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,
Background
and Aim:
Lamivudine (LAM) monotherapy suppresses HBV
replication in only 20-30% of HBeAg-negative cirrhotics treated for 5 years.
Aim of the study was to assess in these patients the 5-yr efficacy of a
sequential LAM to LAM+ADV therapy and its impact on disease progression and
death.
Patients and
Methods:
We prospectively followed up for 60 months (5-99) 124
HbeAg negative cirrhotic patients (106 males, 54 years) who were given
lamivudine alone or LAM+ADV in patients developing lamivudine resistance
(LAM-R). Patients were followed with LFTs and serum HBV-DNA (Versant 3.0,
Bayer, LLQ 3.3 log10 copies/mL) every two months and with US scan every six
months. Clinical LAM-R was when ALT peaked above the ULN and HBV-DNA >6 log
and genotypic LAM-R when ALT remained within the normal range and HBV-DNA
increased to below 6 log.
Results:
Of the 42 patients developing clinical LAM-R, 35 (83%)
were rescued by adding ADV (Group A). By converse, 82 patients were either
long-term responders to LAM monotherapy (n=54) or were added ADV to LAM at the
time of genotypic LAM-R (n=28) (Group B). In the latter group, addition of ADV
led HBV-DNA to became undetectable in all patients within 4 months and to
remain so in the following years. Furthermore, ALT levels remained within the
normal range throughout the study period. The 5-yr rates of undetectable
HBV-DNA were 67% and 100% in Group A and B patients, respectively (p<0.001).
None of the patients developed ADV-R, three patients of Group B seroconverted
to anti-HBs and discontinued antiviral therapy. Clinical decompensation occurred
in 19% patients from group A and in none of the Group B patients (p<0.001),
whereas hepatocellular carcinoma developed in both groups with similar
frequency (29% and 22%). Liver related deaths and liver transplantation
occurred in 21% and 13% of the patients (ns).
Conclusions.
Sequential LAM to LAM+ADV therapy suppresses HBV
replication for at least 5 years in all HBeAg-negative cirrhotics treated at
the time of genotypic LAM-R, preventing clinical decompensation but not HCC.
Poster
984
Abstract
ID: 65022
Category:
J1O: Hepatitis B: Treatment
ROLE OF OCCULT INFECTION OF HEPATITIS B VIRUS ON VIRUSREACTIVATION OCCURING IN NON-HODGKIN LYMPHOMA (NHL) PATIENTS TREATED WITH CHEMOTHERAPY.
m.
persico, second university of naples, chair of internal medicine, naples,
Italy, E. Persico, Second University of, Naples Chair of Internal Medicine,
naples, Italy, C. Marzocchella, Second University of Naples. Chair Of Internal
Medicine, naples, Italy, M. Masarone, Second University of Naples, Chair Of
Internal Medicine, Naples, Italy, V. Laura, Second Unibversity of Naples, Chair
of Internal Medicine, Naples, Italy, F. Carrino, second university of Naples,
Chair of Internal Medeicine, Naples, Italy, A. De Renzo, Federico II
Universitty, Haematology Unit, Naples, Italy, R. Torella, Second university of
naples, Chair of Internal Medicine,
Based on the evidence on liver tissue and blood sera
of specific gene fractions of HBV (core, s and x genes) the occult infection of
HBV was demonstrated. Epidemiological evidences suggest the possible role of
occult infection as cofactor of disease in hepatitis C virus (HCV) related
chronic hepatitis and as possible aetiological agent of liver cancer (HCC). Aim
of the present study was to test the role of occult HBV infection in HBV
related reactivation in patients undergone to chemotherapy for NHL.
Patients and
Methods:
a cohort of 55 consecutive patients with NHL were
studied. They all were tested for routine blood examinations and among all the
other examinations they were asked to perform liver biopsy prior the treatment.
On liver tissue and serum of all patients, three gene fractions of HBV were
assayed (core, s and x) by PCR according to Raimondo et al. Quantitative
HBV-DNA on sera and liver tissue was assessed according to Real-Time PCR
(RT-PCR) in HBsAg+ and HBcAB+ patients. All the patients were followed all over
the time of exposure to the drug and after discontinuation.
Results:
18 out of 55 (33%) were HBcAb+; 15 were HCV-RNA+ (27%)
and 6 HBsAg+ (10%). HBsAg+ patients were treated with pre-emptive lamivudine
therapy. Five (15%) HBcAb+ patients experienced HBV related hepatitis
reactivation and they were found positive for c and s genes on liver tissue
(occult B virus)but not on serum samples. These subjects were compared to a
historical group of HBsAg+ patients (n.9) who also had a disease reactivation
under the same circumstances (pre lamivudine era). In both groups lamivudine
promptly dominated the pathological process and all the patients recovered.
HBV-DNA titration on liver tisssue was significantly higher in HBsAG+ (10^4 -
10^5 copies/ml) and occult B virus patients (10^3 - 10^4 copies/ml)compared to
HBcAB+ subjects in whom the occult virus was not identified (<10^3
copies/ml). Levels of serum HBV-DNA (RT-PCR) were not useful to discriminate
between “occult” HBcAB+ and “non-occult” HBcAB+ patients.
Conclusions:
In NHL the prevalence of HBcAB+ is higher than HBsAG+
and occult infection plays a major role in HBV reactivation as well as overt
HBV infection. However,its onset is not as frequent as in HBsAg+ patients. At
the moment routinely used blood test to identify occult B virus does not exist.
Lamivudine pre-emptive treatment should be also considered in HBcAb+ subjects
undergone chemotherapy for NHL.
Poster
985
Abstract
ID: 65629
Category:
J1O: Hepatitis B: Treatment
Long-term beneficial outcome of Chinese asymptomatic patients with HBeAg-positivechronic hepatitis B on continuous lamivudine therapy: 7-year experience.
M.
Yuen, The University of Hong Kong, Hong Kong, China, W. Seto, The University of
Hong Kong, Hong Kong, China, D. Chow, The University of Hong Kong, Hong Kong,
China, K. Tsui, The University of Hong Kong, Hong Kong, China, D. Wong, The
University of Hong Kong, Hong Kong, China, P. Chan, The University of Hong
Kong, Hong Kong, China, D. But, The University of Hong Kong, Hong Kong, China,
C. Lai, The University of Hong Kong,
Background
Three-year treatment of lamivudine reduces disease
progression in patients with preexisting cirrhosis. The effect of longer
duration of lamivudine treatment in asymptomatic patients is unknown.
Aim
To determine whether long-term lamivudine treatment in
asymptomatic patients can reduce the risk of hepatocellular carcinoma (HCC) and
cirrhosis-related complications.
Patients and
Method
Two hundred and sixty-six HBeAg-positive patients (140
with lamivudine and 126 without treatment serving as controls) were recruited
from the Hepatitis Clinic, Queen Mary Hospital, Hong Kong. They included all
patients who participated in 3 controlled trials of lamivudine (NUCB 3009,
3018, 4003) and all the other patients who fulfilled the inclusion criteria but
were not included in the trials seen at the same period of time (1994-1997).
All lamivudine-treated patients were maintained on lamivudine throughout
follow-up irrespective of HBeAg seroconversion.
Results
There were no differences in the baseline
characteristics and liver biochemistry between the 140 treated patients (M:F
105:35; median age 33.9 years) and the 126 controls (M:F 92:34; median age 33.3
years). The follow-up duration was significantly longer in controls compared to
that of lamivudine-treated patients (median 106.2 vs. 90 months respectively,
p=0.004). There were no differences in the cumulative rates of HbeAg
seroconversion and hepatitis flare between the two groups (p=NS). However
lamivudinetreated patients had a slower decline in albumin levels during the
follow-up period compared to controls (median drop 3 vs. 4 g/L respectively, p=0.025).
93 (66.4%) lamivudine-treated patients and 81 (64.3%) controls had normal ALT
level at the last follow-up. HCC occurred in 1 lamivudine-treated patient and 3
controls. Cirrhosis developed in 6 lamivudine-treated patients and 15 controls.
Using Kaplan-Meier analysis, lamivudine-treated patients had a significantly
lower cumulative risk of development of complications compared to controls (log
rank test, p=0.035). At the time of writing, YMDD mutations were determined in
38 lamivudine-treated patients with elevated transaminases during follow-up. 36
had YMDD mutations. At the last follow-up, there were no differences in the
liver biochemistry between patients with YMDD mutations and controls; 24
(66.7%) of patients with YMDD mutations had normal ALT levels.
Conclusions
Long-term lamivudine treatment can reduce the risk of
complications from CHB in asymptomatic HBeAg-positive patients. Development of
YMDD mutations was not associated with more serious disease when compared to
untreated patients.
Poster
986
Abstract
ID: 65864
Category:
J1O: Hepatitis B: Treatment
Efficacy And Safety Of Entecavir (ETV) And Lamivudine (LVD) In Compensated, Cirrhotic Patients With Chronic Hepatitis B.
E.
Schiff, University of Miami, Miami, FL, W. M. Lee, The University of Texas
Southwestern Medical Center, Dallas, TX, Y. Chao, Tri-Service General Hospital,
Taipei, Taiwan, H. Sette, Hospital das Clinicas, Sao Paulo, Brazil, S.
W. Schalm, Erasmus University Hospital, Rotterdam,
Netherlands, H. Brett-Smith, Bristol-Myers Squibb Pharmaceutical Research
Institute, Wallingford, CT, R. Zink, Bristol-Myers Squibb Pharmaceutical
Research Institute,
Background:
The long-term outcome of chronic HBV treatment depends
upon potent virologic control; antiviral treatment has been shown to slow or
reverse disease progression in patients with advanced liver disease. ETV was
superior to LVD in achieving histologic improvement in Phase III studies of
compensated, treatment-naïve and LVD-refractory patients. This report investigates
if severity of liver disease at baseline influenced treatment response in the
ETV Phase III program.
Methods:
Study ETV-022 and ETV-027 enrolled treatment-naïve,
HBeAg(+) and HBeAg(-) patients, respectively. ETV-026 enrolled LVD-refractory,
HBeAg(+) patients. Liver biopsies were performed before study entry and after
48 weeks of therapy. Baseline cirrhosis was defined in patients with evaluable
biopsies as a Knodell fibrosis score of 4.
Results:
Approximately 8% of patients had cirrhosis at baseline;
the distribution of cirrhotic patients was balanced between treatment groups.
Cirrhotic patients on ETV were more likely than those on LVD to have histologic
improvement, ALT normalization and undetectable HBV DNA, although the
relatively small patient number limits interpretation. Efficacy results after
48 weeks of therapy for treatment-naïve patients according to baseline
cirrhosis status are presented below:
In LVD-refractory patients, the response in the overall
population for ETV over LVD was also seen in cirrhotic patients. Histologic
improvement occurred in 50% and 55% of ETV-treated cirrhotic and non-cirrhotic
patients, and in 22% and 28% of LVD-treated cirrhotic and non-cirrhotic
patients, respectively. In all patients, the incidence of ALT flares with ETV
(2%) and LVD (5%) was the same in cirrhotic and non-cirrhotic patients. Serious
adverse events were reported more frequently in cirrhotic (ETV 10%, LVD 14%)
than non-cirrhotic patients (ETV 7%, LVD 8%). Baseline cirrhosis did not affect
patient discontinuation. ALT >2x baseline + total bilirubin >2x baseline
and 2x ULN was reported in no cirrhotic and in <1% of non-cirrhotic
patients.
Conclusions:
ETV treatment was effective and well-tolerated in compensated,
cirrhotic patients with chronic HBV. In general, ETV response was comparable
between cirrhotic and non-cirrhotic patients.
Poster
988
Abstract
ID: 66881
Category:
J1O: Hepatitis B: Treatment
Lack of implementation of hepatitis B treatment guidelines: why effective antiviral treatment does not reach the patient.
W. F.
Leemans, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
Netherlands, H. L. Zaaijer, Academic Medical Centre, University of Amsterdam,
Amsterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical Center
Rotterdam,
In a previous study we described that only 30 % of
chronic HBV patients with active disease (HBeAg(+) or raised ALT) identified by
the primary care physician reach specialist care (J Hepatol 2004;41:1026-30).
To standardise and improve HBV treatment in specialist care, treatment
guidelines have been developed.
Their impact on specialist care was studied. A
questionnaire was sent to all gastroenterologists and infectious disease specialists
in the Netherlands: 226/591 (38%) responded, 120 (53%) actually saw at least
one HBV infected patient/year and were included in the analysis. Approximately
half of the physicians (52%) saw a few patients a year, 36% a couple a month
and 12% saw patients at least weekly. Most (70%) prescribe antiviral treatment
themselves, increasing from 54% for doctors seeing only a few patients a year
to 90% for those seeing more patients. Physicians who do not prescribe
treatment refer in only 62% to a specialized centre. Less than half (46%) of
the physicians seeing patients work according a protocol. However 72% express a
need for a standardised protocol, independently of the amount of patients seen,
ranging from 50% for those seeing many patients increasing to 94% for those
seeing a few patients a month, suggesting that availability of protocols could
be a problem.
Of those treating patients only 44% has ever used a
nucleoside/nucleotide analogue (NUC), which use increases from 18% for those
seeing only a few patients a year to 78% seeing patients more frequently. In
addition, among those treating patients but not using NUC, 72% do not refer to
a specialised centre. The majority (61%) prescribing NUC do not perform
mutation analysis during treatment , although 91% (p<0.001) has access to
these tests. The use of a protocol does not imply that physicians treat
patients themselves or use nucleoside analogues more often. However among the
specialists using a protocol the access to the standard laboratory tests (HBV
DNA) and specialized tests (resistance, genotype) is higher and resistance
testing is performed more often suggesting that monitoring is improved but
there still is reluctance to initiate treatment.
In conclusion the more patients specialists see the more
likely they will treat patients themselves. About one third of the physicians
do not refer despite they do not treat patients and therefore deprive patients
from treatment. Only 44% of the specialists ever used a NUC and most of them do
not refer leaving e.g. interferon failures devoid of NUC treatment. In the
development of HBV treatment guidelines more attention should be given to
implementation of the guidelines especially with regard to initiation of
treatment.
Poster
989
Abstract
ID: 67344
Category:
J1O: Hepatitis B: Treatment
Antiviral response and resistance surveillance for HBeAg negative patients enrolled in a combination study evaluating emtricitabine plus clevudine versus emtricitabine monotherapy for the treatment of chronic hepatitis B infection.
A.
Snow, Gilead Sciences, Durham, NC, Z. Krastev, University Hospital Multiprofile
Hospital for Active Treatment “St Iva, Sofia, Bulgaria, S. Lim, National
University Hospital Singapore, Singapore, Singapore, T. Ng, Changi General
Hospital Department of Medicine, Singapore, Singapore, . Kotzev,
Multifunctional Active Treatment Hospital “St. Marina”, Varna , Bulgaria, S.
Chan, 142-41 41st Avenue, Suite 10, Flushing , NY, P. Husa, University Hospital
BRNO – BOHUNICE Department of Infectious Disease, CZECH REPUBLIC , Czech
Republic, J. Sperl, Institute of Clinical & Experimental Medicine, Praha 4,
Czech Republic, H. Mommeja-Marin, Gilead Sciences, Durham, NC, K.
Borroto-Esoda, Gilead Sciences, Durham, NC, C. Moxham, Gilead Sciences, Durham,
NC, J. Anderson, Gilead Sciences, Durham, NC, E. Mondou, Gilead Sciences,
Durham, NC, J. Sorbel, Gilead Sciences, Durham, NC, F. Rousseau, Gilead
Sciences,
Purpose:
Evaluate HBV viral load (VL) after 24 weeks of
treatment with either emtricitabine 200 mg (FTC) plus clevudine 10 mg (CLV)
versus FTC monotherapy and to perform resistance surveillance for viremic
patients.
Methods:
Nucleoside naïve or experienced (48 weeks FTC 200 mg
qd) patients were evaluated. Serum HBV DNA was assayed using a Real-Time PCR assay
with a lower limit of detection (LOD) of 250 copies/mL (cp/mL). Genotypic
analysis of the polymerase was performed at week 24 (W24) for viremic (>4700
cp/mL) patients.
Results:
Seventy-eight HBeAg- patients were enrolled; 38 (n=24
experienced and
n=14 naïve) received FTC+CLV and 40 (n=28 experienced
and n=12 naïve) received FTC monotherapy. The median baseline HBV DNA VL was 4
log10 cp/mL. At W24 a -1.6 log10 and -1.4 log10 reduction in serum HBV DNA was
observed for experienced patients in the combination and monotherapy arms,
respectively, and a - 1.9 log10 reduction was observed among naïve patients,
regardless of treatment arm. Among experienced patients, 86% given FTC+CLV
versus 63% given FTC had HBV DNA <250 cp/mL at W24, and among naïve patients,
the proportions were 69% and 67%, respectively. The W24 prevalence of FTC
associated mutations was 7% and 0% among experienced and naïve patients,
respectively.
Conclusion:
In this HBeAg- population, both emtricitabine plus clevudine
and emtricitabine monotherapy produced a favorable antiviral response at week
24 as demonstrated by the median change from baseline in HBV DNA and by the
proportion of patients with HBV DNA below the limit of detection. At week 24 no
naïve patient presented with FTC resistance mutations whereas the rate was 7%
among FTC experienced patients.
Poster
991
Abstract
ID: 67742
Category:
J1O: Hepatitis B: Treatment
Multiphase dynamics of HBeAg Negative and Positive Hepatitis B Virus Infections: evidence for synergistic antiviral effects of Peginterferon Alfa-2a and Lamivudine in high viral load patients.
P.
Colombatto, Hepatology Unit at the Pisa Univerisity Hospital, Pisa, L.
Civitano, Hepatology Unit, Pisa Univerisity Hospital, Pisa, R. Bizzarri, 2 NEST-INFM,
Scuola Normale Superiore, Pisa, Italy, F. Oliveri, Hepatology Unit, Pisa
Univerisity Hospital, Pisa, S. Choudhury, PD M. Roche USA, Nutley, CT, R.
Gieschke, Roche, Basel, Basel, Switzerland, F. Bonino, Scientific Direction,
Fondazione IRCCS Ospedale Maggiore Policlinico,, Milano, M. R. Brunetto,
Hepatology Unit, Pisa Univerisity Hospital,
Background
and Aims.
In HBeAg-positive chronic hepatitis B (CHB) patients
(pts) serum HBV-DNA decline during the 1st month of antiviral therapy show
either a classic biphasic or more complex profile. We studied and compared
viral dynamics of HBeAgnegative and HBeAg-positive CHB pts treated with
lamivudine (LMV) and/or with peginterferon alpha 2a (Peg-IFN2a).
Patients and
Methods.
In our newly developed bio-mathematical model the 1st
rapid drop of virus production (1st phase) can be followed by a further
exponential decline (2nd phase) to an asymptotic value after which the immune
clearance of infected cells becomes the major cause of HBV-DNA decline (3rd phase).
Viral load was measured at days 0, 0.3, 1, 2, 4, 5, 7, 14, 21, 28, 35, 42, 56,
84 and every 6 weeks thereafter, in 72 HBeAg negative and 41 HBeAg-positive pts
who received 48 weeks of either LMV (25 and 15 pts), Peg-IFN2a 180 mcg qw plus
LMV (23 and 14 pts) or Peg-IFN2a 180 mcg qw plus placebo (24 and 12 pts).
Results and
Conclusions.
Baseline HBV-DNA levels were higher in HBeAg-positive
as compared to HBeAg negative pts (9.97 Log10 vs 6.79 Log10; P< 0.001).
During the first month of therapy, viral load decreased more consistently in
HBeAg positive pts (mean Delta variation 0-28 days: -3.59 Log10 vs -2.73 Log10;
P = 0.013). However, the analysis by treatment group showed a significant
difference between HBeAg positive and HBeAg negative pts only in the
Peg-IFN2a+LMV group (Delta 0-28 days: -5.42 Log10 vs -3.28 Log10; P <
0.001), suggesting that in high viral load pts combination therapy accelerate
the early HBV-DNA decline. In pts where viral load dynamics fit our model
(87.5% of HBeAg negative and 61% of HBeAg positive pts), combination therapy
showed significantly higher effectiveness of blocking virus production in HBeAg
positive than in HBeAg negative pts (epsilon = 0.995 vs 0.868, P < 0.001)
and faster 1st and 2nd phase HBV-DNA declines (1st phase = 7.52 vs
2.79 days-1, P = 0.022; 2nd phase = 0.72vs 0.44 days-1, P = 0.008).
Accordingly, in HBeAg positive patients the 1st and 2nd phase
decline were faster in pts treated with combination than in pts treated with
LMV (1st phase = 0.995 vs 0.933, P = 0.044 and 2nd phase = 0.72 vs 0.35 days-1,
P = 0.046).
Conclusion:
direct antiviral effects of LMV and PegIFN2a appear to
be synergistic in patients with high levels of virus production.
Poster
992
Abstract
ID: 60999
Category:
J1O: Hepatitis B: Treatment
Cost-effective strategies in the treatment of chronic hepatitis B (CHB) with adefovir dipivoxil (ADV).
G.
DUSHEIKO, CENTRE FOR HEPATOLOGY, ROYAL FREE HOSPITAL LONDON, UK, LONDON, United
Kingdom (Great Britain), D. MUTIMER, LIVER AND HEPATOLOGY UNIT, QUEEN ELIZABETH
HOSPITAL BIRMINGHAM, UK, EDGBASTON, United Kingdom (Great Britain), H. DAKIN,
ABACUS INTERNATIONAL, BICESTER, United Kingdom (Great Britain), N. HUGHES,
GILEAD SCIENCES, UK, CAMBRIDGE, United Kingdom (Great Britain)
BACKGROUND:
Lamivudine (LAM) was the first oral treatment for CHB,
although its efficacy is limited by drug resistance, with 70% of patients
becoming resistant within 4 years. ADV has a lower risk of resistance and is
active against LAM-resistant HBV. This suggests ADV may be cost-effective if
used first-line and/or second-line (after LAM resistance develops).
OBJECTIVES:
To assess the cost-effectiveness of first and
second-line ADV in the treatment of CHB from the perspective of the UK NHS.
METHODS:
A Markov model using individual patient simulation was
constructed to model disease progression in CHB and calculate the cost per
quality-adjusted life year (QALY) gained. Unlike previous analyses, this model
included patients with HBeAg-negative disease and/or drug resistance. Eleven disease
states were modeled: immunotolerant; viral suppression; active CHB; HBsAg
seroconverted; HBeAg seroconverted; compensated cirrhosis; decompensated
cirrhosis; hepatocellular cancer; liver transplant; post-liver transplant; and
death. Three treatment strategies were compared with LAM followed by no
treatment after resistance develops (“LAM-NT”): continuing LAM irrespective of
whether resistance develops (“LAM-LAM”); LAM followed by ADV after resistance
develops (“second-line ADV”); and ADV followed by LAM after resistance develops
(“first-line ADV”). Costs and resource use were based on a UK costing study and
clinical opinion, disease progression rates with/without treatment were based
on a systematic review and utility scores were based on published estimates.
Costs and benefits were discounted at 3.5% per year.
RESULTS:
Both first and
second-line ADV cost less than £30,000/QALY relative to LAM-NT. First-line ADV
costs £66,000/QALY relative to second-line ADV. In contrast, the common
practice of continuing LAM monotherapy in LAM-resistant patients (LAM-LAM)
costs £33,097/QALY relative to stopping treatment, demonstrating that it is
more cost-effective to switch to ADV when LAM resistance develops.
Poster 993
Abstract
ID: 62050
Category:
J1O: Hepatitis B: Treatment
RESISTANCE TO ADEFOVIR DIPIVOXIL IN PATIENTS WITH LAMIVUDINERESISTANT CHRONIC HEPATITIS B.
C.
Osiowy, Public Health Agency of Canada, Winnipeg, Canada, J. Heathcote, Toronto
Western Hospital, Toronto, Canada, F. Zoulim, INSERM Unit 271, Lyon, France, B.
Willems, Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc,
Montreal, Canada, J. Villeneuve, CHUM - Hôpital Saint-Luc,
Background/Aim:
Adefovir dipivoxil (ADV) has demonstrated activity
against wildtype and lamivudine-resistant strains of hepatitis B virus (HBV).
The aim of this study was to document the efficacy and development of
resistance to ADV in patients with lamivudine-resistant HBV infection treated
with ADV.
Patients and
methods:
116
patients with chronic hepatitis B and lamivudine
resistance were treated with ADV 10mg/day. Following introduction of ADV,
lamivudine was continued in 81 patients and stopped in 35. HBeAg was positive
in 74 cases and negative in 42. Five patients had had liver transplantation
(OLT) prior to starting ADV, and 8 underwent OLT after starting ADV. Follow-up
ranged from 12 to 60 months (mean = 22 months). The presence of mutations of
the HBV-polymerase gene conferring resistance to lamivudine and/or adefovir was
examined using a new INNO-LiPA test (HBV DR v2, Innogenetics). The HBV-DNA
polymerase was also sequenced to analyze nucleotide changes. Serum HBVDNA was
measured by the Bayer b-DNA or the Roche PCR assay.
Results:
After one year of treatment with ADV, 61% of patients
had HBV-DNA viral load below 100,000 copies/ml. This percentage increased to
77% after 2 years. Five patients developed phenotypic resistance to adefovir as
evidenced by a 1 log increase in serum HBV-DNA during treatment (two OLT
patients and 3 non-OLT). Resistance occurred after 1 year of treatment in 4
cases and after 3 years in the fifth case. The N236T mutation in domain D of
the polymerase was detected in 4 of 5 cases. In one additional patient, the
N236T mutation was detected after one year of treatment without evidence of
phenotypic resistance. Among the cases with phenotypic resistance, 2 were
receiving both adefovir and lamivudine (1 OLT, 1 non-OLT) and 3 were receiving
adefovir only (1 OLT, 2 non- OLT).
Conclusion:
Patients with lamivudine-resistant HBV infection
exhibit a slow, but
sustained response to adefovir in all but 2.9% of
non-OLT patients after 1 year of treatment. The occurrence of resistance to ADV
was more frequent in OLT patients (2 of 13 cases)
Poster
994
Abstract
ID: 66086
Category:
J1O: Hepatitis B: Treatment
Predictors of histologic improvement and relationship between sustained response and histology in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40KD) (PEGASYS®).
G. K.
Lau, Queen Mary Hospital, Hong Kong, China, G. Cooksley, Royal Brisbane
Hospital, Brisbane, Australia, P. Marcellin, Hôpital Beaujon, Clichy, France,
T. Piratvisuth, Songklanakarin Hospital, Songkla, Thailand, S. Hadziyannis,
Henry Dunant Hospital, Athens, Greece, P. Farci, Universita di Cagliari,
Cagliari, Italy, M. W. Fried, University of North Carolina, Chapel Hill, NC, F.
Bonino, IRCCS, Milan, Italy, R. Jin, Beijing You An Hospital, Beijing, China,
P. Button, Roche, Dee Why, Australia, M. Popescu, Roche,
Background:
Established treatments for chronic hepatitis B (CHB)
provide improvements in histologic activity that are generally associated with
biochemical and virologic responses. Recent data have shown that peginterferon
alfa-2a (40KD) (PEGASYS®) monotherapy provides histologic improvements in
around half of all patients with HBeAg-positive or -negative CHB.
Objective:
To evaluate baseline predictors of histologic response
and the association between biochemical and virologic outcomes and liver
histology in patients treated with peginterferon alfa-2a monotherapy in two
large, randomized studies.
Methods:
HBeAg-positive (n=271) and -negative (n=177) patients
received 48 weeks of 180 mg peginterferon alfa-2a once-weekly. Histologic
response, assessed 24-weeks post-treatment, was defined as a reduction in
modified HAI score (Ishak) of at least 2 points compared with the pretreatment
score. Multivariate analyses to identify predictors of histologic response
included the following baseline variables: age, gender, genotype, ALT, HBV DNA,
HBeAg titre [HBeAgpositive only], bodyweight and race.
Results:
Among patients with paired biopsy, histologic response
rates at week 72 were 49% [102/207] and 59% [84/142] in the HBeAg-positive and
-negative studies, respectively. High baseline ALT levels were significantly
predictive of histologic response in the HBeAg-positive (P=<0.001) and
-negative studies (P=0.005). In HBeAg-positive patients, low baseline HBeAg
levels were also predictive of histologic response (P=0.001). Baseline HBV DNA
was not a significant predictor of histologic response in either study. In both
studies, there was a significant association between sustained virologic and
biochemical response and improved liver histology at week 72 (P ≤ 0.001).
In the HBeAg-positive study, histologic response was seen in 73% [55/75] of
patients with sustained HBeAg seroconversion at week 72 vs 36% [47/132] of patients
without. The rate of histologic response was highest in patients who had
achieved HBeAg seroconversion by week 24 of treatment (30/35; 86%). In the
HBeAg-negative study, histologic response was seen in 78% [39/50] of patients
with a sustained combined response (normal ALT + HBV DNA <20,000 cp/mL) vs
49% [46/93] of patients without.
Conclusions:
High baseline ALT and low HBeAg levels are
significantly associated with sustained histologic response to peginterferon
alfa-2a. Rates of histologic response are highest in patients achieving HBeAg
seroconversion by week 24 of treatment. In HBeAg-positive and - negative
patients receiving peginterferon alfa-2a, there is a significant association
between sustained response and improved liver histology.
Poster
995
Abstract
ID: 66609
Category:
J1O: Hepatitis B: Treatment
IN VITRO EFFECT OF THYMOSIN-ALPHA1 AND INTERFERON-ALPHA ON TH1 AND TH2 CYTOKINE SYNTHESIS IN PATIENTS WITH HBEAG-NEGATIVE CHRONIC HEPATITIS B.
A.
Gramenzi, Dip. Med. Interna, Cardioangiologia, Epatologia. University of
Bologna, Bologna, Italy, C. Cursaro, Dip. Med. Interna, Cardioangiologia,
Epatologia. University of Bologna, Bologna, Italy, M. Margotti, Dip. Med.
Interna, Cardioangiologia, Epatologia.University of Bologna, Bologna, Italy, I.
Persico, Dip. Med. Interna, Cardioangiologia, Epatologia.University of Bologna,
Bologna, Italy, A. Scuteri, Dip. Med. Interna, Cardioangiologia,
Epatologia.University of Bologna, Bologna, Italy, E. Loggi, Dip. Med. Interna,
Cardioangiologia, Epatologia. University of Bologna, Bologna, Italy, S.
Lorenzini, Dip. Med. Interna, CardioAngiologia, Epatologia. University of
Bologna, Bologna, Italy, M. Bernardi, Dip. Med. Interna, Cardioangiologia,
Epatologia. University of Bologna, Bologna, Italy, P. Andreone, Dip. Med.
Interna, Cardioangiologia, Epatologia. University of Bologna,
Introduction:
Thymosin alpha-1 (TA1) is an immune-modultaing peptide
that has been demonstrated to enhance Th1 cytokine production as well as T-cell
differentiation and maturation. Several clinical studies have shown that TA1 is
effective in the treatment of chronic hepatitis B.
Aim
This study was to evaluate the antiviral and the
Th1/Th2 cytokine response from peripheral blood mononuclear cells (PBMCs) of
patients (pts) with HBeAg-negative chronic HBV and its modulation by TA1 and
interferon-alfa (IFNa).
Methods:
106 PBMCs of 12 pts (mean age: 41±13 yrs; M/F: 9/3)
with HbeAg negative chronic hepatitis B were isolated and cultured in absence
(RPMI) or in presence of IFNa, TA1 or both. Th1 (IL-2, IFN-g) and Th2 cytokine
(IL-4, IL-10) production and the synthesis of the IFN-induced antiviral protein
2’,5’-oligoadenylate synthetase (2- 5OAS) were directly assayed in the
supernatants by commercial kits.
Results
Reported in the table:
No correlation was found between ALT or HBV-DNA serum
levels and cytokines both in RPMI and in stimulated cultures. Similarly, no
correlation was found with 2-5OAS.
Conclusion:
in PBMCs of patients with HBeAg-negative chronic
hepatitis B, the stimulation with TA1 is able to induce a significant increase
in production of IL-2 and 2- 5OAS and a significant decrease in the production
of IL-10. On the contrary IFNa alone does not modify IL-2 production and
significantly increases IL-10 synthesis. Incubation with TA1 and IFNa together
led to an additive or even synergistic effect on the increase of IL-2
synthesis. Furthermore the addition of TA1 to IFNa significantly reversed the
IFNa induced IL-10 increase. Based on this evidence it should be hypothesized
that the efficacy of TA1 in treatment of HBV chronic infection could be
ascribed to both the increase of the Th1 response and the decrease of the Th2
response, associated with persistence of viraemia
Poster
996
Abstract
ID: 66942
Category:
J1O: Hepatitis B: Treatment
Relapse in HBeAg-positive chronic hepatitis B after Peg-Interferon alpha-2b therapy alone or in combination with lamivudine.
H. J.
Flink, 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, Rotterdam, Netherlands, H. L. Janssen, Erasmus MC, University
Medical Center Rotterdam,
Recurrence of serum HBeAg has been reported to be
uncommon both after cessation of interferon and lamivudine therapy for
HBeAg-positive chronic hepatitis B. We investigated the frequency of relapse
after Peg-interferon alpha-2b therapy alone or in combination with lamivudine
in chronic hepatitis B. A total of 266 chronic HBeAgpositive patients were
treated with 100μg Peg-IFN weekly for 52 weeks combined with lamivudine (n
= 130) 100 mg/day or placebo (n = 136). After week 32 the Peg-IFN dose was
reduced to 50μg. The post-treatment follow-up lasted 26 weeks. At the end
of treatment, HBeAg loss was seen in 44% in the combination group and 29% in
the monotherapy group (p = 0.01). Overall, post-treatment HBeAg recurrence was
seen in 27 patients (10%), but was strongly associated with treatment
allocation. Twenty-two patients (17%) receiving the combination with lamivudine
and 5 (4%: p < 0.0001) receiving Peg-IFN alone relapsed for HBeAg after
treatment discontinuation. Except for treatment allocation, no other baseline
variables could be identified as predictive factor for relapse. Among patients
in the combination group post-treatment relapse occurred less frequently after
HBeAg seroconversion (i.e. HBeAg clearance and development of anti-HBe) and was
found in 8 (6%) patients versus 5 (4%, p = 0.35) receiving Peg-IFN alone.
Multivariate analysis showed combination therapy with lamivudine (RR 3.8 CI95%
1.2 to 12, p = 0.02) and absence of anti-HBe at week 52 (RR 6.3 CI95% 2.2 to
16.7, p < 0.0001) as independent predictors for relapse.
In conclusion, recurrence of HBeAg is more often seen
after combination of Peg-IFN with lamivudine than after Peg-IFN monotherapy.
Treatment allocation and absence of anti-HBe at the end of therapy were the
only independent predictors for post-treatment HBeAg relapse.
Poster
997
Abstract
ID: 67313
Category:
J1O: Hepatitis B: Treatment
EFFICACY OF TENOFOVIR IN PATIENTS WITH CHRONIC HEPATITIS B AND RESISTANCE OR SUB-OPTIMAL RESPONSE TO ADEFOVIR.
J.
Villeneuve, CHUM - Hôpital Saint-Luc, Montreal, Canada, B. Willems, CHUM -
Hôpital Saint-Luc, Montreal, Canada, F. Zoulim, INSERM U 271, Lyon, France
Background/Aim:
Adefovir dipivoxil has demonstrated activity against
lamivudineresistant strains of hepatitis B virus (HBV). However, the N236T
mutation in domain D of the hepatitis B virus (HBV) polymerase is associated
with phenotypic resistance to adefovir. In vitro data suggest that the N236T
mutant exhibits only a 4.5 fold decrease in sensitivity to tenofovir. We
therefore examined the efficacy of tenofovir in patients with adefovir
resistance. We also explored the usefulness of tenofovir in patients with
suboptimal response to adefovir, but without genotypic resistance.
Methods:
Two patients who were receiving adefovir because of
lamivudine resistance developed resistance to adefovir, after 36 and 12 months
of treatment respectively. The first case was receiving lamivudine + adefovir
and the second case adefovir monotherapy. The N236T mutation of the
HBV-polymerase was demonstrated by the INNO-LiPA test (HBV DR v2,
Innogenetics). They were treated with tenofovir 300mg id plus lamivudine 100mg
id and adefovir was stopped. Four additional patients without genotypic
resistance, but with sub-optimal response to adefovir were also switched to
tenofovir 300mg id. They were also receiving adefovir + lamivudine because of
lamivudine resistance. These 4 cases had HBV-DNA viral loads of 97 x 106, 42 x
106, 14 x 106 and 3.6 x 106 millions copies/ml after 13, 23, 29 and 25 months
of treatment with adefovir respectively. HBV-DNA viral loads were measured by
the Bayer b-DNA assay (lower limit of detection = 2000 copies/ml).
Results:
The two patients with resistance to adefovir showed a
good response to tenofovir. In the first case, serum HBV-DNA decreased from 93
x 106 copies/ml at baseline to 9,300 copies/ml after 6 months of treatment with
tenofovir. In the second patient, serum HBV-DNA decreased from > 100 x 106
copies/ml at baseline to 23,000 copies/ml after 7 months of treatment. In the 4
patients with sub-optimal response to adefovir, tenofovir treatment produced a
> 1 log drop in viral load after 1 month and a > 2 log drop after 3 months
of therapy.
Conclusion:
Treatment with tenofovir induces a rapid decrease of
HBV-DNA viral load in patients with resistance or sub-optimal response to
adefovir.
Poster
999
Abstract
ID: 67594
Category:
J1O: Hepatitis B: Treatment
Comparison of Tenofovir Versus Adefovir Based Combination Therapy in Subjects with Chronic Hepatitis B.
G. Y.
Im, Mount Sinai Medical Center, New York, NY, A. J. Uriel, Mount Sinai Medical
Center, New York, NY, D. Carriero, Mount Sinai Medical Center, New York, NY, J.
Park, Mount Sinai Medical Center, New York, NY, D. L. Jaffe, Mount Sinai
Medical Center, New York, NY, D. T. Dieterich, Mount Sinai Medical Center, New
Background
Treatment of chronic
Hepatitis B (HBV) infection with lamivudine (3TC) or adefovir (ADV) monotherapy
is associated with the development of resistance. Combination nucleoside/tide
analogue (NA) therapy may maximize viral suppression and decrease the risk of
viral resistance. There is limited data on the use of combination therapy in
HBV, particularly involving tenofovir (TDF).
Aim
To compare the efficacy and
tolerability of TDF and ADV based combination therapy in a cohort of pts with
chronic HBV.
Methods
Pts receiving combination NA
therapy for a minimum of 6 months (mo) were identified from our HBV database.
Efficacy of TDF v ADV based regimens was assessed at 6 and 12 mo on therapy.
Number of pts achieving undetectable HBV DNA (< 160 cps/ml), time to become
undetectable, normalization of ALT, HBV eAg seroconversion, and adverse events
were recorded.
Results
Data on 30 pts was analysed.
21/30 (70%) had previously received ADV or 3TC monotherapy and had been
switched to combination due to failure to become undetectable or viral rebound.
10/30 (30%) were NA naïve. Median age was 35 years (23 – 68), 16/30 (53%) were
Asian, 12/30 (40%) Caucasian, and 23/30 (77%) were male. 20/30 (67%) were HBV
eAg +, all were HIV negative. 13 pts received TDF based regimens, (TDF +
Emtricitabine (FTC) n=8, TDF + 3TC n=5), and 17 had ADV based regimens, (ADV +
FTC, n=4, ADV + 3TC n=13). 13/30 (43%) had BL ALT > 2x ULN, median = 82 U/L
(16 – 228). Median BL HBV DNA (n=29) was 1.4 x 105 cps/ml (2.0x10 2 - 2.0x10
9). Median length of therapy was 14 mo (6 – 31). Median time to HBV DNA <
160 cps/ml was shorter in NA naïve v experienced pts (4.5 v 6.5 mo) but longer
in HBV eAg + v eAg – pts (7 v 5 mo). 6/13 (69%) normalised ALT and 2 pts
seroconverted from HBV eAg + to HBV eAB + during therapy. Efficacy of TDF v ADV
based regimens is outlined below.
3 pts in both ADV and TDF
treatment groups achieved a mean log decrease in HBV DNA of 3.0 and 2.7
respectively, but did not fall to < 160 cps/ml. No adverse events were noted
and serum creatinine was stable on therapy.
Conclusion
In our cohort, ADV based combination regimens achieved a more rapid
fall in HBV DNA than TDF based regimens. Both appear potent and well tolerated.
Further studies are needed to evaluate differences in efficacy between these 2
regimens. Long-term follow up is required to determine if the use of
combination NA therapy will decrease the incidence of drug resistance.
Poster 1000
Abstract
ID: 67971
Category:
J1O: Hepatitis B: Treatment
Tenofovir rescue for patients with lamivudine resistant HBV infection with suboptimal virologic response to adefovir.
F. van Bömmel, Charité Campus Virchow Klinikum,
Berlin, Berlin, H. Feucht, Institut
für Medizinische Mikrobiologie und Immunologie,
Hamburg, Germany, B. Möller,
Hepatologische Schwerpunktpraxis in den Chackpoint
Arkaden, Berlin, Germany, U.
Spengler, Zentrum für Innere Medizin,
Universitätsklinikum Bonn, Bonn, Germany, B.
Zöllner, Institut für Medizinische Mikrobiologie
und Immunologie, Hamburg, C.
Sarrazin, Universitätsklinikum des Saarlandes,
Homburg/Saar, Germany, D. Hüppe,
Gastroenterologische Gemeinschaftspraxis Herne,
Herne, B. Wiedenmann, Charité
Campus Virchow Klinikum, Berlin, Germany, T. Berg,
Charité Campus Virchow
Klinikum, Berlin, Germany
Background:
Variable antiviral effects have been observed in
adefovir dipivoxil (ADV)-treated patients with either wild type or lamivudine
resistant (LAM-R) hepatitis B virus (HBV) infection. While a HBV DNA decline of
≥ 4 log was demonstrated in the majority of patients after 48 weeks
of ADV treatment, incomplete suppression of HBV DNA or null response to ADV
were also found in large scale studies. Here we examined whether tenofovir
disoproxil fumarate (TDF), which has been shown to be highly active against
LAM-R HBV infections is an efficient drug in the treatment of HBV infections
with suboptimal ADV responsiveness.
Methods:
Suboptimal ADV response (HBV DNA decline of less than
3 log or presence of high level viremia greater than 106 log in the absence of
an ADV resistantce mutants) during ADV treatment was documented in 14 patients
with LAM-R chronic HBV infection (mean age 45 years [range25-63]; m/f: 12/2; 13
HBeAg+). Mean period of ADV administration in these patients was 15 months
(range 8-22 months). All 14 patients were directly switched from ADV to TDF at
a daily dose of 300 mg. At this time, mean HBV DNA levels ranged between 5.0 to
7.6 log10 copies/mL (mean 6.6 log10 copies/mL) corresponding to a mean HBV DNA
decline of HBV DNA -0.9 log10 copies/mL (range -3.4 - +1.9 log10copies/mL)
during the ADV treatment phase. No patient had decompensated liver cirrhosis
but 10 patients had elevated ALT levels. HBV DNA levels were measured on a
monthly basis (HBV Monitor, Roche Diagnostics, detection limit 400 copies/ml)
over a period of 6-14 months. All patients were screened for
resistance-associated mutations within the HBV polymerase gene.
Results:
Following the start of tenofovir treatment, at month 3
and month 6 the mean decrease of HBV DNA was -3.1 log10 copies/mL [range 2.0-4.6]
and -3.9 log10 copies/mL [range 1.9-4.6]. During the observed period, 13
patients reached HBV DNA levels below the detection limit (400 copies/ml) and 5
patients with initially elevated ALT reached normal liver enzymes after a mean
duration of 4 months [range 1-9 months] and 6 months [range 1-12 months],
respectively. Two patients lost the HBeAg after 3 and 5 months. At the start of
TDF therapy, mutations at rtL180M and rtM204V were shown in 4 of the patients,
however without effect on the antiviral response. Genotypic ADV resistance was
excluded in all patients by direct sequencing of a region spanning the
polymerase gene from rt103 to rt244 as previously described. No significant
side effects were observed.
Conclusions:
Because of its high antiviral activity tenofovir might
become a highly effective rescue drug for patients with suboptimal response to
adefovil.
Poster
1001
Abstract
ID: 63081
Category:
J1O: Hepatitis B: Treatment
HBV GENOTYPE D AND SWITCH TO ADEFOVIR (ADV) MONOTHERAPY ARE ASSOCIATED WITH INCREASED RISK OF ADV RESISTANCE IN CHRONIC HEPATITIS B (CHB) PATIENTS.
S. K.
Fung, University of Michigan, Ann Arbor, MI, H. Chae, University of Michigan,
Ann Arbor, MI, R. Fontana, University of Michigan, Ann Arbor, MI, H.
Conjeevaram, University of Michigan, Ann Arbor, MI, J. Marrero, University of
Michigan, Ann Arbor, MI, K. Oberhelman, University of Michigan, Ann Arbor, MI,
M. Hussain, University of Michigan, Ann Arbor, MI, A. Lok, University of
Michigan, Ann Arbor, MI
Background:
Adefovir (ADV) resistance is less common and occurs
later than lamivudine (LAM) resistance. A study of 67 HBeAg-ve patients
reported that ADVresistant HBV mutants were detected in 0%, 3%, 11% and 18%
after 1, 2, 3 and 4 years treatment, respectively. Aims: To characterize the
virologic response to ADV, to determine the rate of ADV resistance, and to
explore risk factors associated with suboptimal response and ADV resistance in
patients referred to our Liver Clinic from 5/00 to 3/05.
Methods:
All patients who had received ADV for > 6 months
and had virologic breakthrough (BT) or failed to achieve an initial virologic
response (IVR) were tested for ADV resistance. LAM- and ADV-resistant mutations
were detected by a line probe assay (InnoLipa, DR2) and confirmed by direct
sequencing. HBV DNA was quantified using the Roche Cobas Amplicor assay (LLOD
200 copies/ml). BT was defined as > 1 log c/ml increase in HBV DNA after
initial suppression; IVR was defined as serum HBV DNA <4 log c/ml after 6
months of ADV. The rate of ADV resistance was estimated by Kaplan-Meier
analysis.
Results:
39 CHB patients (36M, 26 Caucasians and 11 Asians,
mean age 48 years, 26 HBeAg+ve) were included and mean duration of treatment
was 20 months (range 7-57). 30 (77%) patients had prior LAM (mean duration 25
months) of whom 14 were switched to ADV monotherapy and 16 received combination
of LAM+ADV; 9 (23%) were started on ADV as de novo therapy. 25 (64%) patients
had LAM breakthrough or confirmed resistance. IVR was observed in only 44%
patients. Factors associated with an IVR included lower HBV DNA (p=0.03) and
the absence of HBeAg (p=0.02) at the onset of ADV treatment. 16 patients had BT
or lack of IVR on ADV and 5 were found to have ADV-resistant mutations (3 rtA181V,
2 rtN236T). All 5 patients with ADV resistance had prior LAM therapy. At the
time ADV resistance was detected, 4 had viral rebound >5 logs and ALT flares
>2XULN. The rate of ADV resistance at months 6, 12, 18, and 24 was 0%, 0%,
9%, and 19%, respectively. Patients with ADV resistance were more likely to
have been switched to ADV monotherapy (100% vs. 36%, p=0.014) and to be
infected with HBV genotype D (60% vs. 9%, p=0.019).
Conclusions:
Half of our patients failed to achieve IVR on ADV.
Lack of IVR was associated with high baseline HBV DNA and presence of HBeAg.
The high rate of ADV resistance (19% at yr 2) in our clinic population may be
related to referral bias and predominance of patients with LAM resistance. ADV
resistance was associated with HBV genotype D and switch to ADV monotherapy.
Combination therapy in patients with LAM resistance may prevent the development
of ADV resistance.
Poster
1002
Abstract
ID: 65139
Category:
J1O: Hepatitis B: Treatment
Pretreatment HBsAg Serum Levels Predict HBsAg Seroconversion in HBeAg-Negative Chronic Hepatitis B (CHBe-) Patients.
E. K.
Manesis, Academic Department of Medicine, Hippokration General Hospital,
Athens, Greece, E. S. Hadziyannis, Academic Department of Medicine,
Hippokration General Hospital, Athens, Greece, O. P. Angelopoulou, Academic
Department of Medicine, Hippokration General Hospital, Athens, Greece, S. J.
Hadziyannis, Department of Medicine & Liver Unit, Henry Dunant Hospital,
Athens, Greece
Background:
Both interferon-alpha (IFN) and nucleos(t)ide
analogues are prescribed in CHBe, but only IFN has lasting effects after
therapy and 30% of IFN-sustained responders seroconvert HBsAg. Although recent
evidence suggests that serum HBsAg levels may reflect the liver cccDNA pool, no
information exists on the effect of IFN and lamivudine (LAM) treatment on serum
HBsAg and on subsequent HBsAg seroconversion.
Methods:
HBsAg and HBV-DNA were quantitated in stored sera by
ADVIA Centaur™ and Versant-3.0™, respectively (Bayer Diagnostics) with a level of
detectability 0.066 IU/mL and 357 IU/mL (2000 copies/mL), respectively. 540
sera of 62 CHBe- patients were analyzed. 44 patients had received 52 IFN
courses (18 sustained responders, including 7 HBsAg-seroconvertors; 17
non-responders, 17 respond-relapsers) for median 12.1 (3.8.26.7) months and 22
patients were on lamivudine (22 responders, including 1 HBsAg seroconvertor, 5
relapsers) with median virological response 46.8 (18.2-58.5) and 18.9
(6.3-43.8) months, respectively. The HBsAg levels were measured at baseline, at
the end of interferon treatment (EOT), at the end of follow up (EFU) in all
cases and in other instances depending on availability of samples.
Results:
Baseline HBsAg levels varied widely (median 3421.4, range
57.3-66000 IU/mL) and were similar in all groups except among seroconvertors,
who had significantly lower levels compared to the other IFN- or LAM-treated
patients (median 1652.1 vs 3478.9 IU/mL, P=0.004). At EOT, paired HBsAg levels
were statistically unchanged in IFN-non-responders and all LAM-treated
patients, compared to baseline, while all IFN-responding groups had
significantly lower levels (median baseline 3723.4 vs EOT 1456.2, P<0.001).
At EFU, paired HBsAg comparisons with the baseline were not significant in
IFN-non-responders and –relapsers, but differed significantly in IFN– sustained
responders (median EFU levels 194.8 IU/mL, P=0.043). Multivariate logistic
regression analysis demonstrated that lower baseline HBsAg levels was the only
significant covariate related to HBsAg seroconversion (P=0.006, relative hazard
0.105, 95% CI 0.021-0.516), whereas age, sex, type- (IFN or LAM) or duration of
treatment, baseline HBV-DNA or ALT levels were not.
Conclusions:
Interferon, but
not lamivudine, significantly suppresses serum HBsAg at the end of therapy in
responding patients only. The effect is temporary in the respond-relapser group
and lasting in the sustained-responder group. Sustained responders who become
HBsAg seroconvertors have significantly lower pretreatment HBsAg and that is
the only significant prognostic variable of seroconversion by multivariate
analysis.
Poster 1003
Abstract
ID: 67109
Category:
J1O: Hepatitis B: Treatment
A MULTICENTER ITALIAN STUDY OF RESCUE ADEFOVIR DIPIVOXIL THERAPY IN LAMIVUDINE RESISTANT PATIENTS: A 2-YEAR ANALYSIS OF 604 PATIENTS.
P.
Lampertico, Dept. Gastroenterology, IRCCS Maggiore Hospital, Milan, Italy, A.
Marzano, Dept. Gastroenterology, Ospedale San Giovanni Battista, Molinette
Hosp, Torino, Italy, M. Levrero, Dept. Internal Medicine, University of Rome La
Sapienza, Roma, Italy, T. Santantonio, Clinic of Infectious Diseases,
University of Bari, Policlinico, Bari, Italy, P. Andreone, Dept Internal
Medicine, University of Bologna, Bologna, Italy, M. Brunetto, Azienda Ospedaliera
Universitaria Pisana, Pisa, Italy, V. Di Marco, Istituto di Clinica Medica,
University of Palermo, Palermo, Italy, S. Fagiuoli, Gastroneterologia, Azienda
Ospedale Università di Padova, Padova, Italy, G. Mazzella, Department of Internal
Medicine and Gastroenterology, University of Bo, Bologna, Italy, G. Raimondo,
Dipartimento di Medicina Interna,, Messina, Italy, f. Adefovir Study Group,
IRCCS Maggiore Hospital,
Intro:
Adefovir dipivoxil (ADV) halts progression of liver
disease in lamivudine-resistant patients but its efficacy and safety in the
general population is largely unknown. To further evaluate these aspects, the
rates of virological response, adefovir resistance (ADV-R), side effects and
liver related-complications were assessed in a large cohort of Italian patients
treated with ADV for LAM-R.
Material and
Methods.
604 LAM-R patients who started ADV treatment between
2002 and 2004 in 25 italian centers involved in the Gilead Sciences sponsored
435 and 550 studies, were enrolled in a prospective cohort study and followed
for 18 months, on average. Mean age was 54 years, 81% were men, 85%
HBeAg-negative, 49% cirrhotics, 53% had concomitant diseases and 46% received
concomitant medications. 51% of the patients switched from LAM to ADV (ADV mono
group) while 49% added ADV to LAM (combo group) throughout the study period.
HBV-DNA was quantified by sensitive assays (LLQ: 2 o 3 log copies/mL); a
virological response was defined as undetectable HBV-DNA, a virological rebound
was defined as > 1 log increase of HBV-DNA compared to on treatment nadir
and confirmed in at least two consecutive months. ADVR was confirmed by
molecular analysis.
Results.
Overall, the 1 and 2 year cumulative probability of
undetectable HBV-DNA was 62% and 78%, respectively. At multivariate analysis,
patients with pre-treatment lower HBV-DNA (p<0.0001), higher ALT levels
(p<0.005) and HBeAg negative (p<0.001) had higher chances of achieving
undetectable HBV-DNA. Time to undetectable HBV-DNA was significantly shorter in
patients with a pre-treatment HBV-DNA below 5 log, than in those with levels
between 5 and 6 or above 6 log (p<0.00001). ALT became normal in 74% and 81%
after 1 and 2 year of therapy, respectively. Older age, lower HBV-DNA and HBeAg
negative were independent predictors of ALT normalization. 31 patients (6%) had
a virological rebound while on ADV, between 7 to 41 months (median 15) from the
start of therapy. ADV-R was looked for in 13 cases and confirmed in 3 patients.
By multivariate analysis, patients treated with ADV monotherapy (p<0.0001)
and those with detectable HBV-DNA at week 24 (p<0.0001) had higher chances
of a virological rebound. ADV was discontinued or the dose was modified in 6%
of the patients, mainly because of impaired renal function. Adverse events
likely related to ADV were reported in 5% of the patients. HCC or clinical
decompensation was observed in 16% of cirrhotics, and 17% died or underwent
liver transplantation.
Conclusions.
ADV-LAM combination therapy in low viremic patients is
the most effective approach to treat lamivudine resistance.
Poster
1004
Abstract
ID: 67505
Category:
J1O: Hepatitis B: Treatment
Antiviral response and resistance surveillance for HBeAg positive patients enrolled in a combination study evaluating emtricitabine plus clevudine versus emtricitabine monotherapy for the treatment of chronic hepatitis B infection.
A.
Snow, Gilead Sciences, Durham, NC, Z. Krastev, University Hospital Multiprofile
Hospital for Active Treatment “St Iva, Sofia, Bulgaria, S. Lim, National
University Hospital Singapore, Singapore, Singapore, T. Ng, Changi General
Hospital Department of Medicine, Singapore, Singapore, . Kotzev,
Multifunctional Active Treatment Hospital “St. Marina”, Varna , Bulgaria, S.
Chan, 142-41 41st Avenue, Suite 10, Flushing , NY, P. Husa, University Hospital
BRNO – BOHUNICE Department of Infectious Disease, CZECH REPUBLIC , Czech
Republic, J. Sperl, Institute of Clinical & Experimental Medicine, Praha 4,
Czech Republic, H. Mommeja-Marin, Gilead Sciences, Durham, NC, K.
Borroto-Esoda, Gilead Sciences, Durham, NC, C. Moxham, Gilead Sciences, Durham,
NC, J. Anderson, Gilead Sciences, Durham, NC, E. Mondou, Gilead Sciences,
Durham, NC, J. Sorbel, Gilead Sciences, Durham, NC, F. Rousseau, Gilead
Sciences,
Purpose:
Evaluate HBV viral load (VL) after 24 weeks of
treatment with either emtricitabine 200 mg (FTC) plus clevudine 10 mg (CLV)
versus FTC monotherapy and to perform resistance surveillance for viremic
patients.
Methods:
Nucleoside naïve or experienced (48 weeks FTC 200 mg
qd) patients were evaluated. Serum HBV DNA was assayed using a Real-Time PCR
assay with a lower limit of detection (LOD) of 250 copies/mL (cp/mL). Genotypic
analysis of the polymerase was performed at week 24 (W24) for viremic (>4700
cp/ml) patients.
Results:
Eighty-five HBeAg+ patients were enrolled; 44 (n=30
experienced and n=14 naïve) received FTC+CLV and 41 (n=25 experienced and n=16
naïve) received FTC monotherapy. The median baseline HBV DNA VL was 7 log10
cp/mL. At W24 a - 3.2 log10 and -2.0 log10 reduction in serum HBV DNA was
observed for experienced patients in the combination and monotherapy arms,
respectively, and a -3.3log10 reduction was observed among naïve patients,
regardless of treatment arm. Among experienced patients, 30% given FTC+CLV
versus 28% given FTC had HBV DNA <250 cp/mL at W24, and among naïve
patients, the proportions were 50% and 19%, respectively. The W24 prevalence of
FTC associated mutations was 22% and 3% among experienced and naïve patients,
respectively.
Conclusion:
In this HBeAg+
population, both emtricitabine plus clevudine and emtricitabine monotherapy
produced a favorable antiviral response at week 24 as demonstrated by the
median change from baseline in HBV DNA and by the proportion of patients with
HBV DNA below the limit of detection. The incidence of mutations associated
with FTC resistance at week 24 was 3% among patients naïve to therapy.
Poster
1005
Abstract
ID: 67520
Category:
J1O: Hepatitis B: Treatment
Lamivudine and Adefovir Versus Adefovir Alone for HBeAg-Positive Chronic Hepatitis B.
M.
Ghany, NIH, Bethesda, MD, G. Lutchman, NIH, Bethesda, MD, D. Kleiner, NIH,
Bethesda, MD, B. Borg, NIH, Bethesda, MD, T. Heller, NIH, Bethesda, MD, J.
Feld, NIH, Bethesda, MD, R. Loomba, NIH, Bethesda, MD, Y. Park, NIH, Bethesda,
MD, T. Liang, NIH, Bethesda, MD, J. Hoofnagle, NIH,
Background:
Therapy of chronic hepatitis B is problematic.
Monotherapy with approved agents is associated with lack of response over time
either due to ineffective antiviral activity or the development of resistance.
Combination therapy may be an attractive option to prevent emergence of
resistance as well as to manage patients with established lamivudine
resistance.
Patients and
Methods:
We initiated a randomized controlled trial of
lamivudine and adefovir versus adefovir alone for patients with HBeAg-positive
and -negative chronic hepatitis B with or without prior lamivudine resistance.
The 1-year trial endpoints were normalization of ALT (Biochemical), lack of
detectable HBV DNA by polymerase chain reaction (Roche Amplicor assay), loss of
HBeAg or HBsAg (Virologic), and improvement in HAI score by ³ 4 points
(Histologic response). This analysis was restricted to the HBeAg positive
cohort. Comparisons between groups were by unpaired t-test.
Results:
To date 26 HBeAg positive patients (22 males, mean age
43 years) have been enrolled, 9 of whom were previously treated and had lamivudine
resistance and 4 of whom had cirrhosis. Results of ALT levels, HBV DNA testing
and liver histology on 22 patients who have finished 1 year of therapy are
shown in the Table.
* P value represents comparison between groups at year
1 by unpaired t-test.
The major difference in the two groups at 1 year was
the degree of inhibition of HBV DNA. The combination group had more dramatic
HBV DNA suppression compared to the monotherapy group, log change 5.94 vs 3.88
respectively, p=0.026. 10/11 patients receiving combination therapy suppressed
HBV DNA <104 copies per ml versus only 6/11 receiving monotherapy. A
combined response of normal ALT, undetectable HBV DNA and improvement in HAI
score by ³4 was seen in 7 combination versus 3 monotherapy patients, (p NS).
Notably no evidence of clinical resistance was seen in any patient at 1 year.
Therapy was well tolerated.
Conclusions:
The combination of
adefovir and lamivudine provided more potent and consistent inhibition of HBV
DNA levels than adefovir alone, but was not associated with further
improvements in biochemical or histological features of disease. Adefovir
monotherapy was associated with an inadequate virologic response in a number of
cases. Longer-term therapy may be required to observe further benefits of
combination therapy over monotherapy.
Poster 1006
Abstract
ID: 67026
Category:
J1O: Hepatitis B: Treatment
Prediction of response based on viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B.
M. J.
ter Borg, 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, Rotterdam, Netherlands, H. L. Janssen, Erasmus MC, University
Medical Center Rotterdam,
Treatment of chronic HBeAg-positive hepatitis B with
pegylated interferon is effective in only 30-40% of the patients. The most
important baseline predictors for response are HBV genotype, low baseline
HBV-DNA and elevated ALT levels. Until now, there are no stopping rules for
pegylated interferon treatment of chronic hepatitis B. To investigate whether
viral dynamics during pegylated interferon alpha-2b (PEG-IFN) monotherapy can
predict response (defined as serum HBeAg loss 26 weeks post treatment), we
analyzed 136 HBeAg-positive chronic hepatitis B patients who participated in a
global randomised trial and who were treated with PEG-IFN 100 μg/week for
52 weeks. PEG-IFN dose was halved after 32 weeks of treatment. Serum HBV-DNA
levels were measured monthly during therapy and 26 weeks post treatment by
Taqman PCR assay.
At the end of follow-up, response was achieved in 49
of 136 patients (36%). During therapy responders exhibited a 4.23 log and
non-responders a 1.22 log HBV-DNA decrease. Overall, early viral kinetics were
not predictive for response. Only for patients with genotype A, responders had
a pronounced decline of HBV-DNA whereas nonresponders remained flat during the
treatment period and follow-up. One log decline of HBV-DNA at week 32 of
treatment was highly predictive for response in genotype A (table). In the
other genotypes, i.e. B, C and D, both responders and non-responders showed a
decline in HBV-DNA during treatment followed by a post-treatment HBV-DNA
rebound in non-responders and a sustained low HBV-DNA in responders.
In conclusion, for HBeAg-positive patients with
genotype A, 1 log HBV-DNA decline after 32 weeks of PEG-IFN was highly
predictive for sustained response. For the other HBV genotypes, on-treatment
HBV-DNA decline did not predict response sufficiently to be used in clinical
practice.
(N = 45)
HBV-DNA at week 32 was
available in 120 patients; 2 patients with genotypes G and F were not analyzed.
Poster
1007
Abstract
ID: 67607
Category:
J1O: Hepatitis B: Treatment
Adefovir alone or combination with lamivudine in patients with lamivudine-resistance chronic HBeAg-negative hepatitis B. A non randomized multicenter controlled study.
S.
Manolakopoulos, Department of Gastroenterology, Polykliniki General Hospital,
Athens, Greece, S. BETHANIS, Polykliniki General Hospital, Athens, Greece, S. Koutsounas,
Reference Center of Hepatitis, IKA, Athens, Greece, J. Goulis, 4th
Department of Internal Medicine, University of Thessaloniki, Thessaloniki,
Greece, A. Saveriadis, 2nd Department of Gastroenterology, Evangelismos General
Hospital, Athens, Greece, E. Xristias, 1st Department of Internal Medicine
Naval Hospital of Athens, Greece, Athens, Greece, A. Christidou, Department of
Gastroenterology, Polykliniki General Hospital, Athens, C. Pavlidis, 2nd
Department of Internal Medicine, General Hospital of IKA, Athens, Greece, C.
Toubanakis, Dpt of Gastroenterology, Polykliniki General Hospital, Athens,
Greece, J. Vlachogiannakos, 2nd Department of Gastroenterology, Evangelismos
General Hospital, Athens, Greece, C. Triantos, Department of Gastroenterology,
Polykliniki General Hospital, Athens, Greece, A. Avgerinos, 2nd Department of
Gastroenterology, Evangelismos General Hospital, Athens, Greece, D.
Tzourmakliotis, Department of Gastroenterology, Polykliniki General Hospital,
Adefovir dipivoxil (ADV) has been recently licensed
for the treatment of chronic hepatitis B (CHB). The drug has been shown to be
effective against wild, precore, lamivudine-resistant forms of CHB and is
associated with a lower resistance rate compared to lamivudine. The efficacy of
lamivudine and ADV combination therapy in patients with HBeAg-negative CHB who
have developed YMDD mutant is not known.
Aim:
To test the hypothesis that ADV+lamivudine combination
therapy in patients with HBeAg-negative lamivudine-resistant CHB is followed by
higher efficacy and safety compared to ADV monotherapy.
Patients and
methods:
In the analysis we included 64 adult patients
(M/F=53/11, median age=58) with CHB who developed breakthrough due to
lamivudine-resistant strains. All patients had compensated liver disease,
elevated transaminse levels and serum HBV DNA¡Ý105 copies/ml before initiation
of ADV. In all patients ADV (10mg once daily) was added to
lamivudine(100mg/daily) for 3 months and thereafter patients were assigned to
continue combination treatment(group 1, 44 patients) or to receive ADV
monotherapy(group 2, 20 patients).
Results:
Baseline parameters were similar between the two
groups. At the time of this analysis the total duration of treatment was 16 to
31, median 26 months. No difference was observed between two groups in the
patients with normal ALT levels at 12th and 24th months ( group 1: 87% / 65%,
group 2: 72%/ 92%). Median reduction of serum HBV DNA at 6th, 12th and 18th
month was 3.17/3.29/4.34 logs respectively in group 1 and 3.41/3.32/3.39 logs
in group 2. The difference became significant at the 18th month (p=0.027). At
12th month serum HBV DNA >105copies/ml was observed in 2 patients (one at
each group) and at 18th month in one patient in group 2. Two patients on ADV
monotherapy developed virological breakthrough at 12th and 15th months of
treatment respectively. None of the patients receiving combination developed
breakthrough phenomenon.
Conclusions:
Our data suggest that ADV is an effective antiviral
agent in patients with HBeAg-negative CHB who developed YMDD mutations.
However, ADV+lamivudine combination appears to confer higher antiviral efficacy
and may prevent ADV-resistant CHB.
Poster
1008
Abstract
ID: 67711
Category:
J1O: Hepatitis B: Treatment
Significant histologic disease in HBV-infected patients with normal to minimally elevated ALT levels at initial evaluation.
M.
Nguyen, Stanford University Medical Center, Pacific Health Foundation, Palo
Alto, CA, H. Trinh, Pacific Health Foundation, San Jose, CA, R. T. Garcia,
Pacific Health Foundation, San Jose, CA, A. Ahmed, Stanford University Medical
Center, Palo Alto, CA, E. Keeffe, Stanford University Medical Center, Palo
Alto, CA
PURPOSE:
Current guidelines recommend
antiviral therapy for chronic hepatitis B (CHB) patients with elevated ALT.
However, many patients who present with “normal” ALT may not have persistently
normal ALT on follow-up and may have significant histologic disease. The
purpose of this study was to define the spectrum of histologic findings in such
patients.
METHODS:
We performed a retrospective
cohort study of all patients with active HBV infection (HBV DNA >10,000
copies/mL) and normal or minimally elevated ALT (up to 2x ULN) evaluated with liver
biopsy at a single U.S. center. Independent predictors of significant histology
(grade 2, stage II or higher) were identified by multivariate analysis.
RESULTS:
A total of 56 patients were
included: ALT normal (n=39; 70%), up to 1.3x ULN (n=8; 14%), or 1.3-2.0x ULN
(n=9; 16%). Mean age was 46±12, 64% were male, 20% had history of alcohol use,
18% had family history of liver cancer or liver-related death, all were Asian,
60% were HBeAg negative, and 43% had HBV DNA >1 million copies/mL at evaluation.
Mean ALT at biopsy was 45±18. Mean ALT per patient was 57±55 (median, 45;
range, 15-365). Average number of ALT tests per patient was4.9±2.6 over a mean
follow-up of 31±29 months. Average number of ALT tests over a 6-month period
per patient was 2.0±0.9. Of those with normal ALT at evaluation, 46% continued
to have normal ALT on long-term follow-up. Of those with normal ALT at 6- month
follow-up, 33% had an elevated ALT on further follow-up. Mild steatosis was
seen in 5 and moderate in 1 patient. Figure shows histologic results.
Significant histologic findings were found in 12% of patients with persistently
normal ALT compared vs. 55% in those with elevated ALT (p=0.003). On
multivariate analysis, only age >45 was an independent predictor of
significant histology (OR=12.9, p=0.008) and only presence of persistently
normal ALT on long-term follow-up (not ALT or HBV DNA levels at evaluation or
6-month follow-up) was an independent predictor of favorable histology
(OR=0.04, p=0.003).
CONCLUSION:
Persistently normal ALT on long-term follow up is a strong predictor of favorable histology, but only 46% of the patients with normal ALT at evaluation and only 33% of patients with normal ALT at 6-month follow-up continued to have normal ALT. Patients who present with normal to minimally elevated ALT should be evaluated carefully with follow-up or liver biopsy, particularly those older than age 45.
Poster
1009
Abstract
ID: 65612
Category:
J1O: Hepatitis B: Treatment
More frequent and earlier emergence of adefovir (ADV) resistance mutations inlamivudine resistant patients treated with ADV compared to previously reportednucleoside-treatment naive patients.
C.
Lee, Konkuk University Medical College, Seoul, Korea, Republic of, J. Yeon, Korea
University Medical College, Seoul, Korea, Republic of, S. Hong, GeneMatrix
Inc., Gyeonggi-do, Korea, Republic of, J. Kim, Korea University Medical
College, Seoul, Korea, Republic of, Y. Seo, Korea University Medical College,
Seoul, Korea, Republic of, H. Chung, GeneMatrix Inc., Yongin-si, Gyeonggi-do,
Korea, Republic of, M. Moon, GeneMatrix Inc., Yongin-si, Korea, Republic of, S.
Kim, GeneMatrix Inc., Yongin-si, Korea, Republic of, W. Yoo, GeneMatrix Inc.,
Yongin-si, Korea, Republic of, K. Byun, Korea University Medical College,
Seoul, Korea, Republic of, S. Yu, Konkuk University Medical College, Seoul,
Korea, Republic of
Background:
The cumulative incidence of
adefovir (ADV) resistant mutations in the nucleoside-treatment naive chronic
hepatitis B (CHB) patients at weeks 48, 96, 144 were known to be 0, 0.8-3% and
~5.9%, respectively. The aim of this study was to analyze the incidence and
clinical consequence of ADV-resistant rtA181V/T and rtN236T mutation in
lamivudine (LMV)-resistant CHB patients who were treated with ADV.
Materials and methods:
Sera were collected from 106 genotypically
confirmed LMVresistant CHB patients who were treated with ADV. The serum HBV
DNA was quantified by real time PCR. The ADV mutant was detected by using
matrix-assistedlaser desorption/ionization time of flight mass
spectrometry (MALDI-TOF MS)-based
genotyping assays, termed Restriction Fragment Mass Polymorphism (RFMP).
Results:
RFMP analysis revealed that
a total of 50 amino acid substitutions developed in the rt domain of the HBV
polymerase in 41 of 106 patients. The rtA181V, rtN236T and rtA181T mutations
were detected in 10, 6 and 34 patients at treatment weeks 3~96, 3~96and 0~96,
respectively. The cumulative incidence of genotypic ADV resistance at weeks 48
and 96 was 32% and 58%, respectively. Serial quantification of the serum HBV
DNA revealed that 16 of 41 patients with genotypic mutation displayed the HBV
DNA rebound. The magnitude of the median log10 HBV DNA reductions at treatment
months twelve was 2.2 vs 3.8 in patients with or without genotypic mutation
(p<0.05).
Conclusion: The emergence of the ADV mutations
in LMV resistant patients who are treated with ADV appeared to present earlier
and is more frequent than in nucleosidetreatment na?e patients. Prolonged
studies are needed to define the long-term clinical outcome in these types of
patients.
Poster
1010
Abstract
ID: 66669
Category:
J1O: Hepatitis B: Treatment
Therapeutic role of preemptive lamivudine therapy for the prevention of hepatitis B virus reactivation in patients with hepatocellular carcinoma undergoing transarterial chemolipiodolization: a randomized controlled study.
J. W.
Jang, Department of Internal Medicine, The Catholic University of Korea, Seoul,
Korea, Republic of, J. Y. Choi, Department of Internal Medicine, The Catholic
University of Korea, Seoul, Korea, Republic of, C. W. KIm, Department of
Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of,
S. H. Bae, Department of Internal Medicine, The Catholic University of Korea,
Seoul, Korea, Republic of, S. K. Yoon, Department of Internal Medicine, The
Catholic University of Korea, Seoul, Korea, Republic of, J. M. Yang, Department
of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic
of, C. D. Lee, Department of Internal Medicine, The Catholic University of
Korea, Seoul, Y. S. Lee, Department of Internal Medicine, The Catholic
University of Korea, Seoul, Korea, Republic of, K. W. Chung, Department of
Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of,
H. S. Sun, Department of Internal Medicine, The Catholic University of Korea,
Seoul, Korea, Republic of
Background/Aim:
Accumulating evidence indicates that most fatal cases
of hepatitis B virus (HBV) reactivation occurring during chemotherapy are
related to the late institution of lamivudine, raising the need for the
preemptive use of antiviral agents. Given the potential risk of
treatmentrelated hepatotoxicity and underlying cirrhosis in hepatocellular
carcicnoma (HCC) patients, the optimal therapeutic strategy and identification
of patients at risk for this complication should be made before transarterial
approach. The aim of this study was to evaluate the efficacy of preemptive
lamivudine therapy in reducing hepatic complications in patients with
HBV-related HCC undergoing transarterial chemo-lipiodolization (TAC), and to
seek predictors of the events.
Methods:
A prospective randomized study was conducted,
recruiting 73 consecutive HCC patients undergoing TAC using combined epirubicin
50 mg/m2 and cisplatin 60 mg/m2 at monthly intervals. Patients were randomly
assigned to receive lamivudine 100 mg daily before TAC (preemptive group) or
not (control group). Hepatitis due to HBV reactivation was defined as a 3-fold
or greater increase of serum ALT in patients with HBV reactivation (a 10-fold
increase of viral load). Virological test was serially done at monthly
intervals, and alanine aminotransferase (ALT) level was measured at biweekly
intervals.
Results:
During the study period, 11 (29.7%) of 37 patients in
the control group and 1 (2.8%) of 36 patients in the preemptive group developed
hepatitis due to HBV reactivation. There was a significantly more occurrence of
hepatitis due to HBV reactivation in the control group than in the preemptive
group (P=0.002). In addition, moderate (ALT >2´the upper limit of normal
[ULN]) or severe (ALT >5´ULN) grade of hepatitis of all causes were more
frequently observed in the control group as compared with the preemptive group
(51.4% vs. 27.8%, P=0.040), irrespective of viral reactivation. There was a
tendency towards more episodes of treatment disruptions in the control group
than in the preemptive group (40.5% vs. 22.2%, P=0.092). With multivariate Cox
regression model, baseline HBV DNA level of >104 copies/ml was independently
predictive of hepatitis due to HBV reactivation during TAC (P=0.046).
Conclusion:
This study provided support for the concept of
preemptive antiviral therapy during transarterial chemo-lipiodolization. The
preemptive use demonstrated an excellent efficacy of reducing HBV reactivation,
overall hepatic morbidity, and treatment disruptions in this setting. This
approach should be considered in all HCC patients with HBV DNA level of >104
copies/ml before transarterial chemotherapy.
Poster
1011
Abstract
ID: 66860
Category:
J1O: Hepatitis B: Treatment
MECHANISTIC BASIS FOR HEPATITIS B VIRUS RESISTANCE TO ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGUES, ADEFOVIR AND TENOFOVIR.
A.
Bartholomeusz, Victorian Infectious Diseases Reference Laboratory, North
Melbourne, Australia, S. Locarnini, Victorian Infectious Diseases Reference
Laboratory, North Melbourne, Australia, A. Ayres, Victorian Infectious Diseases
Reference Laboratory, North Melbourne, Australia, G. Thompson, Victorian
Infectious Diseases Reference Laboratory, North Melbourne, Australia, S.
Bowden, Victorian Infectious Diseases Reference Laboratory, North Melbourne,
Australia, V. Sozzi, Victorian Infectious Disease Reference Laboratory, North
Melbourne, Australia, P. Angus, Austin Hospital, Heidelberg, Australia, W.
Sievert, Monash Medical Centre, Clayton, Australia, J. Sasadeusz, Victorian
Infectious Diseases Service, Parkville, Australia, D. Chalmers, Victorian College
Pharmacy, Parkville, Australia, M. Kuiper, Victorian Partnership for Advanced
Computing, Carlton, B. Rodes, Hospital Carlos III, Madrid, Spain, J. Sheldon,
Hospital Carlos III, Madrid, Spain, V. Soriano, Hospital Carlos III, Madrid,
Background/Aims:
Patients with chronic
hepatitis B are being treated with Lamivudine (LMV) and/or Adefovir (ADV)
whilst patients co-infected with HBV and HIV can be treated with LMV and/or
Tenofovir (TDF) to control HBV replication. Resistance to ADV has been associated
with three clusters of mutations, (i) D and A domains of the HBV polymerase
(pol) which includes the mutation at rtN236T (ii) the B domain mutations at
rtA181T/V and (iii) the C-D interdomain mutations rtV214A, rtQ215S which are
distal to the active site. Resistance to TDF is associated with a mutation at
rtA194T in the B-C interdomain region. The aim of this study was to determine
the crossresistance profiles of these mutations in vitro and analyse the
molecular basis for resistance using molecular modelling.
Methods:
The ADV and TDF resistance
HBV mutations were created by site-directed mutagenesis in an HBV infectious
clone. In vitro phenotypic analysis of the HBV clones was performed by
transient transfection in the presence of ADV, or TDF or LMV using standard
techniques and the IC50 determined from dose-response curves using Table Curve
2D software [Hepatology. 2003;37:27]. A three dimensional model of the HBV pol
based on the HIV reverse transcriptase crystal structures was used to analyse the
HBV mutations.
Results:
In vitro antiviral testing
of the C-D interdomain HBV mutants demonstrated a 4 to 10 fold increase in IC50
to ADV consistent with drug resistance and also a 10 fold increase in IC50 to
LMV. HBV encoding the TDF resistance mutation at rtA194T showed a 7 fold
increase in IC50. Molecular modelling of the two groups of B-C and CD
interdomain mutations revealed that these mutations are in loop regions at the
opposite ends of the beta sheets that encompass the YMDD loop region. These two
interdomain regions appear to be involved in structural integrity of the
polymerase active site even though they are not located within the nucleotide
binding pocket, nor directly interacting with the DNA. Mutations in these
regions can result in conformational changes within the active site, affecting
the cross-sensitivity profile to a number of antiviral agents including LMV.
Conclusion:
We have identified two
distal regions in the HBV polymerase within the HBV polymerase that are
associated with potential multidrug resistance to the class of acyclic
phosphonate nucleoside analogues such as TDF and L-nucleoside analogues such as
LMV. Molecular modelling in association with in vitro testing can aid in
determining the significance of mutations in the context of chemical class
resistance and thus may aid in the choice of the next therapeutic agent.
Abstract ID: 67426
Category: LO1: Public Policy, Epidemiology, and Decision Analysis
Treatment Alternatives for Hepatitis B Cirrhosis: A Cost-Effectiveness Analysis.
F. Kanwal, West Los Angeles VA, Los Angeles, CA,
Los Angeles, CA, M. Farid,
Greater
Los Angeles Healthcare System at West LA, Los Angeles, CA, P. Martin,
Mount
Sinnai Medical School, New York, NY, G. Chen, Cedar Sinnai Medical Center,
Los
Angeles, CA, I. M. Gralnek, Greater Los Angeles Healthcare System at West LA,
Los
Angeles, CA, G. S. Dulai, David Geffen School of Medicine at UCLA, Los Angeles,
CA,
B. M. Spiegel, Greater Los Angeles Healthcare System at West LA, Los Angeles,
CA
Background:
Hepatitis B virus (HBV)
patients with cirrhosis are at high risk for developing costly, morbid, or
mortal events, and therefore require effective therapies. Lamivudine (LAM) is
effective in HBV cirrhosis but is associated with a high rate of viral
resistance. In contrast, newer agents like adefovir dipivoxil (ADV) and
entecavir (ETV) have less viral resistance, but are more expensive. Because
patients with cirrhosis can ill-afford the emergence of viral resistance and
potentially life-threatening viral flares, there is a delicate balance between
avoiding resistance and minimizing cost in the
treatment of HBV cirrhosis.
The most cost-effective approach is uncertain.
Methods:
We performed an economic
analysis to estimate the cost-effectiveness of four treatment strategies in a
hypothetical cohort of 50-year old patients with chronic HBV cirrhosis and
active viral replication: (1) No HBV treatment (“do nothing”), (2) LAM
monotherapy, (3) ADV monotherapy, or (4) LAM with cross-over to ADV upon
resistance (“ADV salvage”). In order to emulate the case-mix in clinical
practice, we included patients with compensated and decompensated cirrhosis.
Because there are currently limited data regarding ETV, we did not include this
agent in the primary
analysis. We instead performed
a hypothesis generating sensitivity analysis incorporating current drug prices
to estimate the potential cost-effectiveness of ETV. We incorporated
probability estimates derived from a systematic review, and adopted cost
estimates from a third party payer perspective. Monthly prices for LAM, ADV,
and ETV were $158, $528, and $720, respectively. The primary outcome was the
incremental cost per quality adjusted life-year (QALY) gained.
Results:
The “do nothing” strategy
was least effective yet least expensive. Compared
with “do nothing,” using ADV
cost an incremental $20,011 per QALY-gained. LAM monotherapy was more expensive
yet less effective than ADV. Compared with ADV, in turn, “ADV salvage” cost an
incremental $107,165. ADV monotherapy was the most cost-effective strategy in
HBV patients with both compensated and decompensated cirrhosis. ETV revealed
“diminishing returns” compared to ADV on the basis of the current 22% higher
cost of ETV.
Conclusions:
These data indicate that ADV
may be the most cost-effective strategy in
patients with HBV cirrhosis,
regardless of the stage of liver disease. Among the new generation of antiviral
agents for HBV, the least expensive agent is likely to remain the most
cost-effective. These findings should be confirmed in prospective clinical
trials that measure the accrued costs and effectiveness of competing agents in
HBV cirrhosis.
Abstract ID: 63446
Category: LO1: Public Policy, Epidemiology, and Decision Analysis
LONG-TERM TREATMENT WITH ADEFOVIR DIPIVOXIL IS MORE COST EFFECTIVE THAN LAMIVUDINE FOR HBeAg-NEGATIVE PATIENTS WITH CHRONIC HEPATITIS B.
M. Buti, Hospital General Universitari Vall
d'Hebron, Barcelona, Spain, M. A. Casado,
Pharmacoeconomics & Outcomes Research Iberia,
Pozuelo de Alarcón, Spain, J. L.
Calleja, Hospital Puerta Hierro, Madrid, Spain, J.
Salmerón, Hospital Clínico San
Cecilio, Granada, Spain, J. Aguilar, Hospital
Virgen del Rocio, Seville, Spain, M.
Rueda,
Gilead Sciences, Inc.,
Vall
d'Hebron, Barcelona,
Aim:
To estimate the
cost-effectiveness of long-term therapy with adefovir dipivoxil (ADV) or
lamivudine (LAM) as therapies for patients with HBeAg-negative chronic
hepatitis B (CHB).
Methods:
A decision analysis model
has been designed for a panel of experts to perform a cost effectiveness
analysis of LAM (100 mg/daily) and ADV (10 mg/daily) over three years of
therapy. Data for each strategy were obtained from published clinical trials.
Virological response was defined by undetectable HBV DNA. The study was
performed from the perspective of the Spanish Public Health System considering
the following direct health costs (in US$): drug acquisition, visits,
diagnostic or laboratory tests to determine virologic response and HBV drug
resistance.
Results:
The following table shows
the results of the base-case analysis (with a 3% annual discount for costs):
The costs associated with
three years therapy with ADV were 2.2 times greater than those of LAM.
Virological response achieved with ADV was 2.5 times greater than that of LAM.
Despite the higher costs associated with ADV, the incremental
cost-effectiveness ratio of ADv versus LAM was lower than the average
cost-effectiveness ratios of ADV or LAM. The sensitivity analysis demonstrated
the robustness of the model, being the response to ADV and LAM at year 3 the
factors that most influence the cost-effectiveness.
Conclusion:
Long-term treatment with ADV
is a cost-effective strategy in patients with chronic HBeAg-negative hepatitis.
Therefore, adefovir dipivoxil should be used as a first line treatment due to the
high percentage of virological response obtained at year 3 and because its cost
per responding patient is lower than that of LAM.