Topic Forum - Posters – Tuesday May 23, 2006 2:15 – 3:45PM
Hepatitis C
HCV Treatment II
B. J. Veldt; E. . Heathcote; H.
Wedemeyer; J. Reichen; W. Hofmann; S. Zeuzem; M. P. Manns; B. E. Hansen; S. W.
Schalm; H. L. Janssen
Introduction:
Patients with chronic hepatitis C may
develop decompensated liver disease and hepatocellular carcinoma (HCC). This
risk is highest in patients with advanced fibrosis. Treatment with interferon
or pegylated interferon may lead to sustained virological response (SVR), which
means undetectable virus at six months after treatment. However, it remains
uncertain whether sustained responders have a better clinical outcome than
non-responders.
Aim:
To investigate whether SVR leads to
an improved clinical outcome in Western patients with hepatitis C and advanced
fibrosis.
Methods:
Retrospective international
multicenter cohort study.
Results:
We included 541 patients with
advanced fibrosis/cirrhosis (Ishak 4-6), with a mean follow-up of 3.3 years.
Three hundred fifty-eight patients had received interferon ± ribavirin and 276
had followed a treatment-regimen containing pegylated interferon. Seventy-one
percent were non-responders (NR) and 29% achieved SVR.
In multiple regression analysis,
genotype 1 and previous non-response were associated with a smaller probability
of achieving an SVR, whereas higher pre-treatment albumin levels and treatment
with pegylated interferon were associated with a higher probability of
achieving SVR.
The five-year occurrence of hepatic
failure and HCC was 0% and 5.6% (95% CI 0.0-12.1) among sustained responders
versus 12.2% (95% CI 8.1-16.3) and 8.2% (95% CI 4.4-11.9) among NR (p<0.01
for liver failure and p=0.04 for HCC). The five-year occurrence of
liver-related death was 2.4% (95% CI 0.0-7.1) among sustained responders and
10.1% (95% CI 6.0-14.3) among NR (p<0.01).
Time dependent Cox regression
analysis showed that non-response, old age, high pre-treatment bilirubin, low
albumin levels and low platelet counts are independently associated with the
development of clinical events during follow-up.
Conclusion:
SVR to (peg)interferon treatment
leads to an improved clinical outcome in patients with hepatitis C and advanced
fibrosis.
V. Buckwold; J. Wei; Z. Huang; C.
Huang; A. Nalca; J. Wells; J. Russell; W. Lang; C. Scribner; D. Blanchett; T.
Alessi; P. Langecker
Background
The fully-glycosylated human omega
interferon produced from CHO-SS cells (IFN-ω) has been shown to be
well-tolerated and to induce a sustained virologic response in patients
infected with HCV genotypes 1, 2 and 3. Here we describe the in vitro antiviral
activity of IFN-ω in comparison to other human interferons (IFNs) against
HCV RNA replicons and related viruses.
Methods
The antiviral activity of human
IFN-α, -β, -γ and -ω was assessed using bovine viral
diarrhea virus (BVDV) and yellow fever virus (YFV). IFN-α and -ω were
examined using West Nile virus (WNV) and HCV RNA replicons, and the bacterial
recombinant IFN-ω (bIFN-ω) was also tested using HCV RNA replicons.
Drug combination analysis of IFN-ω-ribavirin (RBV) was performed using
BVDV and HCV RNA replicons. Transcription factor (TF) profiling was undertaken
to compare 243 TF proteins when HCV RNA replicon-containing Huh7 cells were
exposed to either IFN-α or -ω.
Results
IFN-ω was the most potent IFN
tested. It was found to be 15-fold, 8.8-fold and 7.0-fold more potent than
IFN-α against BVDV, YFV and WNV, respectively. With HCV RNA replicons,
bIFN-ω was comparable in activity to IFN-α (EC50 = 0.20 IU/ml vs.
0.32 IU/ml, respectively), while IFN-ω was 68-fold more potent (EC50 =
0.0047 IU/ml). Drug combination analysis of IFN-ω-RBV in BVDV showed a
synergy of antiviral effects similar to IFN-α-RBV at clinically relevant
concentrations, as well as a unique antagonism of RBV cytotoxic effects by
IFN-ω. Preliminary drug combination analysis of IFN-ω-RBV using HCV
RNA replicons revealed an identical pattern to IFN-α-RBV. TF profiling
indicated that IFN-α upregulated 20 TF proteins. IFN-ω upregulated a
total of 56 TFs, 17 of which were the same as IFN-α. No TFs were
repressed.
Conclusions
IFN-ω was the most potent
antiviral agent of all the IFNs tested. The clear difference in antiviral
activity between bIFN-ω and IFN-ω indicates that glycosylation has an
important effect on its activity. The combination behavior of IFN-ω-RBV
was similar to that of IFN-α-RBV. TF profiling indicates that in addition
to the same set of TFs that IFN-α induced, IFN-ω also activated other
unique TFs, which might be in part responsible for its high potency.
J. Douglass; C. Qualls; C.
Wiggins; J. Dunkelberg; S. Arora
Background:
Ethnicity has been shown to be an important factor in
chronic hepatitis C virus (HCV) therapy. Previous studies have suggested
Hispanic patients have increased treatment discontinuation rates (Cheung RC,
2005) and a nonsignificant trend to lower treatment response when compared to
Non Hispanic Whites (NHW).
AIMS: 1) To determine whether patients of Hispanic
compared to NHW ethnicity with chronic HCV infection have a lower sustained
virologic response (SVR) to pegylated interferon and ribavirin. 2) To determine
the HCV genotype distribution, pretreatment viral load, and treatment
discontinuation rates in Hispanic compared to NHW patients.
Patients and
Methods:
We conducted a retrospective review of the cohort of
all treatment naïve Hispanic and NHW patients with chronic HCV infection at the
University of New Mexico Hospital (n=181) and the Albuquerque Veterans
Administration Hospital (n=83) who have received treatment including 6 months
post therapy with pegylated interferon and ribavirin between 10/2001 and
11/2005. An intention to treat statistical analysis included t-test, Fisher’s
exact test, and logistic regression. A sample size of 258 patients divided
approximately equally between Hispanics and NHWs was adequate to detect a 33%
difference in SVR with an 80% power and an alpha of 0.05.
Results:
Hispanics (n=116) when compared to NHW (n=148) were
similar in age (mean 48.4 +/- 8.8 vs. 48.6 +/-7.5), female gender (42% vs. 32%,
p=.12), body mass index (27.5 vs. 28), and in HCV genotype distribution 1 or 4
(65% vs. 58%), and 2 or 3 (35% vs. 42%). There was no difference in
pretreatment HCV viral load. Pretreatment labs were similar including platelet
count (196 vs. 200 thousand), hematocrit (44.9 vs. 44.9), white blood count
(6.6 vs. 6.8 thousand), and iron percent saturation (34.5% vs. 34.2%). Overall
SVR across genotypes was similar (36.5% vs. 47.3%, p=.10). SVR in genotype 1 or
4 patients was (33% vs. 30%, p=NS). Hispanic genotype 2 or 3 patients had a
lower SVR (42.5% vs. 71%, p=.007). Overall treatment discontinuation rates were
similar (33% vs. 24%, p=.10). In multivariate analysis treatment
discontinuation was the largest predictor of treatment failure (p<.001).
After excluding patients with treatment discontinuation, Hispanic ethnicity
continued to be an independent predictor of lower sustained virologic response
in genotype 2 or 3 patients (59% vs. 86%, p=. 01).
Conclusions:
Hispanic patients with genotype 2 or 3 chronic HCV
infection have lower rates of SVR to treatment with pegylated interferon and
ribavirin. This difference in SVR was not explained by early treatment
discontinuation.
K. Inoue; M. Yamada; T. Watanabe;
H. Yasuda; M. Yoshiba
Purpose:
Persistent infection is a distinguishing feature of
hepatitis C virus (HCV). HCV is able to successfully counter host immunity in
ways that make it easy to establish its persistence. A crucial strategy against
innate immunity is impairment of the IRF-3-IFN-beta induction pathway, in which
HCV impairs the function of IRF-3 and suppresses the induction of IFN system.
IFN-beta accumulation in the liver to a greater extent than that of IFN-alpha
and its half-life is short. We also recently discovered the unique anti-HCV
effect of cyclosporine A (CsA) and reported the effectiveness of IFN-combined
CsA treatment. Taking these previous findings into consideration, we adopted
divided administration of IFN-beta-combined cyclosporine A as an induction
therapy.
Method:
Patients (n= 67;genotype1b 52, genotype2a 15) were
enrolled into the present study to confirm the efficacy, safety and
tolerability of the new treatment. All the patients had serum HCV RNA level
above 100 KIU/ml (median: 1750 KIU/ml (420-15000 KIU/ml)), and liver biopsy
proven chronic hepatitis. The treatments consisted of an induction therapy, an
intensified therapy and a maintenance therapy. The induction therapy comprised
1 MU IFN beta every 4 hours for the first 3 days, 1.5 MU IFN beta every 6 hours
for the next 4 days and 2 MU IFN beta every 8 hours for the following 3 weeks.
The intensified therapy was induction therapy shortened to 2 weeks. The
maintenance therapy comprised repeated intramuscular administration of 6 MU IFN
alpha 2b 3 times weekly for 3 months. CsA (Neoral) was given 4 times daily for
a total dose of 200 mg during the induction and the intensified therapies.
Ribavirin was given twice daily for a total dose of 800 mg (body weight over 60
kg) or a total dose of 600 mg (less than 60 kg) during the maintenance therapy.
Results:
Of the 52 patients with genotype 1b, disappearance of
serum HCV RNA during the induction therapy was 71.2% (37/52), the end treatment
response (ETR) was 84.6(44/52) and sustained virological response (SVR) rate
was 73.1% (38/52). Of 15 patients with genotype 2a, disappearance of serum HCV
RNA during the induction therapy was 100% (15/15), ETR rate was 100% (15/15)
and SVR rate was 93.3%(14/15). Safety analysis showed that all adverse effects
were completely reversible.
Conclusion:
Our present study indicates that the induction therapy
which encounters persistence of HCV achieve better therapeutic effect than the
conventional one.
N. Afdhal; I. Jacobsen; R. Brown; B. Freilich; J.
Santoro; L. Griffel; C. Brass; T. Win-R study group
Fibrosis is a predictor of sustained virological
response (SVR) in hepatitis C (HCV). The majority of prior studies do not
involve enough patients with cirrhosis to truly define the contribution of
advanced fibrosis to SVR and nearly all combine Stage 3 and Stage 4 in their
analyses.
Aims:
To analyze the effect of fibrosis on SVR in the Win-R
trial of 4913 patients receiving PEG-IFN alfa 2b and ribavirin (RBV: fixed dose
FD 800mg or Weight based WBD 800 – 1400mg daily).
Methods:
Fibrosis stage was obtained on biopsies within 3 years
of randomization using the Metavir scoring system by local pathologists. SVR
was determined by PCR negativity (<29 IU/ml) 24 weeks after treatment was
stopped. The effect of Metavir stage 0 – 2 versus 3 - 4 on SVR for each
treatment group was determined as in prior studies. Only patients with weight
> 65kg were included in this anlysis ( n = 4223). The effect of each
individual fibrosis stage on SVR was determined by logistic regression for all
patients (n = 4913) regardless of treatment group.
Patients And
Results:
The distribution of fibrosis score was as follows;
Stage 0 = 654; stage 1 = 1460; Stage 2 = 1324; Stage 3 = 975; Stage 4 = 500.
SVR was no different between WBD (657/1464; 45%) and FD 611/1445; 42%) RBV in
patients with stage 0 – 2 fibrosis. However SVR in stage 3 to 4 was
significantly increased in the WBD group ( 282 / 657; 43%) compared to the FD
group ( 242 / 657; 37%); p = 0.02. In the entire population of patients
logistic regression showed no statistically significant difference in SVR rates
between Stage 0 (44%), Stage 1 (46%), Stage 2 (44%) and Stage 3 (44%). However
all stages were significantly superior to Stage 4 which only had an SVR of 34%
(OR between 1.513 – 1.628 for all groups versus cirrhosis Stage 4; p <
0.0001).
Conclusion:
WBD of RBV is important to increase SVR in patients
with more advanced stages of liver disease. However, overall only cirrhosis is
a negative predictor of SVR when individual fibrosis stage and SVR is
evaluated. The cirrhotic patient represents a difficult to treat patient
requiring optimal therapy including weight based RBV.
Win-R trial was supported
by Schering-Plough
S. Rhodes; H. Erlich; K. Im; J.
Wang; J. Li; T. Bugawan; L. Jeffers; X. Tong; X. Su; L. J. Lee; T. Liang; H.
Yang
Background:
Responses to interferon therapy for hepatitis C virus
(HCV) infection differ between Caucasian (CA) and African Americans (AA) which
implies a role for host genetic factors. Major histocompatibility complex (MHC)
activity is thought to be associated with response to HCV and some MHC alleles
appear associated with self-limited infections. The role of MHC in host
response to therapy is less clear, possibly due to small sample sizes in many
studies. To date there have been no reports on MHC genes and response to
therapy in AA.
Aim:
Our aim is to evaluate the relationship between HLA
alleles and sustained virologic response (SVR) to pegylated interferon plus
ribavirin (PEG+Rb) in a large cohort of CA and AA HCV patients.
Methods:
The Virahep-C study treated 401 HCV infected patients with
PEG+Rb for 24 weeks. Participants HCV-RNA negative at week 24 continued on
therapy for another 24 weeks and were followed to determine SVR (PCR negative
for HCV-RNA at week 72). Genotyping of Class I and II HLA genes was performed
by Roche HLA linear array typing system on 373 participants who consented to
host genetics studies (194/205 CA, 179/196 AA). Alleles with a frequency of 5%
or greater in one racial group and a p-value <0.05 in race-adjusted carrier
analysis were selected for inclusion in regression modeling. A modified Poisson
regression model adjusting for age, gender, race, baseline viral load, Ishak
score, dose received and other alleles provided relative risks.
Results:
An association between the A*02 allele and SVR was
found in univariate analysis of CA (p=0.005) and in race-adjusted analysis
(p=0.003). B*58 and DPB*1701 were associated with SVR in univariate analysis of
AA (p=0.007, p=0.02, respectively) and in race-adjusted analysis (p=0.003,
p=0.008, respectively). All three alleles, when fitted simultaneously in
multivariable regression model, were independently associated with SVR (Table).
Conclusions:
The A*02, B*58 and DPB*1701 alleles are independently
associated with SVR to PEG+Rb therapy. However, these HLA alleles could not explain
the observed racial difference in SVR. The HLA A*02 allele was previously
reported to be associated with self-limited infection in CA population. The
B*58 and DPB*1701 associations, not previously reported, are mainly driven by
AA population which were underrepresented in early studies. Further
confirmation of these associations in independent samples is warranted.
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Allele Frequency |
Modified Poisson
Regression Model |
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|
Allele |
AA(%) |
CA(%) |
RR |
95%CI |
p-value |
|
A*02 |
16 |
27 |
1.3 |
1.05,1.6 |
0.02 |
|
B*58 |
7 |
0.5 |
1.74 |
1.17,2.6 |
0.007 |
|
DPB*1701 |
8 |
1 |
1.46 |
1.02,2.1 |
0.04 |