Topic Forum - Posters – Tuesday May 23, 2006  2:15 – 3:45PM  Hepatitis C

 

HCV Treatment II

 

 

Abstract 651 – Sustained virological response leads to an improved clinical outcome in patients with chronic hepatitis C and advanced fibrosis

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.

 


Abstract 652 – Antiviral Activity of CHO-SS-Derived Omega Interferon and Other Interferons Against HCV RNA Replicons and Related Viruses

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.

 


Abstract 653 – Hispanic Patients with Genotype 2 or 3 Chronic Hepatitis C have Lower Rates of Sustained Virologic Response to Treatment with Pegylated Interferon and Ribavirin.

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.

 


Abstract 654 – How to break the persistence of HCV infection; New strategy based on recent progress of immunology

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.


Abstract 655 – The effect of liver fibrosis and cirrhosis on SVR in 4913 patients with hepatitis C; Results from the Win-R trial

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


Abstract 656 – Association between HLA allele A*02, B*58, DPB*1701 and sustained virologic response to pegylated interferon and ribavirin therapy in chronic HCV genotype 1-infected, treatment naïve Caucasian and African Americans

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.

 

 

 

Allele Frequency

Modified Poisson Regression Model

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