Tuesday
Posters: HBV May 23rd 8:00
AM-8:00 AM
H. Chae;
H. Hann
High incidence of viral BT has been the major
disadvantage of lamivudine (LAM) in the treatment of CHB. With the advent of
new antivirals, LAM may become less in demand as the first line drug.
Nevertheless, it is becoming increasingly clear that the management of CHB
requires a long term therapy and the cost of treatment becomes an important
issue for those with low income/without medical insurance. Therefore, in a
retrospective study, we investigated if there are factors most closely
associated with viral BT during LAM therapy, and thus, we could identify a
subgroup of patients (pts) who may still benefit from LAM without developing BT
at an early stage of treatment.
Materials
and Methods:
Of the CHB pts treated during the period of 2000-2004,
the study included only those; 1) who received LAM >12 months, 2) whose
baseline HBV DNA levels were ≥3 log (by PCR ) and 3) who showed optimal
response (HBV DNA decrease >2 log and/or HBV DNA < 4 log after 1 year
treatment). Viral BT was defined as > 1 log HBV DNA increase following the
initial viral suppression.
Results:
88 pts (59 males) met the eligibility criteria. They
were all Asian Americans, with the mean age of 46±12 years (yr). Of the 88 pts,
38 (43%) were infected at birth. The median duration of therapy was 25 (12-57)
months (mos). At baseline, median ALT was 66 IU/L
(11-3395), the mean log HBV DNA level for 88 pts was 6.1±1.6; for 39
HBeAg(+)pts was 6.6 ± 1.5 and for 45 HBeAg(-)pts, 5.6±1.5 (HBeAg data missing
in 4). The mean log reductions of HBV DNA from baseline for all pts were
3.7±2.1 at 6 mos, 4.1±2.1 at 1 yr, but 2.7±3.0 at 2
year due to the presence of BT in some patients. HBeAg loss was 17%, 23% and 28
% at yr 1, 2, and 3. Excluding those with normal or missing ALT, normalization
of ALT was 81% and 84% at 6 and 12 mos. The %BT for pts with HBV DNA >6 log
(n=40) was 10%, 30%, and 72% at yr 1, 2, and 3, and for pts with HBV DNA
≤ 6 log (n=41) %BT was 2%, 12% and 41% at yr 1, 2, and 3. When all
factors (gender, duration of infection, baseline HBV DNA, HBeAg status, and
baseline ALT) were analyzed by Cox regression, the most important factor
associated with viral BT was the baseline HBV DNA level. Pts with baseline HBV
DNA > 6 log had higher %BT than those with HBV DNA <6 log (p=0.04).
Conclusions:
Our study indicates that the most important factor
associated with the development of viral BT with LAM is the baseline HBV DNA
level regardless of HBeAg status. Therefore, pts with baseline HBV DNA level
≤ 6 log may benefit from LAM therapy. For CHB pts with low level of viral
replication, and with financial disadvantages, LAM may still remain an
affordable and effective therapy.
H. L. Hann;
H. Chae; S. R. Dunn
Patients with chronic hepatitis B (CHB) who developed
LAM resistance were treated with TNV or ADV. In some, LAM was continued or
added later. In this retrospective study we compared the suppressive activities
of TNV and ADV against LAM resistant HBV.
Materials
and Methods:
109 patients (86 M, 23 F), all Asian Americans except
1 Caucasian male, were included in the study. All had viral breakthrough during
LAM therapy and received TNV or ADV for ≥ 6 months (mos).
Reduction of HBV DNA and ALT normalization were assessed at 6 and 12 mos. HBeAg
loss was examined within 24 mos.
Results:
44 patients (37M, 7F) received TNV (12 with LAM) and
65 (49M, 16F) received ADV (18 with LAM). Median ages for TNV and ADV groups (grps) were 49 years (32-68) and 45 years (22-68)
respectively. Median duration of therapy was 13 mos
(ranges 6-38) for TNV grp and 17 mos
(ranges 6-34) for ADV grp. Baseline ALT levels (IU/L)
were 77.0 ± 86.2 and 100.4 ± 195.0 for TNV and ADV (P=0.46).
As shown in the table, baseline HBV DNA levels were
similar for both grps. Mean HBV DNA reduction (Log10
copies/ml) at 6 and 12 mos was stronger for TNV than
ADV. Viral reduction>3 log (at 12 mos) was greater
for TNV than ADV. HBeAg loss in 24 mos showed no
difference. ALT normalization (6 mos) was 55% and 66%
for TNV and ADV respectively. Using single factor, two-tailed ANOVA, 4 grps, TNV (n=32), TNV+LAM (n=12), ADV (n=47) and ADV+LAM
(n=18), were compared. There was no difference in 4 grps
with respect to the baseline DNA or baseline ALT. However, HBV DNA reduction at
6 mos was greater for TNV+LAM grp
than either ADV grps. Furthermore, no patient
developed viral breakthrough during the 6- 38 mos
observation period.
Conclusion:
Our results suggest that for LAM resistant HBV, TNV,
alone or combined with LAM exerts a greater viral reduction than ADV. However,
there is no difference in HBeAg loss or ALT normalization. It appears that
stronger HBV DNA reduction may not necessarily speed up the HBeAg loss. Viral
breakthrough appears low with TNV with or without LAM.
|
|
TNV |
ADV |
p
value |
|
No. Pts |
44 (12 with LAM) |
65 (18 with LAM) |
|
|
Duration of
Treatment |
13 mos (6-38) |
17 mos (6-34) |
|
|
Baseline HBV DNA
(log10 copies/ml) |
6.23+/-1.66 |
6.49+/-1.56 |
0.404 |
|
Mean HBV DNA log
reduction (6 mos) |
3.65+/-1.75 (n=30)
|
1.94+/-1.98 (n=45)
|
0.00 |
|
Mean HBV DNA log
reduction(12 mos) |
5.03+/-1.64 (n=15)
|
2.36+/-2.37 (n=42)
|
0.00 |
|
DNA reduction>3
log |
63% |
28% |
0.013 |
|
HBeAg loss (in 24 mos) |
4.5% (2/44) |
7.7% |
0.699 |
T1842. Predicting Liver Disease
Complications (Hcc And Cirrhosis) In Patients With Chronic Hepatitis B
Infection Using A Risk Function Model: The R.E.V.E.A.L.- HBV Study
C. Chen; H. Yang; U. H. Iloeje; C. Jen; S. You; Y. Liaw
Background
& Aims:
Predicting CHB patients at risk of progressing to
liver complications is a clinical challenge. Our objective was to develop a
prediction model using readily available non-invasive clinical information in
CHB infected subjects.
Methods:
Information from HBsAg-positive
(anti-HCV-negative) subjects recruited from 7 townships in Taiwan between 1991
and 1992 was used for these analyses. Subjects were randomized into two groups
(training and validation) on a 1:1 basis. HCC and cirrhosis cases were
ascertained via computerized linkage to the Taiwanese National Cancer Registry
and Death Certificates Profiles or by ultrasound examination. Additionally,
medical charts were reviewed using a structured abstraction form to confirm the
diagnoses. HCC was confirmed by one of the following: cyto-histopathology;
focal liver lesions by two coincident imaging studies (ultrasonography,
CT Scan, MRI and/or angiography); focal liver lesion on one imaging study and
an alpha fetoprotein (AFP) level >400 ng/mL.
Multivariate logistic regression models were used to identify the predictive
variables, and the model accuracy determined by the Area Under the Receiver
Operator Characteristic curves (AUROC).
Results:
N=3582/3653 without baseline cirrhosis were included.
The mean follow-up time was 11 years. The training set 1791/3582 (50%), was
comparable to the validation set for all variables and outcome events
(p>0.05). The best fitting models had Age and HBV DNA as the strongest
predictors of future liver complications. For HCC only model AUROC=0.8450;
concordant percent 96.4%; discordant percent 3.6%; model goodness of fit
p=0.49. The risk (OR [95% CI]) associated with age 60-65 was 17.5 [6.4-47.5]
[reference group 30-39]; and HBV DNA >= 105 copies/mL was 8.9[4-19.9]
[reference<300 copies/mL]. For HCC/cirrhosis model AUROC=0.7713; concordant
percent 88.5%; discordant percent 11.5%; model goodness of fit p=0.71. The risk
(OR [95% CI]) associated with age 60-65 was 4.3 [2.5-7.5] [reference group
30-39]; and HBV DNA >= 105 copies/mL was 4.9 [3.3-7.5] [reference <300
copies/mL]. AUROC in the validation group was 0.86 (HCC model); 0.79
(HCC/cirrhosis model).
Conclusion:
Risk stratification for liver disease complications in
CHB-infected persons is possible using a model comprised of readily available
non-invasive clinical information. This model may be useful in making
management decisions.
D. Kim; J. Lee; D. Lee; M. Choi; K. Koh; S. Paik; B. Yoo
Backgrounds
and Aims:
It is suggested that various mutations in the
hepatitis B virus (HBV) polymerase genes, such as rtA181V/T, rtN236T, and
rtP237H, could induce resistance to adefovir dipivoxil. A recent research has
reported that primary resistance to adefovir can occur as a consequence of a
long-term lamivudine treatment. The aim of this study was to elucidate the
incidence of primary resistance mutation to adefovir in patients with YMDD
mutation and to assess the clinical course of those patients.
Patients and
Methods:
A total of 293 patients with hepatitis B were
enrolled. In those patients, lamivudine had been switched to adefovir because
of YMDD mutation and lamivudine resistance. Twenty-eight patients (13 with
prior lamivudine use) without YMDD mutation were selected as controls. Serum
samples were obtained before commencement of adefovir therapy. Adefovir
resistance mutations were screened by restriction fragment mass polymorphism
(RFMP) for rt181, rt236, rt237 and rt238 and confirmed by direct sequencing of
the HBV polymerase gene.
Results:
Out of the included patients, 11 patients (3.7%) were
found to have primary adefovir resistance mutation (rtA181V/T in 2 and rtP237H
in 9 patients). None of the control patients was found to have any adefovir
resistance mutation. During a median follow-up of 14 months (9-25 months) after
initiation of adefovir therapy, alanine aminotransferase (ALT) levels decreased
to below upper normal limit and remained normal (23±9 IU/L) in all patients.
HBV DNA levels decreased to undetectable level (<0.5 pg/ml by Digene Hybrid Capture Assay II) and remained undetectable
in all patients except in one patient in whom the lowest level was 13.7 pg/ml.
There were no significant differences in the duration of lamivudine use,
pretreatment ALT levels, pretreatment HBV DNA levels, and frequency of
pretreatment HBeAg positivity between the patients
who developed a resistance mutation and those who did not (p>0.05).
Conclusion:
The incidence of primary adefovir resistant mutation
was 3.7% in patients with YMDD mutation and resistance to lamivudine. Although
phenotypic resistance was rare among the patients with primary resistance
mutation in a short-term follow-up, long-term observation may be required to clarify
the clinical significance of those mutations.
T. Chang; M. L. Shiffman; M. Tong; Y. Liaw; P. Komolmit; J. Sorbel; S. Arterburn; E. Mondou; S. Chuck;
P. Marcellin
Background
and aims:
HBeAg seroconversion (HBeAg loss with development of
anti-HBe) has been considered an important
therapeutic marker in the treatment of CHB in HBeAg+ patients. Study 481
evaluated the durability of seroconversion following adefovir dipivoxil (ADV)
treatment.
Methods:
Study 481 enrolled CHB patients with compensated liver
function who had confirmed seroconversion to anti-HBe
and HBV DNA < 100,000 copies/mL by Roche Amplicor
PCR assay during treatment with adefovir dipivoxil 10 mg once daily. Patients
were followed off treatment with serologic assessments at least every 24 weeks.
Results:
At entry (n=45) median age was 34 years, 64% male, 73%
Asian, 27% Caucasian, median serum HBV DNA 3.00 log copies/mL (min-max, 2.6,
3.2), and median ALT 25 IU/L (min-max, 9,110). Median duration of ADV treatment
before seroconversion was 54.4 weeks (Q1, Q3; 24.1, 75.4) and after
seroconversion was 37 weeks (Q1, Q3; 27.0, 72.1). Median follow-up off drug was
143 weeks (Q1, Q3, 110, 193; range 13-245). Four patients (9%) did not maintain
seroconversion at follow-up weeks 12 (n=3) and 16 (n=1) (at the time of seroreversion all had HBV DNA >100,000 copies/mL; ALT
84-222 IU/L). Forty-one patients (91%) maintained durable seroconversion at the
last 2 assessments and most were followed for several years: 15 (37%) for 2-3
years and 19 (46%) for over 3 years. There was no difference in entry
characteristics (serum HBV DNA, ALT, age, gender) for patients with and without
durable seroconversion. Median duration of ADV treatment before seroconversion
was longer (108 versus 48 weeks) for patients who seroreverted.
Seroreverters received less ADV after seroconversion
than those with durable seroconversion (median 22 versus 41 weeks). All 4 seroreverters were Asian and all had HBV genotype C. The
distribution of genotype among durable seroconverters
was 10 A; 9 B; 17 C; 4 D; 1 G. For all patients, the median HBV DNA at the last
timepoint off drug was 3.04 log copies/mL (Q1, Q3;
3.00, 4.15; 44% < 1000 copies/mL), and median absolute ALT was 28 IU/mL (Q1,
Q3; 21, 41).
Conclusions:
Seroconversion to anti-HBe
was durable off ADV treatment in 91% of patients over a median follow-up of 3
years. Four patients (9%) lost seroconversion and reverted to HBeAg+ within 16
weeks of the end of treatment; these 4 patients were genotype C and received
less ADV after seroconversion (maximum 32 weeks) than patients with durable
seroconversion.
T1845. Entecavir (Etv) Is Associated With An Improvement In
Liver Histology And A Reduction In Hbv Dna In Patients With Lamivudine-Refractory Hbeag(+) Regardless Of Baseline Characteristics
M. L. Shiffman;
Z. Goodman; P. J. Paul; T. D. Boyer; M. Sherman; Y. Batur;
A. Boron-Kaczmarska; J. Vaughan; R. G. Hindes
Background:
In a recently conducted prospective, randomized
controlled trial patients with lamivudine (LVD)-refractory (LVDR) chronic HBV
were treated with entecavir (ETV) or remained on LVD for at least 48 weeks. At
Week 48, ETV treatment resulted in an HBV DNA reduction of 5.11 log10 copies/mL
versus 0.48 log10 copies/mL for LVD, while histologic
improvement occurred in 55% of ETV and 28% of LVD patients. The present
analysis evaluates whether baseline factors are predictive of response to
ETV/LVD at 48 weeks.
Methods:
All patients with LVDR enrolled in this trial were
analyzed according to whether they developed histologic
improvement and/or HBV DNA <300 copies/mL. The relationship between efficacy
results and baseline disease and demographic subgroups was then assessed.
Disease-related variables included baseline ALT, HBV DNA, and HBV genotype.
Demographic variables included geographic region, race, age and gender. Histologic improvement was defined as a ≥2-point
decrease in Knodell necroinflammatory score and no
worsening of fibrosis (worsening: ≥1-point increase in Knodell fibrosis
score).
Results:
No relationship between patient demographic variables
and disease-related variables existed with respect to either histologic or virologic response to ETV.
Conclusions:
The proportion of patients with LVDR who exhibit histologic improvement and HBV DNA <300 copies/mL is
significantly greater when converted to ETV as opposed to remaining on LVDR.
Such improvement occurs in patient groups regardless of demographic
characteristics, HBV genotype and the serum level of ALT or HBV DNA.
|
|
Histologic Improvement |
HBV DNA <300 copies/mL |
||
|
Baseline Variable |
ETV n (%) |
LVD n (%) |
ETV n (%) |
LVD n (%) |
|
HBV Genotype |
18/33 (55) |
7/28 (25) |
12/37 (32) |
0/32 (0) |
|
ALT |
27/58 (47) |
17/59 (29) |
8/66 (12) |
0/76 (0) |
|
HBV DNA |
8/11 (73) |
5/9 (56) |
9/22 (41)‡ |
0/25(0)‡ |
|
‡<108 copies/mL
HBV DNA |
||||
T1846. Hepatitis B screening and prevention
- Is our knowledge adequate for the future?
A. Barmaki;
R. Shandil; S. Mohanty; A. Sahota
BACKGROUND:
There are more than 1.25 million carriers of the
Hepatitis B virus (HBV) in the United States, with an increased prevalence in
populations with high-risk behaviors as well as specific ethnic subgroups from
high endemic areas. Primary care physicians (PCP) are the first to encounter
these patients and it is their duty to manage them appropriately. Multiple
studies have assessed PCP's knowledge on hepatitis C, but none exist for HBV.
AIM/METHODS:
To determine internal medicine residents' practice
knowledge on HBV screening, evaluation and prevention a survey was administered
to members of a large university-based residency program.
RESULTS:
Eighty one (51%) out of 160 residents completed the
survey, with an equal representation from each post graduate year; 70% were US
graduates and 42% had managed more than 10 patients with HBV over the last
year. Table 1 reflects HBV screening knowledge of internal medicine residents
and Table 2 represents their vaccination knowledge. Only 48% of residents would
vaccinate HBV infected patients for hepatitis A virus (HAV). 64% of residents
knew the vaccination schedule for HBV and 37% for HAV. Although there is no
vaccine for hepatitis C, 15% of residents replied they would vaccinate for it.
Only 58% of residents correctly identified anti-HBs
as the serological marker to be tested in patients vaccinated for HBV. In
patients with chronic HBV, 44% of residents would not screen for co-infection
with HCV, 38% would not check HBeAg and 62% would not check for HBeAb.
CONCLUSIONS:
We conclude that hepatitis B knowledge for early
screening/evaluation is inadequate among internal medicine physicians in
training. Future primary care providers should receive increased focused
educational intervention on HBV to improve quality of care.
|
Undertested population |
Overtested population |
|
Pregnant females-
42% |
History of blood
transfusion in 1990- 42% |
|
Multiple tattoos-
38% |
Immigrants from
Japan- 42% |
|
Immigrants from
Korea- 38% |
History of alcohol
abuse- 28% |
|
Homosexual men- 37% |
Everyone- 6% |
|
Mother with
hepatitis B- 30% |
|
|
IV drug abuse- 20% |
|
|
HIV- 14% |
|
|
Undervaccinated population |
Overvaccinated population |
|
Household members of
HBV infected patients- 41% |
Patients with
congestive heart failure- 20% |
|
Hemodialysis
patients- 28% |
Every patient- 14% |
|
Newborns of HBV
mothers- 16% |
|
|
Healthcare workers-
6% |
|
E. Bridges
Background:
Telbivudine is a novel nucleoside presently undergoing
phase III clinical evaluation for the treatment of chronic hepatitis B. A
series of preclinical studies were undertaken to support clinical development
of this agent, including chronic toxicity, carcinogenic potential, and
reproductive toxicity. In these studies, telbivudine was investigated in large
multiples of the human clinical maximum plasma concentrations (Cmax) and total exposure (area under the curve, AUC)
achieved at the recommended human dose, 600 mg/day.
Methods
& Results:
Chronic toxicologic studies
were conducted over 6 months in rats, and 9 months in cynomolgus
monkeys, with oral telbivudine doses of 0, 250, 500 and 1000 mg/kg/day. There
were no telbivudine-related effects on physiology in either species. The
no-observed-adverse-effect level for chronic dosing was considered to be 1000
mg/kg/day (10x Cmax, 6-8x AUC) in both species.
In a 2-year carcinogenicity study, Sprague-Dawley rats were dosed orally with telbivudine at 0, 500,
1000, or 2000 mg/kg/day. There was no evidence of oncogenicity
in rats treated with telbivudine at dosages up to 2000 mg/kg/day (15x Cmax, 14x AUC) for ≥85 weeks.
Carcinogenicity was also evaluated in CB6F1-TgrasH2
transgenic-mice after 26 weeks of telbivudine doses of 0, 500, 1000 or 2000
mg/kg/day. No differences were found in the incidence of neoplastic
or non-neoplastic changes, comparing the high-dose
(2000 mg/kg; 31x Cmax, 14x AUC) group and control.
Developmental and reproductive toxicity was evaluated
in ICH-recommended assays in rats and rabbits. No significant effects were
observed in general reproductive fertility in rats treated with 2000 mg/kg/day
(15 xCmax, 14x AUC). No effects on embryo-fetal or
postnatal development were observed in rats and rabbits treated with 1000
mg/kg/day (10-19x Cmax, 6-37x AUC).
Conclusions:
Large multiples of anticipated telbivudine exposure in
humans were evaluated for chronic toxicity, carcinogenicity, and reproductive
and developmental toxicity and shown to have no significant toxic effects in
relevant animal models, suggesting minimal risk for cumulative toxicity,
carcinogenicity, or reproductive toxicity in humans.
D. L. Veenstra;
U. H. Iloeje; E. Tafesse;
S. D. Sullivan; A. Cross; A. M. Di Bisceglie; R. G. Gish
Background
and Aims:
The objective of this study was to evaluate the impact
of HBeAg seroconversion and viral suppression on the relative
cost-effectiveness of antiviral therapies for HBeAg-positive chronic hepatitis
B.
Methods:
We enhanced a previously validated disease simulation
model to include assessment of the impact of HBV DNA viral load on disease
progression. The model included 14 distinct health states, which were used to
track clinical outcomes such as HBeAg and HBsAg
seroconversion, drug resistance, disease progression, and death. Patients with
drug resistance were switched to salvage therapy. A lifetime analysis was
conducted from a US payer perspective. Efficacy data were derived only from
randomized controlled clinical trials. The risk of cirrhosis based on HBV DNA
viral load was derived from a population-based prospective cohort study of
3,582 untreated hepatitis B infected patients (the R.E.V.E.A.L.-HBV Study).
One-way and probabilistic sensitivity analyses were conducted to evaluate
uncertainty in the analyses.
Results:
Assessment of patients who did not seroconvert HBeAg
but achieved complete (PCR negative) on-treatment viral suppression (48% of
entecavir, 20% of lamivudine, and 9% of adefovir patients in year 1) increased
the difference in life expectancy in an RCT-based analysis of 2-year entecavir
vs. lamivudine treatment from 0.54 to 0.79 years per patient treated compared
to evaluation of seroconversion only. Total discounted healthcare costs decreased
from $3,574 to $3,245, and the discounted incremental cost-effectiveness ratio
(ICER) decreased from $10,911 to $7,264 per quality-adjusted life-year (QALY).
An analysis of 2-yr entecavir vs. adefovir treatment showed an increase in the
difference in life expectancy from 0.16 to 0.43 years and a decrease in the
ICER from $10,474/QALY to $3,050/QALY. In a projected analysis of 4-year
entecavir vs. lamivudine treatment, the difference in life expectancy increased
from 0.84 to 1.56 years, and the ICER was $4,214/QALY.
Conclusions:
Our results indicate entecavir is cost-effective
compared to either lamivudine or adefovir, and that both seroconversion and
complete viral suppression have an important impact on the long-term outcomes
of HBV anti-viral therapy. Our analysis also highlights the importance of using
randomized controlled clinical trial data to appropriately assess the
cost-effectiveness of chronic HBV treatments.
T1850. Lamivudine Monotherapy In Hbeag-Negative Chronic Hepatitis B: Prediction
Of Response-Breakthrough And Long-Term Clinical Outcome
S. Manolakopoulos;
S. Bethanis; J. Elefsiniotis;
S. Karatapanis; C. Triantos;
G. Sourvinos; G. Touloumi;
M. Economou; J. Vlachogiannakos;
D. Spandidos; A. Avgerinos; D. Tzourmakliotis
Objectives:
The aim of this study was to determine the factors and
characteristics associated with initial response, virological breakthrough
(VBR) and biochemical breakthrough (BBR) in patients with HBeAg-negative CHB
receiving long-term lamivudine.
Methods:
This retrospective study included 79 (M/F=64/15)
consecutive adult patients with HBeAg-negative CHB who started lamivudine
monotherapy 100mg daily between March 1999 and September 2003 at four centers
in Greece. They were followed up until March 2004. Virological response was
considered the clearance of serum HBV DNA by PCR assay and biochemical response
as the decline of transaminase levels within normal
range. VBR was considered as the reappearance of HBV DNA by PCR after initial
response and BBR as the increase of AST/ALT levels to >1.5 ULN after initial
biochemical response. The parameters examined at Cox proportional hazards model
included: gender, age, past history of interferon-α treatment, transaminase levels, HBV DNA, BMI, necroinflammation
and fibrosis, genotype, changes in precore and core
variants and HBV DNA at 6 months of therapy.
Results:
The median duration of lamivudine monotherapy was
31(range 6-56) months. 27 patients had baseline cirrhosis. Initial virologic
and biochemical response was observed in 73 (92.4%) and 70 (88.6%) patients
respectively, while 34 (46.6%) and 15 (20.5%) patients developed VBR and BBR
respectively. High levels of necroinflammation in
biopsy were associated with a higher probability of initial virological and
biochemical response. Patients with pretreatment serum HBV DNA of more than
1.000.000 copies/ml were 3.2 (1.47-6.95, p=0.003) times more likely to develop
VBR. 46% of the patients with BBR had transaminase>3ULN
after a median of 18 months from initial biochemical response. One patient
developed HCC. Two patients died, one with baseline cirrhosis due to liver
failure during breakthrough.
Conclusion:
In HBeAg-negative CHB, initial response to lamivudine
therapy is associated with necroinflammation, while
baseline serum HBV DNA exceeding 1.000.000 copies/ml is a strong predictor for
breakthrough due to drug-resistant mutations. Severe complications are uncommon
and are associated with BBR and pre-existing cirrhosis.
F. Poordad;
D. T. Dieterich; A. D. Min; D. Shouval;
C. Lai; H. Cheinquer; T. Chang; R. Zink; J. Zhu; H.
Brett-Smith
Background:
Entecavir (ETV) demonstrated superior virologic,
biochemical and histologic benefit compared to
lamivudine (LVD) at Week 48 in HBeAg(-) chronic hepatitis B (CHB) patients. HBV
DNA suppression to <300 copies/mL occurred in 90% of ETV patients and 72% of
LVD patients. Efficacy and safety through 96-weeks of treatment is reported
here.
Methods:
638 HBeAg(-) CHB patients were randomized 1:1 and
treated with ETV 0.5 mg (N=325) or LVD 100 mg (N=313) for 1 year. At Week 52,
patient management decisions were made based on Week 48 laboratory results: 85%
(275/325) of ETV patients and 78% (245/313) of LVD patients achieved Response
(HBV DNA <0.7 MEq/mL by bDNA assay and ALT
<1.25 x ULN) and discontinued therapy. Non-responders (HBV DNA ≥0.7 MEq/mL) also discontinued therapy (3 ETV and 18 LVD
patients). Eleven percent in both treatment groups (ETV 34/325, LVD 34/313)
achieved Virologic Response (HBV DNA <0.7 MEq/mL
but ALT ≥1.25 x ULN) and continued blinded therapy through Week 96.
Efficacy and safety were evaluated at end of dosing.
Results:
26 ETV and 28 LVD patients continued to a second year
of therapy. Of these, 96% of ETV-treated and 64% of LVD-treated patients
maintained Virologic Response (HBV DNA <300 copies/mL by PCR) at end of
dosing. 88% of ETV patients and 81% of LVD-treated patients had both HBV DNA
<0.7 MEq/mL by bDNA assay and ALT <1.25 x ULN.
Safety profile for ETV was comparable to LVD.
Conclusions:
In HBeAg(-) CHB patients, treatment with ETV 0.5 mg up
to 96 weeks results in a significantly better viral load reduction than LVD,
with 96% of patients maintaining this end point through a second year of
treatment and with a comparable safety profile to LVD.
|
||||||||||||||||
T1852. Nitazoxanide in Treating Chronic Hepatitis B: In vitro
Activity and a Clinical Case Report
J. Rossignol;
B. E. Korba; S. M. Kabil
Nitazoxanide is an anti-infective drug
from a new class called the thiazolides. It is
marketed in the United States for treating gastroenteritis caused by
Cryptosporidium parvum and Giardia
lamblia and is in late stages of development for
treating Clostridium difficile-associated disease.
Based on earlier screening suggesting antiviral properties of the thiazolides, we tested nitazoxanide
and its active circulating metabolite, tizoxanide,
against hepatitis B virus in cell cultures. We also report the results of a
patient with chronic hepatitis B treated with nitazoxanide
after previously failing a long course of lamivudine.
Methods.
Nitazoxanide, tizoxanide
and lamivudine were evaluated for activity against hepatitis B virus in 2.2.15
cell cultures. A 48 year-old Egyptian male with chronic hepatitis B refractory
to lamivudine was treated with nitazoxanide. He was
HBeAg-positive before treatment with a viral load of 5,250,000 copies per mm3
and ALT of 53. Nitazoxanide was administered by oral
route, 500 mg twice daily with food for 24 weeks, and the patient was evaluated
every 4 weeks during treatment. Evaluations included physical examination,
laboratory safety tests and RT PCR for quantitation
of HBV DNA.
Results.
The activity of nitazoxanide,
tizoxanide and lamivudine against HBV replication in
2.2.15 cell cultures is presented below:
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