd., Rehovot,
Israel, J. Ben- Porath, XTL Biopharmaceuticals Ltd., Rehovot, Israel, S.
Shahar, XTL Biopharmaceuticals Ltd., Rehovot, Israel, T. Waisman, XTL
Biopharmaceuticals Ltd., Rehovot, Israel, N. Haberman, XTL Biopharmaceuticals
Ltd., Rehovot, Israel, D. Terkieltaub, XTL Biopharmaceuticals Ltd., Rehovot,
Israel, S. Dagan, XTL Biopharmaceuticals Ltd.,
Introduction:
Long-term immunoprophylaxis
with hepatitis B immunoglobulin (HBIG) is used for the prevention of recurrent
hepatitis B virus (HBV) infection after liver transplantation. The most
prevalent immune escape mutation from HBIG treatment is at position 145 (G145R)
on the hepatitis B surface antigen (HBsAg). This mutation abolishes the
neutralizing effect of HBIG, implying that neutralizing antibodies are directed
to this region.
Purpose:
To test whether neutralizing
monoclonal antibodies directed to different epitopes on HBsAg could be
effective in decreasing selection pressure for the HBIGresistance mutation.
Methods:
HepeX-B consists of two
human monoclonal antibodies (HumAbs): HBVAB17 that recognizes a conformational
epitope and HBV-AB19 that recognizes a linear epitope on HBsAg. Epitope mapping
was performed by reacting antibodies to overlapping 15-mer linear antigen-derived
peptides. HBsAg harboring the G145R mutation was constructed and expressed in a
baculovirus expression system.
Results:
The epitope to which
HBV-AB19 binds was fully mapped. The core sequence of the epitope is CTKPTDGNC
at positions 139-147. The cysteines surrounding this epitope are involved in
binding, indicating that this is not a standard linear epitope. Changes at
positions 141-145 resulted in a strong decrease of binding. The conformational
epitope to which HBV-AB17 binds could not be mapped by this method. Western
blot analysis showed that HBV-AB17 could recognize the wild type (wt) as well
as the G145R mutated HBsAg whereas HBV-AB19 recognized only the wt antigen.
Furthermore, FACS analysis of Hi-5 cells expressing the mutated HBsAg on their
membrane demonstrated that only HBV-AB17 could bind to these cells. Cells
expressing the wt HBsAg were recognized by both HumAbs. The neutralizing
activity of HBV-AB17 and HBV-AB19 against virus harboring the G145R mutated
HBsAg is being studied in a mouse model for HBV infection.
Conclusions:
The two HumAbs that comprise
HepeX-B are directed against different epitopes on HBsAg. HBV-AB19 binds to a
linear epitope that includes the sensitive site for the G145R immune escape
mutation. Hence, HBV-AB19 did not recognize the G145R mutated HBsAg. The
mutation at position 145 did not abolish the binding of HBV-AB17 to HBsAg. The
binding to distinct epitopes on HBsAg and the fact that one of the HumAbs is
not affected by the G145R mutation lower the probability of emergence of escape
mutants due to HepeX-B therapy. Thus, HepeX-B could offer an alternative
therapy to liver transplant patients who had escaped HBIG monotherapy.
Poster
971
Abstract
ID: 65234
Category:
J1O: Hepatitis B: Treatment
Impact of IFN on progression of liver disease in Hepatitis B “e” antigen (HBeAg) negative chronic hepatitis B (CHB) patients: a long term Italian multicenter A.I.S.F.study.
F. Oliveri, Uo Gastroenterologia e Epatologia, Az.
Osp. Univ. Pisana, Pisa, Italy, M. Puoti, Clinica Malattie Infettive e
Tropicali, AO Spedali Civili, Brescia, Italy, T. Santantonio, Clinica Malattie
Infettive, Az. Osp. Policlinico Consorziale, Bari, Italy, P. Lampertico,
Divisione di Epatologia, IRCCS Ospedale Maggiore Policlinico, Milano, Italy, G.
Colloredo, Divisione Medicina, Policlinico San Pietro, Ponte San Pietro, Italy,
G. Niro, Gastroenterologia Casa Sollievo della Sofferenza, San Giovanni
Rotondo, Italy, G. Fattovich, Dipartimento di Gastroenterologia, Università di
Verona, Verona, Italy, F. Morisco, Gastroenterologia, Dip. Scienza d. Alimenti,
Univ. Napoli Federico II, Napoli, Italy, A. Marrone, Div. Medicina Interna ed
Epatologia, Seconda Università di Napoli, Napoli, Italy, P. Costa, Divisione
Malattie Infettive Ospedale "C. Poma", Mantova, Italy, M. Felder,
Divisione di Gastroenterologia, Ospedale Centrale Bolzano, Bolzano, Italy, P.
Cacciatore, Clinica Malattie Infettive, Università di Chieti, Chieti, Italy, A.
Smedile, UO Gastroenterologia Ospedaliera, Osp S. Giovanni Battista
"Molinette", Torino, Italy, M. R. Brunetto, Uo Gastroenterologia e
Epatologia, Az Osp Univ. Pisana,
HBeAg negative CHB is a progressive disease with low
spontaneous and drug induced resolution rates. We evaluated the Sustained
Response (SR) rate to IFN and factors influencing both treatment and disease
outcome in a large series of patients (pts).
We followed up prospectively 558 anti-HBe positive CHB
pts (451 males and 107 females; mean age 41 y, range 12-66 y) from 13 Italian
Centers. Patients were treated for at least 3 months (m) with alpha-IFN from
1985 to 2001: 437 (78%) pts experienced single IFN courses whereas 121 (22%) 2
or more courses. Mean follow up after end of treatment (EOT) 54 m (range 1-205
m). SR = normal ALT, HBV-DNA <10 pg/ml and IgM anti-HBc <0.2 IMx index
for at least 12 m after EOT.
At baseline chronic hepatitis with cirrhosis was
present in 150 (27%) pts, moderatesevere steatosis in 49 (9%). At first IFN
treatment 319 (57,2%) pts achieved EOT response: 96 (17,2%) maintained response
(SR), and 223 (40%) relapsed. The relapse occurred within 12 m after EOT in 183
(32,8%) pts, within 24 m in 24 (4,3%) pts, within 36 m in 10 (1,8%) pts and
thereafter (till to 84 m) in the remaining 6. After relapse 14 (2,5%) pts developed
persistently normal ALT and undetectable HBV-DNA (Persistent Remission after
Relapse, PRR). The Long Term Response (LTR=SR+PRR) rate in naives (19,7%) was
the same of that in retreated (19,8%) pts. At multivariate analysis (MVA) age
younger than 40 y (p=0,011) and duration of treatment (p<0,000001) were
independently associated with SR, that was observed in 6,8%, 15.9% and 30.7% of
pts treated up to 6 m, 7-12 m and more than 1 y (mean 19 m) respectively. HBsAg
clearance was observed in 47 (35%) of 134 LTR (anti-HBs seroconversion in 32).
During follow up 43 (7,7%) pts developed End Stage Complications (ESC:
jaundice, ascites, var.bleeding, encephalopathy) and/or Hepatocellular
Carcinoma (HCC in 27, 4,8%). Four pts were transplanted because of HCC and 1
for terminal cirrhosis (t.c.); 14 (2,5%) died 15-100 m after EOT because of HCC
(10), t.c.(3) and extraepatic tumor (1). Among 43 ESC pts 31 had baseline
cirrhosis, only 1 was female. At MVA female sex, younger age, absent-mild
steatosis, absence of cirrhosis and LTR to IFN were significantly and
independently associated with a better outcome. In baseline cirrhotic pts, at
MVA LTR was significantly associated with the absence of ESC except HCC.
Conclusions:
In HBeAg negative CHB standard IFN therapy warrants an
overall LTR of 20%; a correct identification of SR requires a long term
follow-up as relapse may occur late. LTR is associated with a better clinical
outcome: in patients with cirrhosis IFN may avoid clinical decompensation, but
not HCC.
Poster
973
Abstract
ID: 66027
Category:
J1O: Hepatitis B: Treatment
Unsuitability of Kaplan-Meier Estimates for determining long-term response rates in patients receiving treatment for chronic hepatitis B.
G. Cooksley,
Royal Brisbane Hospital, Brisbane, Australia, G. K. Lau, Queen Mary
Hospital,
Hong Kong, China, T. Piratvisuth, Songklanakarin Hospital, Songkla,
Thailand,
M. Popescu, Roche, Basel, Switzerland, P. McCloud, Roche, Dee Why,
Background:
Kaplan-Meier (KM) estimates were originally developed
to assess survival rates using death as the measured outcome. Recently, this
statistical method has been used to assess the long-term efficacy of antiviral
therapy for chronic hepatitis B (CHB). A basic assumption of the KM approach is
that a patient who achieves an outcome (eg death) will always have that outcome
whether they remain in the study or not. Since relapse occurs in CHB, we
discuss the appropriateness of the KM approach in determining response to
anti-HBV therapy.
Objective:
To compare HBeAg response rates obtained using the
intent-to-treat (ITT) principle, which assumes that patients with missing data
do not have a response, with rates obtained by KM estimation in patients
enrolled in a large, randomized clinical trial.
Methods:
HBeAg-positive patients were treated for 48 weeks with
180 mg peginterferon alfa-2a (40KD) (PEGASYS®) once-weekly (qw) + oral placebo
once-daily (qd), 180 mg peginterferon alfa-2a qw + 100 mg lamivudine qd, or 100
mg lamivudine qd. HBeAg seroconversion rates during treatment and up to 24
weeks post-treatment (week 72) were reanalyzed using the KM method.
Results:
HBeAg seroconversion rates at the end of treatment
(week 48) in the ITT population were 27% [72/271] with peginterferon alfa-2a
alone, 24% [64/271] with peginterferon alfa-2a + lamivudine and 20% [55/272]
with lamivudine alone. Corresponding KM estimates of HBeAg seroconversion at
week 48 (day 337) were 36% with peginterferon alfa-2a (+9% over ITT), 29% with
combination therapy (+5% over ITT) and 24% with lamivudine (+4% over ITT). In
the ITT population, HBeAg seroconversion rates 24 weeks post-treatment (week
72) were significantly higher with peginterferon alfa-2a alone (32% [87/271];
P<0.001) and peginterferon alfa-2a + lamivudine (27% [74/271]; P=0.023) than
with lamivudine alone (19% [52/272]). KM estimates of HBeAg seroconversion
rates at week 72 (day 504) were 43% with peginterferon alfa- 2a (+11% over
ITT), 38% with the combination therapy (+11% over ITT) and 30% with lamivudine
(+11% over ITT).
Conclusions:
Using data from this large, randomized study,
estimated rates of HbeAg seroconversion generated using the KM method were
substantially higher than the HBeAg seroconversion rates generated using an ITT
analysis. These findings suggest that KM estimation is not an appropriate
statistical method for measuring long-term efficacy of antiviral therapy in
patients with CHB as it biases the data. Results generated using KM estimates
should be interpreted with caution especially when the associated rates of
relapse are not also analyzed.
Poster
974
Abstract
ID: 66851
Category:
J1O: Hepatitis B: Treatment
VIROLOGICAL BREAKTHROUGH IS NOT A DETRIMENTAL PHENOMENON IN PATIENTS WITH COMPENSATED CIRRHOSIS: RESULTS OF A LONG TERM LAMIVUDINE THERAPY
.
Y.
Cakaloglu, Istanbul Medical Faculty Department of Gastroenterohepatology,
Istanbul, NJ, Turkey, S. Kaymakoglu, Istanbul Medical Facutly Department of
Gastroenterohepatology, Istanbul, NJ, Turkey, F. Akyüz, Istanbul Faculty of
Medicine, Istanbul, NJ, Turkey, D. Ibrisim, Istanbul Medical Faculty Department
of Gastroenterohepatology, Istanbul, NJ, Turkey, K. Demir, Istanbul Medical
Faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey, D. Onel,
Istanbul Medical Facutly Department of Microbiology, Istanbul, NJ, Turkey, E.
Ahishali, Istanbul Medical Facutly
Department of Gastroenterohepatology, Istanbul, NJ, Turkey, B. Pinarbasi,
Istanbul Medical faculty Department of Gastroenterohepatology, Istanbul, NJ, F.
Besisik, Istanbul Medical Faculty Department of Gastroenterohepatology,
Istanbul, NJ, Turkey, Z. Mungan, Istanbul Medical faculty Department of
Gastroenterohepatology, Istanbul, NJ, Turkey, S. Badur, Istanbul Medical
Faculty Department of Microbiology, Istanbul, NJ, Turkey, A. Okten, Istanbul
Medical Faculty Department of Gastroenterohepatology,
Development of virological breakthrough during
long-term lamivudine (LMV) therapy may result in fatal exacerbations in
decompensated cirrhosis. The clinical results of virological breakthrough are
still controversial in compensated or mildly decompensated cirrhosis.
Aim:
To evaluate the clinical significance of virologic breakthrough
which develops during the long-term lamivudine therapy in patients with HBV
related cirrhosis and the effects on clinical course and complications.
Material-Methods:
A hundred patients with HBV related cirrhosis (Child A
50, B 40, C
10) were enrolled and continuously treated with
lamivudine 100 mg/day for 30±19 (12- 84) months. Baseline HBV DNA was positive
(Hybridization, Digene) and ALT levels were high (>1.5XULN) in all patients.
Normalization of ALT, negativity of HBV DNA (PCR<400-2000 copy/ml) and HBeAg
seroconversion were accepted as on-therapy response. Reappearance of HBV DNA
during the treatment was accepted as virologic breakthrough. Clinical course
and complications were evaluated in patients with and without virologic
breakthrough.
Results:
End of follow-up virologic and biochemical response
rates were 56% and 58%, respectively (65.2% and 63.2% in HBeAg negative 70
patients and 32% and 46.4% in HBeAg positive 30 patients respectively-
p<0.05). Virologic breakthrough developed in 25 patients (10 HBeAg positive,
15 HBeAg negative) in mean 33±15 months during LMV therapy. Of these 25
patients 11 (44%) had normal ALT. None of 14 patients with elevated ALT (2 had
ALT level >10XULN) developed decompensation in liver disease. Although, CPT score
did not significantly changed in total group, an important decrease was
detected in patients without virological breakthrough. On the contrary
virologic breakthrough was associated with a statistically significant increase
in CPT scores (from 6.08±1.2 to 7.2±2.3, p<0.02). Also the frequency of
complications of cirrhosis decreased with LMV treatment in comparison to
pretreatment period. There was no significant difference in rate of
complications between patients with and without virologic breakthrough.
Thirteen patients (3 virologic breakthrough) developed hepatocellular carcinoma
(HCC) in mean 29±19 months (Cumulative HCC incidence 5.6%). Seven patients (2
virologic breakthrough) died within 41±21 months (5 HCC, 1 AML-M4, 1 hepatic
encephalopathy and spontanoeus bacterial peritonitis). Three patients underwent
liver transplantation.
Conclusion:
Long-term LMV therapy results in significant
improvement in laboratory and clinical parameters of cirrhosis. Virologic
breakthrough is not associated with clinical deterioration in compensated and
mildly decompensated cirrhotics.
Poster
976
Abstract
ID: 67260
Category:
J1O: Hepatitis B: Treatment
Factors associated with sustained virologic response 1 year after treatment with peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy for HBeAg-negative chronic hepatitis B.
P.
Marcellin, Hôpital Beaujon, Clichy, France, F. Bonino, IRCCS, Milan, Italy, G.
K. Lau, Queen Mary Hospital, Hong Kong, China, P. Farci, Universita di
Cagliari, Cagliari Italy, C. Yurdaydin,
University of Ankara, Ankara, Turkey, T. Piratvisuth, Songklanakarin Hospital,
Songkla, Thailand, R. Jin, Beijing You An Hospital, Beijing, China, S. Gurel,
University of Uludag, Bursa, Turkey, S. Hadziyannis, Henry Dunant Hospital,
Athens, Greece, Z. Lu, Ruijin Hospital, Shanghai, China, M. Popescu, Roche,
Background:
In patients with HBeAg-negative chronic hepatitis B
(CHB), peginterferon alfa-2a (40KD) (PEGASYS®) alone or combined with
lamivudine provides significantly higher response rates 24 weeks post-treatment
compared with lamivudine alone. Multivariate analysis identified age, baseline
ALT and baseline HBV DNA as significant predictors of virologic response (HBV
DNA <20,000 copies/ml) to peginterferon alfa-2a when assessed 24 weeks post-treatment.
Objective:
To evaluate factors associated with sustained
virologic response (defined as 48 weeks post-treatment response) to
peginterferon alfa-2a monotherapy.
Methods:
HBeAg-negative patients (n=177) were treated for 48
weeks with 180 mg peginterferon alfa-2a (40KD) (PEGASYS®) once-weekly. HBV DNA
was measured regularly during the 48 week post-treatment follow-up period
(weeks 48, 52, 56, 60, 64, 72, 84 and 96). Analyses performed to identify
baseline and on-treatment factors associated with post-treatment virologic
response included the following variables: gender; race; age; bodyweight;
baseline ALT; baseline HBV DNA; end of treatment HBV DNA; and HBV genotype.
Results:
Of 144 patients who had a virologic response (<20,000
copies/ml) to peginterferon alfa-2a monotherapy at the end of treatment, 89 had
available data 48 weeks post-treatment. Of these patients, 49 (55%) sustained
HBV DNA levels <100,000 cp/mL during the 48 week follow-up period [among
these, 22 (25%) had HBV DNA levels between 20,000 and 100,000 copies/ml; and 27
(30%) had HBV DNA <20,000 cp/mL]. atients with sustained virologic response
had higher mean ALT levels at baseline (94.7 IU/L) compared with patients with
relapse (77.6 IU/L). Mean baseline HBV DNA levels were 7.18 and 6.99 log for
sustained responders and relapsers, respectively. HBV DNA level at the end of
treatment was not different in patients with sustained response and those with
relapse (2.5 and 2.6 log, respectively). The rate of sustained virologic
response according to HBV genotype was 60% [3/5], 43% [12/28], 64% [27/42] and
50% [5/10] for genotypes A, B, C and D, respectively (P=0.08 for comparison of
genotype B vs C).
Conclusions:
In patients with HBeAg-negative CHB, a finite 48-week
course of peginterferon alfa-2a was able to induce virologic response that was
sustained 48 weeks post-treatment in more than half of the patients. There was
no clear predictor of sustained response to peginterferon alfa-2a. However,
there was a trend toward better response in patients with high ALT at baseline
or who were infected with HBV genotype C. Baseline or end-of-treatment HBV DNA
levels were not indicative of sustained virologic response.
Poster
977
Abstract
ID: 61484
Category:
J1O: Hepatitis B: Treatment
Efficacy of Tenofovir against HBV in HIV/HBV coinfected patients.
G.
Klausen, Praxiszentrum Kaiserdamm, Berlin, Germany, A. Moll, Praxiszentrum
Kaiserdamm, Berlin, Germany, J. Gölz, Praxiszentrum Kaiserdamm, Berlin,
Germany, D. Schleehauf, Praxiszentrum Kaiserdamm, Berlin, D. Prziwara,
Praxiszentrum Kaiserdamm, Berlin, S. Nzimegne-Gölz, Praxiszentrum Kaiserdamm,
Berlin
Backround:
Tenofovir (TDF) is licensed for the treatment of HIV
and is known to be active and potent as well against hepatitis B virus. Anyhow,
there is still a lack of data about the efficacy of TDF against HBV in HIV/HBV
coinfected patients. In our center we treated 37 HIV/HBV coinfected patients
with TDF containing antiretroviral therapies since January 2002. 21 of those
had a viral load of hepatitis B of more than 100000 IE/ml bevor the start of
TDF. 10 of these patients had previously shown a clinically diagnosed
resistance of HBV against Lamivudine (LAM).
Methods:
Retrospective analysis of the virological
effectiveness of TDF against HBV in 21 HIV patients with highly replicative HBV
coinfection, who were treated with a TDF containing antiretroviral therapy.
Previous LAM resistance of HBV was defined as an increase of HBV of 2 log or
more under treatment with LAM.
Results:
The 21 patients were all male and were in average 41
years old (range: 37-49). The average time on TDF was 27 month (range: 12-39)
and the average viral load of HBV (VL) at baseline was 1.7x10log12 IE/ml
(range: 2x10log5-1x10log13; N=21). At month 6 after start of treatment, the
average VL was 743042 IE/ml(n=19), at month 12 it was 3769 IE/ml (n=17) and at
month 24 the average VL was 230 IE/ml (n=15). The 10 patients with HBV
resistance against LAM showed the following results: Baseline: VL 1,2x10log12
IE/ml (n=10), month 6: 33425 IE/ml (n=8), month 12: 7019 IE/ml (n=9), month 24:
386 IE/ml (n=8). In the reported patients we did not see any viral break
through of HBV of more than 1 log under therapy with TDF so fare.
Conclusion:
According to our experience TDF is a long-term
effective drug against HBV in HIV/HBV coinfeted patients with or without HBV
resistance against LAM.
Poster
978
Abstract
ID: 62282
Category:
J1O: Hepatitis B: Treatment
Hepatitis B Virus Genotype B Is Associated With Better Response to Thymosin alfa-1 Therapy Than Genotype C.
R.
Chien, Chang Gung Memorial Hospital and University, Keelung, Taiwan, Keelung,
Taiwan,
Y. Liaw, Liver Research Unit, Chang Gung Memorial Hospital,
Background:
Hepatitis B virus (HBV) genotype has been reported to
correlate with response to interferon (IFN) treatment in several studies. The
relationship between HBV genotype and thymosin α 1 (T 1) treatment is
unknown. We retrospectively examine HBV genotypes, precore and core promoter
mutations in patients treated by T α 1 and analyze the correlation between
complete response (CR; ALT normalization plus seroclearance of HBeAg and
HBV-DNA by solution hybridization) of T α 1 therapy and HBV genotype.
Patients and
Methods:
98 patients with clinicopathologically proven chronic
hepatitis B were randomized allocated to three groups: 1) T6 group (n=32)
received a 26-week course of T α 1 with a 1.6 mg subcutaneous injection
two times a week; 2) T12 group (n=34) received the same regimen as T6 group,
but T α 1 therapy extended for 52 weeks; 3) T0 group (n=32) served as a
control and was followed up for 18 months without specific treatment.
Retrospectively analyze the HBV genotype, precore and core promoter mutation using
stored serum and correlated with CR.
Results:
There were 90 stored serum available for HBV
genotyping from patients completing the treatment and follow-up study (29 in T6
group; 31 in T12 group and 30 in T0 group). Of them, 49 (54%) were genotype B
and 41 (46%) were genotype C. Genotype C had a higher frequency of core
promoter mutation. Stepwise logistic regression analysis showed that genotype
(odds ratio [1] OR, 3.747; 95% confidence
interval [1] CI,1.066- 13.170;
P=0.039), precore mutation (OR, 6.285; 95% CI, 1.874-21.086; P=0.003) and T
α -1 treatment (OR, 12.045; 95% CI, 2.220-65.354; P=0.004) as independent
factors associated with CR. The CR of T α -1 was higher in patients with
genotype B compared to patients with genotype C (52% of genotype B vs 24% of genotype
C; P=0.036) and in patients with precore mutation (14/22 or 64% in responder vs
6/31 or 19% in nonresponder; P=0.002).
Conclusion:
Genotype, presence of precore mutation and T α-1
therapy were independent predictors to CR. Genotype B, compared to genotype C,
is associated with a higher response rate to T α 1 therapy.
Poster
979
Abstract
ID: 63873
Category:
J1O: Hepatitis B: Treatment
Long-term experience of adefovir dipivoxil add-on therapy in chronic hepatitis B patients co-infected with HIV and lamivudine-resistant HBV : Absence of adefovir resistance mutation selection.
V.
THIBAULT, Virology lab. CERVI - GH PITIE SALPETRIERE, PARIS, France, Y.
BENHAMOU, GH PITIE SALPETRIERE, PARIS, France, M. VALANTIN, GH PITIE
SALPETRIERE, PARIS, France, C. L. BROSGART, GILEAD, Foster city, CA, S. XIONG,
GILEAD, Foster city, CA
Sequential monotherapy with lamivudine (LAM) and
adefovir dipivoxyl (ADV) for chronic hepatitis B may quickly lead to the
selection of resistant HBV. By contrast, a strategy based on add-on ADV therapy
after LAM resistance emergence may be more effective.
We have analyzed the incidence of ADV resistance in
HIV patients who have been treated for up to 5 years with a combination of ADV
and LAM after development of LAM-resistance (LAM-R). In 2000, 35 HIV-patients
were enrolled in an open label study of ADV add-on therapy after emergence of
LAM-R HBV. In this follow-up study, all patients who presented residual HBV
replication by PCR between year 4 and 5 of treatment were studied for the presence
of HBV polymerase resistance mutations on serum samples. The HBV-RT was
sequenced and compared to the sequences obtained before ADV introduction.
Among the 35 patients included in the initial cohort,
29 were still followed at year 4 and 14 had an undetectable viral load by PCR
(<200 copies/mL). 15 had available samples with a viral load high enough to
perform sequencing analysis. Median duration of add-on ADV of these 15 patients
was 235 weeks and the median HBVDNA was 3.55 log10 cop./mL. 14/15 patients had
constant fluctuating low viral loads between 2.3 (LLD) and 5 log10 cop./mL with
no evidence of viral breakthrough. 10/15 patients had the same LAM-resistant
pattern as their baseline sequence rtV173L/L180M/M204V (n=2); rtL180M/M204V
(n=8) and no noticeable change was observed in their RT sequences along time.
2/10 of them had ADV replaced by tenofovir (TDF) when the background HIV
treatment required adjustment. 4/15 patients lost their LAM-R mutations. For 2
of them failure of compliance was documented. For the 2 remaining, analysis of
their HIV and HBV viral load kinetics clearly suggested lack of compliance.
1/15 patient had a viral breakthrough with a HBVDNA rise over 1 log10 on two
consecutive samples. At that time, LAM-R mutations rtV173L/L180M/M204V were
still present but no ADV mutation (rtA181V/T or rtN236T) or new conserved site
mutations were identified; ADV was replaced by tenofovir and HBV DNA started to
decline. Sequential monotherapy, after LAM–R breakthrough, could potentially
increase the risk of subsequent HBV resistance selection. A strategy based on
ADV add-on therapy seems very effective and is very unlikely to select for
double ADV and LAM resistant variants, even in difficult to treat patients such
those with HIV coinfection. The persistence of initially present LAM-R
mutations, the low variability of the RT sequence and the absence of selection
of further compensatory mutation indicate a strong pressure on a replication
impaired virus.
Poster
981
Abstract
ID: 64190
Category:
J1O: Hepatitis B: Treatment
SEQUENTIAL ANTIVIRAL THERAPY LEADS TO THE EMERGENCE OF MULTIPLE DRUG RESISTANT HEPATITIS B VIRUS.
S.
Villet, INSERM unit 271, Lyon, France, C. Pichoud, INSERM unit 271, Lyon,
France, A. Ollivet, INSERM unit 271, Lyon, France, J. Villeneuve, Hôpital
Saint-Luc , Division of Hepatology, Montreal, Canada, C. Trepo, INSERM unit
271, Lyon, France, F. Zoulim, INSERM unit 271, Lyon,
We analysed the genotypic and phenotypic evolution of
the viral quasi-species of 2 patients with chronic hepatitis B who failed
antiviral therapy: one received successively lamivudine, add-on adefovir +
lamivudine, followed by a lamivudine + adefovir + Hepatitis B immunoglobulins
(HBIg) after liver transplantation, and the 2nd received IFN, lamivudine then
entecavir. For genotypic analysis, a 1142 bp region of the polymerase gene
encompassing the rt domain and overlapping the S gene was amplified by PCR for
each sample, cloned and sequenced. For phenotypic analysis, an HBV
replication-competent plasmid was constructed from HBV DNA isolated from
patient serum (Durantel et al. Hepatology 2004). The rt gene from the selected
clones previously sequenced was then subcloned in this vector. Transfection of
these HBV mutants in hepatoma cell line led us to determine their replication
efficiency and drug susceptibility.At baseline, all HBV genomes carried a
wild-type (wt) rt gene but, for the first patient, 36 % harbored the P120S
mutation within the S gene associated with vaccine escape. Following viral
breakthrough to LAM monotherapy, a complex mixture of LAM-resistant HBV strains
emerged, with the prevalence of the rtL180M+M204V mutant for the first patient
and of the rtV173L+L180M+M204V mutant for the second. In vitro, all the tested
mutants showed a 1000 fold resistance to LAM relative to wt HBV. Following the
switch to ADV for the first patient, or to ETV for the second, the viral load
dropped but rose again after 3 and 2 years of therapy respectively. During this
rebound, we observed a complex mixture of LAM + ADV or ETV resistant strains.
For the first patient, the selection of only one HBV mutant was finally
observed. This mutant harbored the rtV173L+L180M+A181V+N236T mutations, a
combination of resistance mutations to both drugs, and the sP120S mutation escaping
to HBIg. Interestingly, the main LAM resistance mutation rtM204V disappeared
from the viral population. The dominance of this complex rt mutant may be
explained by our in vitro findings of a greater resistance to ADV+ LAM, and a
level of replication equivalent to wt HBV. For the second patient, we observed
a mixture of 3 mutants during rebound. All these mutants had the rtS202G
mutation, not yet described, but also the rtL180M+M204V LAM resistance
mutations despite the absence of LAM during ETV therapy. All these mutants were
resistant to both LAM and ETV in vitro. Our results show the evolution of viral
quasi-species towards the selection of mutants escaping to multiple selective
pressures. This suggests that de novo combination therapy should be further
evaluated to prevent drug resistance.
Poster
982
Abstract
ID: 64393
Category:
J1O: Hepatitis B: Treatment
HBV DNA levels at week 9 and number of HBV core gene mutations predict outcome of lamivudine/interferon á treatment in infancy-acquired chronic hepatitis B.
I.
Kraslova-Carey, Institute of Liver Studies, London, United Kingdom (Great
Britain), L. D'Antiga, Institute of Liver Studies, London, United Kingdom
(Great Britain), M. Cavers, Institute of Liver Studies, London, United Kingdom
(Great Britain), Y. Ma, Institute of Liver Studies, London, United Kingdom
(Great Britain), S. Bansal, Institute of Liver Studies, London, United Kingdom
(Great Britain), J. A. Byrne, Institute of Liver Studies, London, United
Kingdom (Great Britain), G. Mieli-Vergani, Institute of Liver Studies, London,
United Kingdom (Great Britain), D. Vergani, Institute of Liver Studies, London,
United Kingdom (Great Britain)
Background:
During the immune tolerance phase that characterizes
infancy-acquired chronic hepatitis B, hepatitis B virus (HBV) wild-type and
variant strains coexist, although the wild-type dominates. During combination
antiviral treatment most wild-type strains are eliminated and stable HBV core
antigen variants become prevalent. The emergence of mutations within HBV core
immunodominant epitopes may interfere with effective immune response and viral
control.
Aim:
To evaluate the dynamic changes in serum HBV DNA
levels during combined antiviral treatment in relation to the emergence of mutations
within the HBV core gene and to study their contribution to treatment outcome.
Patients:
Twenty-three children (8 males, median age 10.2 years,
range 2.9-16.8) with infancy-acquired hepatitis B (all HBeAg positive) were
treated with lamivudine (3mg/kg/d) for 52 weeks and interferon α (5MU/m2
TIW) from week 9 for 44 weeks. According to treatment outcome, patients were
divided into 5 responders (R) and 18 nonresponders (NR). Seven untreated HBeAg
positive paediatric patients (3 males, median age 9.8 years, range 3.8-14.1)
served as controls (C).
Methods:
HBV DNA levels were measured in serial serum samples
by real-time TaqMan PCR before (treatment week 0– TW0), during (TW2, TW9, TW28,
TW52) and after (follow-up week– FUW24) antiviral treatment. The number of HBV
DNA copies per ng of genomic liver DNA was evaluated at baseline by the same
method. Mutations within the HBV core gene were determined at baseline within
the liver and in sequential serum samples by restriction fragment length
polymorphism after nested PCR, and by direct sequencing at the same time-points
as HBV DNA levels.
Results:
HBV DNA viral load in liver (log10 copies/ng of liver
genomic DNA) and in serum (log10 copies/ml) is shown in the table (mean±SEM).
The decrease in the number of HBV DNA copies/ml in
serum was significantly higher among responders (p=0.003) from TW9. The number
of mutations within the HBV core gene was significantly higher in
non-responders (4.38±0.6) than responders (1.25±0.5, p=0.023) at TW28. There
was a strong correlation between serum HBV DNA levels and number of mutations
in HBV core gene was found (p=0.002) among treated patients.
Conclusion:
A decrease of HBV DNA levels > 3.5 log10 copies/ml
at TW9 predicts therapy outcome. The strong correlation between HBV DNA levels
and the number of mutations within the HBV core gene suggests that variant
strains contribute to virus control failure.
Poster
983
Abstract
ID: 64955
Category:
J1O: Hepatitis B: Treatment
FIVE YEARS OF SEQUENTIAL LAM TO LAM+ADV THERAPY SUPPRESSES HBV REPLICATION IN MOST HBEAg-NEGATIVE CIRRHOTICS, PREVENTING DECOMPENSATION BUT NOT HEPATOCELLULAR CARCINOMA.
P.
Lampertico, IRCCS Maggiore Hospital, Milan, M. Vigano, IRCCS Maggiore Hospital,
Milan, Italy, E. Manenti, IRCCS Maggiore Hospital, Milan, Italy, M. Iavarone,
IRCCS Maggiore Hospital, Milan, Italy, G. Lunghi, IRCCS Maggiore Hospital,
Milan, Italy, M. Colombo, IRCCS Maggiore Hospital,