May 17, 2005

 

Abstract ID: T1096

Treatment With Combination Peginterferon Alfa-2b And ribavirin Of Recurrent Hepatitis C in Liver Transplant recipients Nonresponsive To Interferon Alfa-2b And ribavirin

 

A. Samanta, A. Mandalapu, A. Fisher, D. Wilson, A. de la Torre, K.M. Klein, B. Koneru

 

Introduction

Hepatitis C recurs in virtually all liver transplant recipients, runs an aggressive course and causes graft dysfunction and loss. Treatment with interferon and ribavirin has not impacted the disease progression. Outcome data on pegylated interferon plus ribavirin treatment of nonresponders to interferon plus ribavirin for post transplant hepatitis C is scarce and end point of treatment not well defined.

 

Aim

To study treatment efficacy of peginterferon alfa-2b plus ribavirin for post-transplant recurrent hepatitis C nonresponsive to interferon alfa-2b plus ribavirin.

 

 

Methods

Twenty-six patients with post transplant hepatitis C recurrence, unresponsive to interferon alfa 2b and ribavirin were treated with peginterferon alfa-2bplus ribavirin. Criteria for hepatitis C recurrence included elevated ALT and AST, circulating HCV-RNA, histologic features of hepatitis and absence of rejection. Patients were treated with weekly pegylated interferon alfa 2b 1.5 mcg/kg and daily ribavirin starting at 400 mg (increased to 1000 mg). Erythropoietin and G-CSF were given when required.

 

 

Results

Mean age was 52.4 + 7.5 years; 85% were male. Twenty-three patients (88.5%) completed treatment for 24 to 60 weeks and three (11.5%) stopped medication for drug intolerance. Tolerated dose for peginterferon was 88+42 mcg/week (range 32-240 mcg/week) and for ribavirin was 600+200 mg/day (range 400-1000 mg/day). Dose interruption for peginterferon occurred in 12 (46%) and 15 (57%) required erythropoietin and/or G-CSF. At end of treatment, ALT, AST and HCV-RNA (57+28 IU, 60+40 IU and 500,000+200,000 copies/ml respectively) decreased significantly (p<0.05) from pretreatment values (109+82 IU, 90+70 IU, and 4,000,000+6,000,000 copies/ml respectively). Intent-to-treat analysis showed end of treatment biochemical response (normalization of transaminases) in 10 patients (38%) and HCV-RNA clearance in 5 (19%). Sustained response (undetectable HCV-RNA at six months after treatment) occurred in one (4%).

 

Conclusions

 

Treatment of post transplant hepatitis C recurrence with peginterferon alfa-2b plus ribavirin for 24-60 weeks in nonresponders to interferon alfa 2b plus ribavirin achieves viral decrease in many patients with improvement in transaminases at the end of treatment. However, sustained viral clearance is achieved in a few (4%). Dose reduction or interruption for drug intolerance limits therapy in post transplant population. Longer duration of therapy may prove beneficial.

 


 

Abstract ID: T1415

 

Effect Of Helicobacter Pylori Infection on Hepatitis C Virus Infection

 

H.T. El-Zimaity, B. Yoffe, T. Tabassi, B. Hollinger, S.A. Abudayyeh, Z.Z. Nurgalieva, F. Hammoud, B.S. Anand

 

Background

Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). It has been observed that African Americans (AA) have a higher infection rate, an inferior response to anti-viral treatment, and are more likely to develop HCC compared to Whites. It is unclear why these ethnic differences occur. A possible explanation is the confounding effect of concurrent infections such as H. pylori (HP) is more prevalent in AA. HP might influences HCV infection by altering the host immune response. Aim: To compare HCV viral load and treatment response in HP positive vs. HP negative patients.

 

Methods

HCV was confirmed by positive HCV-RNA by PCR. HCV viral load was determined at baseline (prior to treatment), after 24 and 48 weeks of treatment, and at 6 month after stopping anti-viral therapy. Sustained virology response (SVR) was defined as negative HCV-PCR 6 months post therapy. Patients were treated with interferon alone or interferon and ribavirin combination therapy. HP status was assessed by serology (HM-CAP; Enteric Products Inc, Stony Brook, NY).

 

Results

107 patients with HCV infection were included (42 received monotherapy and 65 combination therapy). 42 (39%) were HP antibody positive. The SVR rate was lower among HP positive patients compared to HP negative patients (19% vs. 43%) (p = 0.01). By ordered logistic regression analysis, other factors associated with a lower SVR rate were genotype 1 and being African American. The baseline viral load was also lower in HP negative patients compared to HP positive patients (p<0.001). After treatment, the mean viral load in the non-responder patients (27 HP negative and 32 HP positive) was higher in HP positive patients (2.32 x 106 + 3.2 vs. 1.51 x 106 + 4.8 copies) (p = 0.056).

 

Conclusion

HP infection is associated with significantly lower sustained virologic response rate and a higher HCV viral load compared to patients without HP infection. The lower SVR rate in AA may be explained by the higher prevalence of H. pylori infection. Eradication of H. pylori infection might result in a significant improvement in the outcome of HCV treatment.


 

Abstract ID: 436

 

Hepatitis C Is a Risk Factor for Intrahepatic Cholangiocarcinoma

 

Y.H. Shaib, H.B. El-Serag, M. Hassan

 

Background

Risk factors of cholangiocarcinoma are not well defined. This study evaluates viral hepatitis (HCV, HBV) and liver cirrhosis as risk factors for intrahepatic (ICC) and extrahepatic cholangiocarcinoma (ECC).

 

Methods

A hospital-based prospective case-control study. Cases were patients with histologically confirmed cholangiocarcinoma referred to M.D. Anderson cancer center between 1992-2002 and were matched (1:2 for ICC and 1:1 for ECC) by age and gender to controls obtained from the companions of patients with a diagnosis of cancer, other than hepatobiliary cancers. Data were collected using a structured questionnaire about liver disease, family history, diabetes, smoking, and alcohol. Blood samples from all participants were tested for HBs Ag, HBc and anti-HCV antibodies. Comparisons were conduced in bivariate and multivariable logistic regression analyses.

 

Results

We identified 246 cases (83 cases with ICC and 163 with ECC) and 156 controls (Table). There were no significant differences between cases and controls in age, gender, and race.

 

ICC Cases

(N=83)

ECC Cases

(N=163)

Controls

(N=156)

Mean Age (SD)

59.8 (11.4)

61.1 (10.2)

59.8(11.8)

Gender

 

 

 

Women

37 (44.6%)

67 (41.1%)

58(37.2%)

Race

 

 

 

White

67 (80.7 %)

126 (77.3%)

123 (78.8%)

Other

16 (19.3%)

37 (22.7%)

33 (21.2%)

 

Compared with controls, ICC cases had higher prevalence of anti-HCV antibodies (6.0 % vs. 1.3 %, p=0.04) and Anti HBc antibodies (10.8% vs. 0.65 %, p=0.0002) but not HBs Ag (1.2% vs. 0.7%, p=0.7). The race-adjusted odds ratio for HCV was 4.5 (1.1-34.5) and for Anti HBc antibodies was18.3 (3.3-340.0). The prevalence of diabetes (14.5 % vs.9.2 %, p=0.2), smoking (44.6 % vs. 47.4 %, p=0.7) and alcohol (55.4 % vs.57.9 %, p=0.7) were not significantly different between ICC cases and controls. Most of the ICC patients with HCV (80%) had liver cirrhosis. Only 2 ICC cases (2.4 %) had ulcerative colitis or sclerosing cholangitis. The prevalence of most of the risk factors was not different between ECC cases and controls: anti HCV (3.7% vs. 1.3%, p=0.2), HBs Ag (0 vs. 0.6 %, p=0.3), diabetes (11.6 vs. 9.2 %, p=0.5), and smoking (47.2 % vs. 47.4 %, p=0.9). The prevalence of cirrhosis was significantly higher among patients with ICC than those with ECC (24.1% vs. 4.9 %, p<0.0001).

 

Conclusion

Chronic HCV and possibly HBV are risk factors for ICC but not ECC. Liver cirrhosis is a common and strong risk factor for ICC and less so for ECC.


 

Abstract ID: 535

 

Prospective Study Of the Prevalence and Racial Differences in Gallbladder Disease Among Men With Chronic Hepatitis C Virus Infection

 

L. Kapelusznik, E.J. Bini

 

BACKGROUND

The association between chronic hepatitis C virus (HCV) infection and gallbladder disease (GBD) is controversial. The aims of this prospective study were to determine the prevalence of GBD among men with chronic HCV infection and to evaluate racial differences in the prevalence of GBD in this population.

 

METHODS

727 men with a positive HCV antibody test were interviewed by research coordinators who obtained detailed demographic and clinical data, and all patients had routine laboratory testing, HCV PCR testing, and abdominal ultrasonography. GBD was defined as the presence of one or more gallstones or evidence of prior cholecystectomy on ultrasonography.

 

RESULTS

Among the 727 men, 564 (77.6%) were HCV RNA(+); the remaining 163 HCV RNA(-) patients served as controls. Overall, the mean age was 51.9 +/- 8.5 years and there were 32.3% non-Hispanic whites, 42.1% non-Hispanic blacks, 24.6% Hispanics, and 1.0% other racial groups. The age and race distribution were similar in the HCV positive and control groups. The prevalence of gallstones (20.6% vs. 7.4%, p <0.001), cholecystectomy (8.2% vs. 1.8%, p = 0.002), and the combined endpoint of GBD (28.7% vs. 9.2%, p <0.001) were all significantly higher in HCV positive patients compared with controls. The prevalence of GBD among our controls was no different from U.S. men of similar age (Gastroenterology 1999;117:632-639). After adjusting for age and race, the odds of GBD (OR = 4.31; 95% CI, 2.39 - 7.76; p <0.001) was significantly higher among HCV positive patients compared to controls. These findings remained highly significant after adjusting for education, income, alcohol use, smoking, diabetes, cholesterol, body mass index, and recent weight loss. Among HCV positive patients, the prevalence of GBD increased with age and was 20.4% in men <50 years old, 30.5% in those 50 - 59 years old, and 45.2% in those >=60 years old (p <0.001). The prevalence of GBD in HCV positive men was 47.2% in Hispanics, 30.2% in non-Hispanic whites, 16.7% in other racial groups, and 16.3% in non-Hispanic blacks (p <0.001). Patients with genotype 3 had the highest prevalence of GBD (49.0%) as compared with 26.3% in genotype 1, 32.1% in genotype 2, and 23.1% in those with other genotypes (p = 0.009).

 

CONCLUSIONS

The prevalence of GBD was significantly higher in HCV positive men compared to men without HCV infection. Among HCV positive men, there were marked racial and HCV genotype differences in the prevalence of GBD.


 

Abstract ID: 524

 

Tumor Suppressor P53 Inhibits Replication Of Hepatitis C Virus Subgenomic Replicon in Human Hepatoma Cells

 

N. Dharel, N. Kato, H. Taniguchi, M. Otsuka, M. Moriyama, R. Muroyama, Y. Wang, R. Shao, T. Kawabe, M. Omata

 

Background & Aims

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide. Host cellular factors regulating HCV replication are still to be elucidated.

 

 

Methods

1)    Naive Huh7 cells and Huh7-168 (high replication permissive Huh7 cells), were transfected with subgenomic HCV replicon and their replication permissiveness was compared.

2)    p53 expression among high or low-replication permissive cells was examined by Western blot.

3)    p53 expression in Huh7 cells non-permissive to HCV replicon was silenced by siRNA, and the p53 knocked down cells were transfected with HCV replicon.

4)    p53 overexpressing plasmid or p53 silencing plasmid were co-transfected with HCV replicon into Huh7-168, and colony formation assay was performed.

5)    p53 overexpressing plasmid was transfected into replicon harboring cells, and immunofluorescence staining of p53 and HCV NS5A was performed.

6)    p53 mutant with point mutation at cell cycle regulating or apoptosis regulating residue was constructed, and their effect on HCV replication was compared to that of the wild type p53.

 

Results

1)    Numerous neomycin resistant colonies were obtained from Huh7-168 but no colony was obtained from nave Huh7 cells.

2)    Higher-replication supporting cells (confirmed by Western blotting for NS5B and real time RT-PCR) had a tendency of lower p53 expression.

3)    Following p53 silencing, replication non-permissive nave Huh7 cells supported a high level replication of HCV replicon.

4)    p53 overexpression reduced the number of colonies, whereas p53 silencing increased.

5)    HCV NS5A expression was low in cells overexpressing p53, whereas high expression of HCV NS5A was seen in p53 knocked down cells.

6)    Mutant p53 with point mutation at cell cycle regulating or apoptosis regulating residue suppressed HCV replication as well as the wild type.

 

Conclusions

p53 inhibits HCV replication independent of cell cycle arrest and apoptotic function. Exploration of the mechanism of this hitherto unrecognized link between p53 and HCV could enhance the understanding of HCV replication, and could lead to the development of better therapeutic options.

 


 

Abstract ID: 538

Effect Of Ondansetron, a 5-Ht3 Receptor Antagonist, on Fatigue in Chronic Hepatitis C : a Randomized Double Blind Placebo Controlled Study

 

P. THIERRY, V. GEOFFROY, C. FAREDJ, A. ZEINA, R. CHRISTOPHE, H. PIERRE MICHEL, T. ALBERT

 

Background & aims

There is a lack of available effective therapy for fatigue associated with chronic hepatitis C (CHC). The serotonin antagonist ondansetron has shown its efficacy in the chronic fatigue syndrome. The present randomized, placebo-controlled double blind trial investigated the effect of orally administered ondansetron on fatigue in CHC.

 

Methods

Thirty six patients with CHC were included if fatigue was their predominant symptom and they scored more than 4 on a visual analog scale (0-10). During the study, fatigue and depression were measured at day 0, 15, 30 and 60 using validated self report questionnaire (Fatigue Impact Scale and Beck Depression Inventory). The patients were randomized to receive ondansetron tablets 4 mg bid or placebo for one month followed by an additional four weeks observation.

 

Results

The fatigue score was 85.428.2 and 98.226.9 in the ondansetron and placebo group respectively (NS). Ondansetron significantly reduced the fatigue score with more than 30% improvement at day 15 (57.138.9, p<0.01), day 30 (54.537.6, p<0.01) and day 60 (60.837.3, p<0.01) whereas placebo did not. Overall, the reduction of fatigue was significantly higher with ondansetron as compared with placebo (ANOVA for repeated measurements), either for the whole follow-up (p=0.03) or restricted to the treatment period only (p=0.04). Ondansetron also significantly reduced the depression scores.

 

Conclusions

The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has a significant positive effect on fatigue in CHC. These observations support the concept that fatigue involves serotoninergic pathways and may encourage the further evaluation of the efficacy of ondansetron on fatigue in chronic liver diseases.


 

Abstract ID: 527

 

Initial Results Of a Phase 1B, Multiple-Dose Study Of VX-950, a Hepatitis C Virus Protease Inhibitor

 

H.W. Reesink, S. Zeuzem, A. van Vliet, L. McNair, S. Purdy, H. Chu, P.L. Jansen

 

Background

VX-950 is an orally administered, highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS34A protease that is designed to block HCV replication. VX-950 is among the most advanced direct antivirals in clinical development for the treatment of HCV infection. A single-dose Phase 1 study conducted in healthy subjects demonstrated that VX-950 was well tolerated at all dose levels up to 1250 mg, with good bioavailability. A multiple-dose study is now underway that includes healthy subjects and subjects with chronic Hepatitis C. This abstract reports on the initial results in the healthy subject component of the study.

 

Methods

The VX04-950-101 clinical study includes three panels of eight healthy subjects (Part A) and three panels of twelve subjects with Hepatitis C (Part B). In Part A, subjects are dosed for 5 days at doses of 450 mg, 750 mg, and 1250 mg, or placebo. In Part B, subjects will be dosed for 14 days at doses of 450 mg, 750 mg and 1250 mg, or placebo. The primary objective of the study is to assess safety and tolerability; the secondary objective is to assess antiviral activity in subjects with Hepatitis C.

 

Results

At this time, dosing of the first two panels of healthy subjects in Part A of the clinical study has been completed, and dosing of the third panel is ongoing. VX-950 has been well tolerated, with no serious adverse events. All adverse events possibly related to VX-950 were mild, and no subject has discontinued from the study. Pharmacokinetic (PK) assessment showed that VX-950 is orally bioavailable, and steady state was attained within 24 to 48 hours of dosing initiation. The minimum average trough concentration is about 400 ng/mL, exceeding 50% of the inhibitory concentration in the VX-950 replicon assay (IC50 = 240 ng/mL) and infectious virus assay (IC50 = 196 ng/mL).

 

Discussion

VX-950 has been well tolerated for 5 days in healthy subjects. The PK behavior of the drug is consistent with the prior single dose PK results. At steady state, trough concentrations in the blood were significantly higher than the IC50 for the drug. Based on these data and extensive pre-clinical data on plasma-to-liver drug concentration ratios, the doses are also expected to yield liver exposures that exceed 90% of the inhibitory concentration (replicon IC90 = 476 ng/mL). Part B of the study, in subjects with chronic Hepatitis C, is currently underway.


Presentation Number: S929

Significant Variation Between HCV Treatment Acceptance and Enrollment Rates Among Sites in a Large Multicenter National Study

 

S.L. Currie, T.L. Wright, E.J. Bini, H. Shen, H.S. Yee, F. VA-HCV-001 Research Group

 

Background

Many patients chronically infected with the hepatitis C virus (HCV) are not considered treatment (Tx) candidates and for those whom Tx is recommended, many decline. However, there are also many patients that do agree to Tx, but do not initiate Tx. Little is known about this group.

 

Objective

To examine whether there are site variations in the number of persons who are HCV Tx candidates who agree to Tx, but who do not initiate Tx.

 

Methods

Data were prospectively collected in 4,084 HCV RNA positive, Tx naive patients at 24 VAMCs undergoing evaluation for interferon and ribavirin therapy between December 1999 and December 2000. All sites had a trained hepatologist as well as dedicated staff for the study and Tx candidacy was determined according to standardized inclusion/exclusion criteria. Persons considered candidates who agreed to Tx were assessed on whether Tx was actually initiated, by site. Enrollment variations were recorded, using one of the sites as a reference.

 

Patient Characteristics

o      Age, years (IQR) =46.0 (46.053.0)

o      Male gender = 97.2%

o      Caucasian = 56.6%

o      African American = 29.4%

o      Hispanic = 9.5%

o      Service during Vietnam Era = 76.7%

o      Less than or equal to 12 years of education = 47.1%

o      Income less than $10,000 or less = 39.0%

o      Consumed 3 or more drinks/day = 73.6%

o      Injection drug use = 60.0%

 

Results

o      Overall, 32.2% (95% CI, 30.8% 33.7%) were candidates for HCV treatment according to the standardized criteria, and

o      40.7% (95% CI, 39.2% 42.3%) were candidates in the opinion of the treating clinician.

o      Of the 1,624 patients who were offered treatment, 377 (23%) declined and 1247 (77%) agreed to be treated.

o      In those patients who agreed to be treated, 721 (58%) enrolled in treatment.

o      Among the 17 sites, there was significant variation in the percentage of persons who were offered and agreed to be treated and those who actually initiated treatment, ranging from 30% to 94% across the sites.

o      Using one site as a reference, univariate analysis showed that 9 of the 16 sites had statistically significant variations, with one site over 12.5 times less likely to have their patients initiate Tx (OR 12.54, 95% CI, 4.77 - 32.99).

 

Conclusion

Known barriers to HCV treatment include: relative and absolute contraindications to treatment, local resources available to support patients on therapy and patient unwillingness to be treated. In the current study, all of these potential barriers were removed.

 

Despite the availability of therapy, our data show significant variation in treatment initiation rates, which may suggest yet another barrier to HCV treatment.

 

Further study is needed to identify the factors that reduce initiation of HCV treatment, once patients have met criteria and have agreed to be treated.

 

Strategies should be developed to improve initiation rates and reduce such significant variations in care.

 

Despite standardized candidacy selection, staff and HCV treatment resources being available, our data suggest that there are significant variations in the number of treatment candidates who agreed to be treated and who were actually enrolled. The gap between acceptance and enrollment needs to be further investigated and include factors such as geography, provider experience and patient follow-up