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Digestive Disease Conference: Day Two

Alan Franciscus
Editor-in-Chief, HCV Advocate

Abstract 213
Clinical Significance of Pegylated Interferon Induced Neutropenia: Results from the WIN-R Trial


Abstract 215
The Safety, Efficacy and Pharmacokinetics of Peginterferon alfa-2a (40KD)(PEGASYS<) in Children With Chronic Hepatitis C


Abstract 216
Aggressive Psychiatric Intervention Based on Clinical Suspicion, Not Standardized Depression Scores, Increases Adherence to Pegylated Interferon and Ribavirin Therapy for Hepatitis C


Abstract 217
Histological Improvement in Patients with Pegylated Interferon Alpha-2b plus Ribavirin Who Were Previously Non-Responders to Rebetron


Abstract 230
HCV Vertical Transmission: Long-Term Prospective Study


Abstract 232
Steatosis Influences the Early Virologic Response Rate in Patients with Chronic Hepatitis C Infection


Abstract 233
Interferon and Interferon plus Ribavirin in Hepatocellular Carcinoma Prevention: A Prospective Study on Patients with HCV Related Cirrhosis.


Abstract 234
Use of Carotenoid-Based Functional Food Minimizes the Severity of Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C: a Randomized Study


Abstract 235
Reasons for Discontinuation of Treatment for Chronic Hepatitis C. An Interim Analysis of the Frontier Trial.


Abstract 237
Micro-nutrients and Liver Injury in the U.S. Population


Abstract 249
The Impact of Protease Inhibitors (PI) on the Histologic Spectrum of Liver Disease in HCV-HIV Coinfection.


Abstract 250
Viral Clearance Occurs Very Early During the Natural Resolution of Transfusion-acquired Hepatitis C Virus Infections


Abstract 251
HCV RNA Quasispecies Evolution Associated with End Stage Liver Disease in a Longitudinal Cohort of HCV and HCV/HIV Infected Hemophilics


Abstract 252
Comparison of Hepatitis C Virus (HCV)-related Liver Disease Between Caucasians (C) and African Americans (AA): Analysis of HCV in the Virginia Department of Corrections (DOC).


Abstract 1388
Interaction of Steatosis and Non-Alcoholic Steatohepatitis (NASH) with Chronic Hepatitis C


Abstract 1603
Combining INF alfa 2b with PEG-INF alfa-2b and Ribavirin in the treatment of Non-responders to previous therapy and Nieve Genotype 1 patients with Chronic Active Hepatitis C.


Abstract 1605
Impact of Treatment On Liver Fibrosis In Autoimmune Hepatitis and Chronic Hepatitis B


Abstract 1610
Is There Any Relation Between CD81 Polymorphisms, HCV and the Presence of Cryoglobulinemia?


Abstract 1611
Lifestyle and Genetic Risk Factors for Progression of Hepatitis C


Abstract 1613
Safety, Tolerability And Efficacy Of Interferon Alfa 2b And Ribavirin Combination Therapy In HCV Patients With Cirrhosis


Abstract 1614
Severity of Liver Disease in HCV Infected Dialysis Patients Awaiting Renal Transplantation


Abstract 1616
The ?32 Mutation of the Chemokine-receptor 5 Gene is Neither Correlated with Chronic Hepatitis C nor Does it Predict Response to Therapy with Interferon-a and Ribavirin


Abstract 1618
Effect of a Low Iron Diet in Chronic Hepatitis C


Abstract 1621
Prevalence of Hepatitis C Virus (HCV) Infection in Non-Hodgkin's Lymphoma (NHL). Systematic Review and Meta-analysis


Abstract 1622
Racial Differences in Treatment Response to Hepatitis C Virus in a Large Urban Health System


Abstract 1625
The Rate of Treatment of Hepatitis C in Patients Co-infected With HIV in an Urban Medical Center


Abstract 1626
The Role of Helicobacter Pylori Infection on the Natural History of HCV and the Impact on the Response to Therapy


Abstract 1628
Is Hepatitis C Genotype a Major Determinant in The Decision to Perform Liver Biopsy in Patients with Chronic Hepatitis C?


Abstract 12603
Combining INF alfa 2b with PEG-INF alfa-2b and Ribavirin in the treatment of Non-responders to previous therapy and Nieve Genotype 1 patients with Chronic Active Hepatitis C

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Abstract 213
Clinical Significance of Pegylated Interferon Induced Neutropenia: Results from the WIN-R Trial

Furqaan Ahmed, Ira M. Jacobson, Robert S. Brown Jr., Nezam Afdhal, Raymond Rubin, James Spivey, Bradley Freilich, Fredric Regenstein, David Bernstein, Robert Doig, Clifford Brass, Win-R. Study Group

Background:

Neutropenia occurs commonly in patients treated with pegylated interferon and ribavirin (Manns, Lancet 2001;358:958-65). The clinical significance of this neutropenia remains uncertain.

Aim:

The aim of this study was to determine if there is a correlation between the occurrence of neutropenia and the development of serious infections while on combination therapy.

Method:

We provide data on infectious serious adverse events (SAE) from the WIN-R Trial, a U.S. multicenter study comparing fixed (800mg) versus weight based (800-1400mg) daily dosing of ribavirin in combination with pegylated interferon alfa-2b (pegintron) 1.5 µg/kg/week. We reviewed serious infections and ANC data at weeks 0,2,4,8,12,18,24,30,36,42, and 48.

Results:

Of the 4243 patients enrolled in the study, 30 (0.7%) developed infectious serious adverse events (SAE) while on therapy. These 16 male and 14 female patients ranged in age from 35-63 years (mean 47 years). The infections included pneumonia (10), UTI (3), cellulitis (3), URTI (2), abscess (4), and one case each of cat scratch disease, salmonella colitis, furuncle, meningitis, appendicitis with perforation, tibial hardware infection, bacteremia, and invasive C. jejuni diarrhea.

Reviewing available data, 24 patients received antibiotics, 27 were hospitalized, and 7 required surgical intervention. One patient died with pneumonia. Complete ANC data was available for 25 of the infectious SAE patients. The ANC fell below 1000 at some point in 14 (56%) patients. The overall mean nadir ANC in all patients was 1317±822. The mean nadir ANC for the SAE patients was not significantly different than that for the rest of the patients (1198±757 vs. 1318±823, p=0.46).

The proportion of patients who developed ANC <750 was similar in both groups (20%). In patients with infectious SAEs, the mean ANC prior to infection was significantly higher than the mean nadir ANC(2286±1676 vs. 1198±757, p=0.005). The nadir and pre-infection ANCs were the same in only 15% (3/20) of patients. The mean timing of the nadir ANC and the onset of infection were similar (week 18 vs. week 16). Additional data regarding this issue is being accumulated.

Conclusions:

  1. Patients who develop serious infections while on combination therapy with pegylated interferon alfa-2b and ribavirin do not have significantly lower mean nadir ANCs.
  2. Infectious serious adverse events generally did not occur at the time of nadir ANC.
  3. Criteria and utility for dose reduction of peginterferon and the use of granulocyte stimulating factor to treat neutropenia require further assessment.

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Abstract 215
The Safety, Efficacy and Pharmacokinetics of Peginterferon alfa-2a (40KD) (PEGASYS®) in Children With Chronic Hepatitis C

Kathleen B. Schwarz, Johns Hopkins University School of Medicine, Parvathi Mohan, Children's National Medical Center, Michael Narkewicz, University of Colorado School of Medicine, Department of Pediatrics, Jean Pappas Molleston, James Whitcomb Riley Hospital for Children, Helen S. Te, University of Chicago, Sylvia Hu, Susan Sheridan, Matthew Lamb, Stephen C. Pappas, George Harb, Roche, Nutley

Introduction:

The prevalence of children infected with HCV in the United States is estimated at 0.2% in children aged under12 years and 0.4% in those aged 12 to 19 years. New infection are primarily acquired by perinatal (vertical –mother to child) transmission. Generally, children infected with HCV exhibit no symptoms, have normal or near normal ALT levels and have their rate of disease progression is slower compared to adults with infected with HCV. Currently, no therapies are FDA approved for treatment of chronic hepatitis C in children.

Objective:

The objective of this study was to investigate the safety, efficacy and pharmacokinetic characteristics of peginterferon alfa-2a (40KD) PEGASYS® and study the HCV kinetics in children aged 2 to 8 years with chronic hepatitis C infection.

Study Design:

  • PEGASYS® SC once weekly for 48 weeks
  • Dose: Body Surface Area (BSA) in m2 X 180 µg/1.73 m2
  • Blood sampling:
    • Pre-dose at wk 1, 4, 8, 12, 24, 40 and 48
    • Post-dose (wk 1 and 24) at 24, 96 and 168 hr
  • Serum concentrations analyzed by a quantitative ELISA
  • Bayesian estimates of pharmacokinetic parameters

Abstract 237
Micro-nutrients and Liver Injury in the U.S. Population

Constance E. Ruhl, James E. Everhart

Background & Aims:

Oxidative stress is thought to play a role in the liver injury due to nonalcoholic steatohepatitis (NASH). Hepatic iron may promote liver injury, whereas certain vitamins and minerals (antioxidants) may inhibit it, but few clinical studies have examined such relationships. We analysed the associations of serum iron measures and antioxidant concentrations with abnormal serum alanine aminotransferase (ALT) activity in a national, population-based study.

Methods:

Serum transferrin saturation and serum iron, vitamins C and E, selenium, and five carotenoid concentrations were measured in 13,605 adult participants in the third U.S. National Health and Nutrition Examination Survey, 1988-1994.

Exclusions included excessive alcohol consumption, hepatitis B or C, and iron overload. Liver injury was indicated by elevated serum ALT activity (> 43 U/L). Serum nutrient concentrations were expressed as deciles (10th percentiles). All analyses incorporated sample weights and the design effects of the survey.

Results:

  • Elevated ALT activity was found in 3.1% of the population.
  • In univariate analysis, factors associated with abnormal ALT activity (p<0.05) included higher serum transferrin saturation and iron and selenium concentrations, and lower serum vitamin C, alpha carotene, beta carotene, and lutein/zeaxanthin concentrations.
  • In multivariate logistic regression analyses, elevated ALT was positively associated with increasing deciles of transferrin saturation and iron concentration and negatively associated with increasing deciles of alpha carotene, beta carotene, beta cryptoxanthin, and lutein/zeaxanthin concentrations (table 1).
  • A variable combining the five carotenoid measures was also negatively associated with abnormal ALT (odds ratio per decile increase = 0.89, 95% CI=0.83-0.95). Vitamin C was inversely associated, but only at the highest serum concentrations.
Multivariate-adjusted Logistic Regression Odds Ratios for Relationships with Elevated ALT

Serum nutrient (deciles) OR 95% CI/td>
Transferrin saturation 1.10 1.03-1.18
Iron 1.13 1.06-1.21
Vitamin C 0.96 0.90-1.02
Vitamin E 1.04 0.96-1.13
Selenium 1.05 0.99-1.12
Alpha carotene 0.82 0.72-0.94
Beta carotene 0.91 0.86-0.96
Beta cryptoxanthin 0.91 0.84-0.99
Lutein/zeaxanthin 0.90 0.84-0.96
Lycopene 0.95 0.89-1.02


Conclusion:

In this large, national, population-based study, the risk of liver injury most likely due to NASH was associated with increased serum iron and decreased serum antioxidants, particularly carotenoids.

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Abstract 249
The Impact of Protease Inhibitors (PI) on the Histologic Spectrum of Liver Disease in HCV-HIV Coinfection.

Richard K. Sterling, Mary S. Wilson, Arun J. Sanyal, Velimir A. Luketic, R. T. Stravitz, Melissa J. Contos, A. S. Mills, Mitchell L. Shiffman

Introduction:

HCV-HIV coinfection is common. With the initiation of HAART, patients with HIV are now living longer. Most studies on liver histology in coinfection were performed prior to HAART and its impact on liver histology is not clear. Although the use of PIs have been suggested to reduce progression of fibrosis, this remains controversial.

Aim:

To assess the impact of Protease Inhibitors on the spectrum of liver disease in HCV-HIV coinfection.

Methods:

A retrospective analysis of consecutive HCV-HIV coinfected patients between 1998 and 2002 was performed. All patients were HIV +, HCV RNA +, and HBV surface antigen negative. A cohort of HIV uninfected HCV patients evaluated during the same time period were used as controls. Patients were excluded if they had recent or active opportunistic infection, creatinine > 1.5, platelet < 80,000, history of liver decompensation, or evidence of other liver disease. The Knodell histologic activity index (HAI) was assessed blindly regarding HAART therapy and advanced fibrosis was defined as bridging fibrosis or cirrhosis. Data are expressed as mean (+ SD).

Results:

The demographics of 101 coinfected patients, mean age 43, 75% male and 82% African American, reflect our urban HIV clinic population. The mean HIV load was 1.52 log copies/ml and 48% had undetectable HIV RNA. The mean CD4 count was 528 cells/mm3 (range 52-2332) and 11% had CD4 < 200. Data on HAART use was available in 93 patients of which 92% were on a mean of 3.02 (range 0-7) antiretroviral medications including nucleoside reverse transcription inhibitors (NRTIs) (98%), non-NRTIs (45%), and PIs (54%). When patients were stratified by use of PI, we observed no significant differences in virologic, immunologic, biochemical, or histologic parameters between those whose HAART regimen included a PI compared to those who did not or to HIV uninfectected controls.

Conclusions:

Despite a high frequency of normal ALT, HCV-HIV patients on stable HAART have a significant proportion with advanced fibrosis. The use of Protease Inhibitors had little impact on biochemical and histologic parameters of HCV. Prospective studies are needed to determine the impact of Protease Inhibitors on HCV disease progression. Until then, the use of a Protease Inhibitors in the treatment of HIV in HCV coinfected patients should be dictated by the need to control HIV and not to decrease the severity of HCV related liver disease.

Group N CD4 cells/ mm3 CD4 < 200 % Log HIV RNA ALT U/L NL ALT % HAI Adv Fib %
HAART w/PI 47 468 (254) 13 1.08 (1.66) 82 (54) 54 6.89 (3.7) 34
HAART w/o PI 46 590 (420) 11 1.85( 1.90) 82 (51) 51 7.30 (3.5) 31
Controls 302 n/a n/a n/a 94 (70) 49 7.03 (3.0) 24


Editor’s Note:

Comments made during this session included:

  • There was no difference between Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors
  • No differences were seen in ALT or HAI
  • No differences were seen by race
  • Steatosis – did not find much steatosis as compared to HCV mono infected

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Abstract 250
Viral Clearance Occurs Very Early During the Natural Resolution of Transfusion-acquired Hepatitis C Virus Infections

Elaine Eyster, Jeffrey Sanders, James Goedert

Introduction:

It is generally accepted that about 20% of persons who acquire hepatitis C virus (HCV) infections recover and become HCV RNA negative, but the timing of viral clearance is poorly understood. We documented the timing of spontaneous HCV RNA clearance in 12 patients from a well-characterized hemophilia cohort. Hemophilia is an inherited disease that affects mostly males and prevents blood clotting. It is treated by lifelong injections of clotting factors made with serum obtained from multiple donors. There is almost a 100% incidence of HCV in hemophiliacs that received clotting factors contaminated with HCV before 1987.

Patients/Methods:

Ten were male and two were female. All were HIV negative and none had been treated with interferon. Duration of infection ranged from 15 to 24 years (median 19 years). HCV RNA assays were performed on archived serum samples collected at most 2 months to 4 years after the primary HCV infection had occurred, using the COBAS Amplicor assay (Roche). PCR positive samples were quantitated with the Versant bDNA assay (Bayer)and genotyped with the InnoLiPA reverse hybridization assay (Bayer).

Results:

HCV RNA was undetectable by PCR in the initial anti HCV positive samples from 8 patients (66%). In 3 patients, HCV RNA was detected by PCR but not by bDNA, and in one patient, it was detected at a low level by bDNA (4,839 IU/ml, cut off <615 IU/ml).

Eight of the 12 had been infected with HCV by age 8.5 years (range 2.5 to 54 years). By comparison, seven of 8 controls with persistent viremia matched for age, sex and duration of blood product exposure had results ranging from 4,644 to 678,515 IU/ml (median 43,532) (p=.0008). PCR testing on samples collected longitudinally over the course of the next 10-20 years (median 6 per patient, range 3-10) revealed that three of the 4 patients with HCV RNA detectable in their initial samples cleared virus during the next year.

Three were genotype 1 and one was genotype 2. Overall, the maximum duration of infection before clearance:

  • 7 months or less in 4 (36%) and
  • 1-2 years in 6 patients (55%) with yearly samples.
  • One patient had persistence of HCV RNA for 5 years before clearance while receiving only sterilized concentrates, demonstrating that clearance can occur once chronic infection is established.
Reinfection was observed in only one patient and occurred while he was receiving unsterilized clotting factor concentrates.

Conclusion::
  • We conclude that HCV clearance usually but not always occurs within 1-2 years after infection and is more likely in those with lower than in those with higher early viral loads.
  • In the patients that spontaneously cleared HCV, ALT have remained normal and there has been no disease progression

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Abstract 251
HCV RNA Quasispecies Evolution Associated with End Stage Liver Disease in a Longitudinal Cohort of HCV and HCV/HIV Infected Hemophilics

Hong Qin, Susan D. Rouster, Erica Keenan, Paul S. Horn, Elaine Eyster, Margaret Koziel, James Goedert, Kenneth E. Sherman

Background:

Hemophilic patients who received blood products/factor concentrates prior to 1987 have among the highest rates of HCV infection often in association with HIV. We evaluated the HCV RNA quasispecies evolution in longitudinally collected specimens comparing those with progression to decompensated liver disease (ESLD) to those with compensated chronic hepatitis.

Methods:

Serially collected serum samples were obtained from the NCI Multicenter Hemophilia Cohort Study (MHCS). Index cases were derived from patients who progressed to end stage liver disease. Controls were matched for age, gender, duration of infection, presence or absence of HIV coinfection, and HCV genotype. Samples from early infection (E) were compared to those obtained after onset of ESLD in the index patient (L). The HVR1 coding region was amplified, subcloned and sequenced. Predicted amino acid sequences were compared for clonal variability and evolution. Complexity and diversity were determined.

Results:

One hundred eleven subclones derived from 9 patients followed over a mean duration of 9.5 year (S.E.= 1.2 years) were sequenced and evaluated for non-synonomous amino acid substitution. At baseline, no statistically significant difference in quasispecies complexity was observed between outcome cohorts. However, subjects who clinically progressed to end stage liver disease demonstrated significantly decreased quasispecies complexity over time (p=0.016) and compared to the control group in samples collected at the L timepoint (p=0.018). In non-progressor patients, 75% of all species demonstrated variation of one or more amino acid. In contrast, only 37% of clones derived from patients who developed end stage liver disease demonstrated heterogeneity in their HCV envelope HVR1 amino acid sequence. Narrowing of the quasispecies distribution occurred in both HCV/HIV coinfected and monoinfected patients who progressed to end stage liver disease. Nucleotide diversity also decreased in subjects developing ESLD. The mean Kimura pairwise difference comparison demonstrated the greatest evolution in HCV/HIV coinfected patients who progressed to end stage liver disease.

Conclusion:

Hemophilics with HCV coinfection appear to reduce their quasispecies complexity with one dominant species in subjects who progress to ESLD while non-progressor controls maintain their complexity by constant mutation. These data suggest that selection of fit mutants become the dominant species or decreased immune selection is associated with liver disease progression in hemophilic HCV infected patients.

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Abstract 252
Comparison of Hepatitis C Virus (HCV)-related Liver Disease Between Caucasians (C) and African Americans (AA): Analysis of HCV in the Virginia Department of Corrections (DOC).

Richard K. Sterling, Velimir A. Luketic, R. T. Stravitz, Arun J. Sanyal, Melissa J. Contos, A. S. Mills, Mitchell L. Shiffman

Introduction:

Differences in HCV between Caucasians and African Americans remain controversial. Previous studies have been limited by size and heterogeneity of the populations studied. Although HCV is common in the Department of Corrections, the spectrum of liver disease in this setting has not been well characterized and offers a unique opportunity to compare the spectrum of liver disease between Caucasians and African Americans in a relatively homogeneous population.

Aim:

To describe the biochemical, virologic, and histologic spectrum of HCV in the Department of Corrections.

Methods:

A retrospective analysis of consecutive inmates biopsied for chronic HCV between October 1998 and July 2002 was performed. All patients included were anti-HCV+, had a platelet count >70,000, an INR <1.4, and no evidence of hepatic decompensation. Patients were excluded from analysis if they were HIV positive, HBV SAg positive, had evidence of other liver disease, or creatinine >2.0 mg/dl. HCV RNA and genotyping were obtained at time of biopsy and liver histology assessed by Knodell histologic activity index (HAI) with histologically significant disease defined as total HAI >4 or any degree of fibrosis and advanced disease as presence of bridging fibrosis (BF) or cirrhosis (Cx).

Results:

Three hundred and two inmates meeting criteria were analyzed. The mean age was 41, 91% were male, and 51% Caucasian. The mean ALT was 94 U/l and 49% had a normal ALT at the time of biopsy. HCV RNA was positive in all tested and 80% were genotype 1. The total HAI was 7.03: 85% had significant hepatitis and 24% had advanced fibrosis. When stratified by race:

  • African Americans were more likely genotype 1 (94% versus 67%; p<.001) and have lower ALT (79 U/l versus 106 U/l; p=.01) with similar overall HAI (6.99 versus 7.59; p=.09) compared to Caucasians.
  • While African Americans had slightly lower fibrosis scores (1.12 versus 1.40; p=.047), there were no differences in percentage of advanced fibrosis (22 versus 28). Those with mild disease (HAI <5) had lower ALT values (68 U/l versus 98 U/l; p<.001) and higher percent with normal ALT (70 versus 46; p=.004) compared to those with significant disease.
  • The sensitivity, specificity, positive and negative predictive values for a normal ALT to predict mild disease were 70%, 53%, 22% and 90% and for an elevated ALT to predict significant histology were 90%, 21%, 53%, and 69%, respectively.
Conclusions:

Significant hepatitis is seen in the majority of inmates with HCV and 24% have advanced fibrosis. There were no clinically significant differences between Caucasians and African Americans. Because ALT had poor accuracy, liver biopsy is essential to identify those with significant or advanced histopathology that might benefit from anti-HCV therapy.

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Abstract 1388
Interaction of Steatosis and Non-Alcoholic Steatohepatitis (NASH) with Chronic Hepatitis C

Zobair M. Younossi, Arthur J. McCullough, Janus P. Ong, David S. Barnes, Anthony Post, Kevin D. Mullen, William Carey, Robert O'Shea, Gavin Levinthal, Terry Gramlich, Lisa M. Martin, Diane Bringman, Anthony S. Tavill, Roy Ferguson

Introduction:

Hepatic steatosis or superimposed NASH may affect HCV-related fibrosis and the efficacy of anti-viral therapy.

Aim:

The aim of this study was to determine the relationship of hepatic steatosis and NASH with chronic hepatitis C (CH-C).

Design:

Patients with CH-C and available liver biopsies who completed a regimen of pegylated interferon alpha-2b (PEG-IFN), ribavirin (RIBA) and amantadine (AMANT) were included {PEG-IFN 1.5 mcg/kg weekly, RIBA 1000-1200 mg/d and AMANT 200 mg/d for 4 weeks, followed by PEG-IFN 0.5 mcg/kg weekly, RIBA 1000-1200 mg/d and AMANT 200 mg/d for another 20 weeks}.

Patients with undetectable HCV RNA at week 24 continued this regimen for 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow up were considered to have SVR. All biopsies were read by one hepatopathologist using METAVIR, modified HAI as well as a Fatty Liver Pathologic protocol.

Patients' baseline clinico-demographic data as well as virologic response were associated with the extent of steatosis (>33% vs. <33%) and the type of fatty liver (No Fatty Liver vs. Steatosis vs. NASH) seen on the biopsy.

Results:

Of 119 patients, 69% were male, age 47.4±5.68, BMI 29.0±4.99, waist/hip ratio (W/H) 0.90±0.08, 79% being white, 84.2% with genotype 1, 6.7% with genotype 2, 7.5% with genotype 3, 0.8% with genotype 4, and 40% with advanced fibrosis (METAVIR F3 and 4). Patients with higher grade of steatosis (>33%, n=14) were more obese (BMI 32.83±1.67 vs. 28.49±0.45, p=0.034), more likely to have HCV genotype 3 (21.4% vs. 5.7%, p=0.037) and advanced fibrosis (64.3% vs. 37.1%, p=0.048) than those patients with lower grade of steatosis (<33%, n=105).

Furthermore, in comparing patients with superimposed NASH (n=22) to those with Steatosis (n=49) and those without Steatosis (n=48), patients with NASH had more evidence of obesity (BMI: 30.64±1.2 vs. 29.90±0.76 vs. 27.33±0.59, p=0.008, W/H 0.97 vs. 0.91 vs. 0.87, p<0.001) and advanced fibrosis (68.2% vs. 44.9% vs. 22.9%, p=0.001).

Neither the extent of steatosis nor the presence of superimposed NASH had an impact on SVR. Race, gender and age did not affect extent of steatosis or presence of superimposed NASH.

Conclusions:

Markers of obesity (BMI and W/H) and HCV genotype 3 are associated with extent of steatosis and type of fatty liver. Higher grade of steatosis and superimposed NASH were associated with advanced fibrosis but not the efficacy of the anti-viral regimen.

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Abstract 1603
Combining INF alfa 2b with PEG-INF alfa-2b and Ribavirin in the treatment of Non-responders to previous therapy and Nieve Genotype 1 patients with Chronic Active Hepatitis C.

Scott M. Gioe

Introduction:

The treatment of patients with Chronic HCV has improved dramatically over the past few years.

We are now seeing sustained virological response rates of 54-59% (41-16% - genotype 1, 88% - genotype 2 & 3) It has been suggested with Peg-IFN alfa 2b that this could be increased to 61% (48%-genotype 1; 88% - genotype 2 & 3) if the ribavirin is weight based dosing with interferon.

PEG-INF alfa 2b(PEG) and Ribavirin (RBV) has recently been shown to have an improved sustained response rate over IFN alfa 2b(INF) and RBV. The improved response is related to the sustained levels of interferon and the weight basing of PEG. Protein pegylation does come with a price as the viral activity of PEG is only 35% that of INF. It is hypothesized that a combination of the two drugs may offer high viral activity as well as sustained pressure on the virus and improve sustain response rates.

Aim:

The aim of this study is to prospectively evaluate the use of a combination of PEG and INF, along with RBV in the treatment of patients with Chronic Active Hepatitis C in naïve genotype 1 patients and non-responders to at least six months of INF +/- RBV therapy.

Methods:

Patients eligible for the study receive PEG at 1.0ug /kg SQ every Saturday. INF is dosed at 3mil or 5mil units SQ every Monday, Wednesday, and Friday (0.5ug/kg/wk) and RBV is given at doses of 12-15 mg/kg/day.

Ribavirin dose adjustments are based on standard treatment practices of the treating physician. IFN dose adjusted for an ANC <750,000 or for platelets <50,000. The use of epoetin alpha and GCSF is permitted in protocol. Quantitative viral load levels obtained pre-treatment and at 12 weeks. A level is drawn at 24 weeks if the 12-week level was still positive.

Patients with persistence of HCV RNA at 24 weeks will be considered non-responders and treatment discontinued at that point. Initial responders will complete 48 weeks of therapy. A qualitative HCV RNA will be check at week 72 on all initial responders to assess sustained response.

All the patients in the non-responder groups have completed 72 weeks and sustained response rates are available.

Treatment duration is for 48 weeks unless HCV RNA is detectable at 24 weeks.

Results:

Results: A total of 35 patients (10 non-responders. and 25 Naive) have been enrolled in the study thus far and 34 patients have been on treatment for at least 12 weeks and have HCV RNA levels for analysis.

Non-responders

  • Six of 10 (60%) of patients had biopsy proven cirrhosis
  • Seven of these patients had genotype 1
  • Nine (90%) had been non-responders to combo – interferon plus ribavirin
  • Eight patients (80%) were initial responders to therapy
  • Three (30%) went on to be sustained virological responders
  • Of the SVR group two of the three had failed combo treatment
  • Two of 4 patients without cirrhosis were sustained responders
Naïve genotype 1 patients
  • Ten of 25 patients (40%) have high viral load
  • Sixteen patients are male (64%)
Naïve genotype 1 patients
  • Initial response rates data is available on 24 of the 25 patients
  • Sixteen (67%) had undetectable HCV RNA
  • At 12 weeks 20 (83%) had undetectable HCV RNA at 24 weeks
  • There did not appear to be any difference between high viral load and low viral load
Dose reductions
  • Three of 34 patients (9%) required dose reductions of interferon
  • Eight of 24 patients (24%) have had their ribavirin doses reduced
Conclusion:

The combination of PEG/INF/RBV in the schedule and doses outlined above can be given safely. Initial response rates to PEG/INF/RBV combination therapy in this difficult to treat patient population are very good and are better than those reported for PEG/RBV. Initial response rates do not insure sustained response rates (SRR). More patients need to be enrolled and sustained response rates need to be obtained in order to draw firm conclusions on its superiority. If these results persist and SRR are high, this could be a method to maximize the effects of interferon in the treatment of this difficult patient population. A large multicenter prospective randomized controlled study comparing PEG/RBV with PEG/INF/RBV in the above patient populations should be performed to see if there is a clinically significant difference in response rates.

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Abstract 1605
Impact of Treatment On Liver Fibrosis In Autoimmune Hepatitis and Chronic Hepatitis B

Reza Malekzadeh, Mehdi Mohamadnejad, Siavosh Nasseri-Moghaddam, Nasser Rakhshani, Seyed Mohamad Tavangar, Amir Ali Sohrabpoor, Soosan Tahaghoghi, Shahin Merat, Nasser Kamalian

Background:

Impact of treatment on fibrosis progression in autoimmune hepatitis (AIH) and chronic hepatitis B (CHB) is unknown. We assessed the changes in liver fibrosis before and after treatment in these two conditions.

Methods:

Fourteen AIH and 20 CHB patients who had paired liver biopsies were enrolled. Six AIH patients were treated with cyclosporine-A for 6 months followed by prednisolone and azathioprine, the rest were treated with prednisolone and azathioprine (median: 2.9 years). Patients with CHB had received lamivudine (median: 1.4 years). Before treatment, the fibrosis progression rate per year (FPR) was estimated as the ratio between fibrosis stage in Modified Hepatitis Activity Index (1 U, 1 stage; 6 U, cirrhosis) and the duration of disease before treatment. Post-treatment FPR was calculated by dividing the observed difference between stages by the interval between biopsies.

Results:

Median interval between biopsies was 2.97 and 2.98 years in patients with AIH and CHB respectively. Median fibrosis stage decreased from 4.07 to 2.35 in patients with AIH (P=0.002). In CHB patients fibrosis stage decreased with treatment but it was not statistically significant (3.15 vs. 2.55; P=0.156). Median FPR in AIH decreased from 5.728 U/year to -0.779 U/year (P< 0.001). Median FPR in CHB decreased from 0.472 U/year to -0.145 U/year (p=0.04). Median FPR before treatment was significantly higher in AIH than CHB (5.728 vs. 0.472 U/year; P< 0.001). Median fibrosis regression rate post-treatment was significantly higher in AIH than CHB (-0.779 vs. -0.145 U/year; P < 0.05). In AIH patients, fibrosis worsened in 1 (7%), improved in 9 (64%), and remained unchanged in 4 (29%). In all 6 AIH patients who were treated with cyclosporine-A, fibrosis improved post-treatment. The use of cyclosporine-A was associated with improvement of fibrosis in AIH (P=0.02). Among 20 patients with CHB, fibrosis worsened in 5 (25%), improved in 10 (50%), and remained unchanged in 5 (25%).

Conclusion:

Liver fibrosis progression before treatment and fibrosis regression after treatment is more rapid in AIH than in CHB. A 6 months course of cyclosporine-A followed by prednisolone and azathioprine may improve fibrosis better than prednisolone and azathioprine in AIH.

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Abstract 1610
Is There Any Relation Between CD81 Polymorphisms, HCV and the Presence of Cryoglobulinemia?

Supriya Joshi, Joshua Schimmer, Elizabeth J. Heathcote, Robert Rottapel

Background:

Mixed cryoglobulinemia (MC) is a complication of chronic hepatitis C virus (HCV) infection--detectable in 50% of HCV patients, but only 1% of patients with HCV have symptomatic cryoglobulinemia. Symptoms may include cutaneous, purpura, arthritis and neuropathy and may predispose to lymphoproliferative disorders. Entry of HCV into hepatocytes and B lymphocytes may result from binding to CD81, a nonglycosylated tetraspanin protein that is widely expressed and involved in immune regulation, B cell stimulation, cell to cell interaction, and neuro-signaling.

Objective:

To determine if polymorphisms in the CD 81 coding reason exist and may be correlated with decrease in laboratory manifestations of cryoglobulinemia. Polymorphisms in the CD81 coding region may predispose patients with HCV to the development of mixed cryoglobulinemia.

Methods:

Forty-three patients with HCV were selected for investigation. Patients with HCV +/- laboratory and clinical evidence of mixed cryoglobulinemia. 34 patients with hepatitis C were examined as well as 16 HCV negative healthy controls (HC). A retrospective chart review assessed patient demographics, manifestations of MC, cryocrit, liver histology, genotype and viral load when available. Lymphocytes were collected from fresh blood samples and RNA was isolated. RT-PCR was used to create a cDNA library for each patient and the CD81 coding region was amplified by PCR, inserted into the pCR® 2.1 TOPO® vector and transformed into competent 1-shot E. coli bacteria. Four clones from each patient were selected for CD81 sequencing and reproducible mutations were identified.

Results:

Sequence analysis was completed for 59 individuals, 16 HC, 9 HCV+/MC- and 34 HCV+/MC+, 22 (64.7%) of whom were symptomatic. Nucleotide aberrancies were found in 5 pts, 4 HCV+/+MC (12%), 0 HCV+/-MC (0%) and 1 HC (6%). Manifestations of MC included 1 skin, 1 renal, 1 skin/neuropathy, 1 skin/renal and 1 skin/renal/arthritis. No patient had overt lymphoma. Of the 5 patients with a CD81 polymorphism, 4 had changes in the coding sequence for the second extracellular region of the protein, to which HCV is reported to bind. However, of those 5 patients, 3 had DNA changes that did not correspond with a change in amino acid coding.

Conclusions:

  • Polymorphisms of CD81 may predispose to the development of MC in patients infected with HCV.
  • As 3 out of 5 polymorphisms did not result in amino acid substitution.
  • 2 polymorphisms did not rise to amino acid changes
  • The frequency of CD 81 polymorphisms in the human population and in the HCV affects cohorts will require the analysis of larger sample sizes
  • Polymorphisms in CD 81 may affect disease susceptibility in HCV patients

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Abstract 1611
Lifestyle and Genetic Risk Factors for Progression of Hepatitis C

Sara H. Olson, Nancy Lau, Sandy Iyer, Daniel Egan, Irene Orlow, Jay Cowan, Temima Markovits, Robert C. Kurtz, Marianne Berwick

Introduction:

In patients with hepatitis C, previous studies have indicated that risk factors for progression and hepatocellular carcinoma (HCC) include male gender, older age, and older age at infection. Some studies have reported slower progression in blacks than in whites. Individual differences in genes that are involved in the process of inflammation may also affect progression. We studied these and other potential risk factors in a hospital-based study in NYC. Our interviewers approach people in the clinics at Memorial Sloan-Kettering and North General Hospitals, obtain informed consent, administer a questionnaire, and collect mouthwash specimens for DNA. Participants fill out questionnaires on diet, family history, and quality of life. This analysis reports on 116 patients for whom data on stage based on liver biopsy were available, and includes 24 with hepatocellular carcinoma (HCC). Based on the questionnaire, we estimated route of infection (transfusion, intravenous drug use (IVDU), or other route), age at infection, and length of time infected. We studied the association of these variables, as well as age, gender, race, and GSTM1 genotype (null or present) with stage of disease. Stage of disease was dichotomized into early (stage 0, I, II, n=58) and late (stage III, IV or HCC, n=58). In univariate analysis, older age, higher number of years infected, infection at later ages (twenties or older), and infection through IVDU were significantly associated with increased risk of higher-stage disease. Odds ratios (ORs) were 6.3 for age >=60; 2.6 for infected >=35 years; 2.6 if infected in ones 20s vs earlier; and 2.6 if infected by IVDU. Older age remained a significant risk factor in all multivariate analyses and was a stronger factor than number of years infected or age at infection. Adjustment for age increased the strength of the association for IVDU (OR=5.0). Gender and race were not significantly associated with stage. With stratification by age, however, male gender increased risk among younger patients (OR=5.3), but not among older patients (OR=1.2). In addition, risk associated with IVDU was higher among younger patients (OR=7.6) than among older patients (OR=1.9). Patients who had the null genotype of GSTM1 were at higher risk, with an odds ratio of 2.4 (p=.04) after controlling for race. The number of patients with higher-stage liver disease is likely to increase as the infected population ages and as IVDU becomes a more prevalent mode of infection. Differences in genes involved in inflammation may affect individual risk.

Background:

4 million people in the United States are infected with hepatitis C and are at increased risk for cirrhosis and hepatocellular carcinoma (HCC). Progression of disease widely varies among individuals. We are studying risk factors for progression including genetic susceptibility in a hospital-based case controlled study in New York City.

Method:

Study Participants

  • Patients at Memorial Sloane Kettering Cancer Center or North Central Hospital
  • Positive for HCV by PCR
  • > or = 18 years of age
  • Able to speak English
Data Collection
  • Questionnaire to determine route of infection and risk factors for progression; administered by interviewer
  • Diet history (Block96Brief)
  • Quality of Life (QOL) – SF-36
  • Family history of cancer
  • Mouthwash specimen for genotyping
Data Analysis
  • 116 patients of whom we had data on stage based upon liver biopsy
  • Includes 24 patients with hepatocellular carcinoma (HCC)
  • Assigned route of transmission based on responses to questionnaire
  • Estimated age of infection and length of time infected by questionnaire
  • Compared those with earlier stage (0, I, II, n=58) to those with late stage (III, IV) or HCC n=58
  • Results of genotyping available on a subgroup of respondents
Results:

Age, age infected and length of time infected-Older age at interview or at diagnosis of HCC was a strong risk factor for late stage liver disease. The age at infection or length of time infected had less influence. In multivariate analyses, we adjusted separately for gender, race and route of infection. Being > or = 60 years of age at interview or diagnosis remained strongly associated with risk after adjustment.

Gender-Men were at slightly elevated risk of later stage liver disease in our study population. Male gender was a strong risk factor among younger patients, but not among older patients.

Route of Injection-People infected by injection drug use compared to other routes were at somewhat increased risk of late stage liver disease. This effect was stronger after adjustment for age. The effect of injection drug use was stronger among younger patients.

Genetic Susceptibility-Patients who were null for GSM-1 were at increased risk of later stage liver disease. As expected genotype was associated with race; among blacks, 25% had the null genotype, compared to 52% among whites. The association with later stage remained after adjustment for race.

Conclusions:

The number of patients with higher stage liver disease is likely to increase as the infected population ages and as IVDU becomes a more prevalent mode of infection. Genetic variation my influence risk of progression.

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Abstract 1613
Safety, Tolerability And Efficacy Of Interferon Alfa 2b And Ribavirin Combination Therapy In HCV Patients With Cirrhosis

Ravi Ravinuthala, Vosudesh Pai, Dilip Moonka, Kimberly Brown

Introduction and Purpose:

HCV infected patients with advanced liver disease are high risk for treatment with combination therapy with Interferon and Ribavirin due to tolerability and safety issues. However, successful treatment halts progression of the disease and reduces risk of HCC, but limited data is available. We report our experience in treating this high risk group.

Materials and Methods:

Patients attending the Henry Ford Liver Center, Detroit, MI with cirrhosis or severe bridging fibrosis on liver biopsy were included in this study. All patients received standard combination therapy with Interferon 3 MU thrice-a-week and ribavirin 1000 or 1200 mg twice a day depending on the weight where possible. Side effects, laboratories were monitored monthly and dose was modified if necessary. Hemopoetic growth factors were used only if deemed necessary by the treating physician. HCV RNA was checked at the end of six months, one year and 18 months. Treatment was stopped if HCV RNA was positive at 6 months of treatment. If negative at 6 months, treatment was continued for 12 months. End of treatment response (ETR) was defined as negative HCV RNA at 12 months of treatment and sustained viral response (SVR) meant negative HCV RNA at 18 months.

Results:

62 patients were included in the study. 2 (3%) patients did not complete the treatment due to side effects and were excluded from final analysis. 69% were Caucasian and 31% were African American. Male to female ratio was 7:3 (68% male; 32% female). Age ranged from 33-69 with a mean of 49.5. Cirrhosis was present in (50%) and (40%) had bridging fibrosis on biopsy. All patients were clinically Child's A class at the time of treatment although some had decompensation in the past. Majority were genotype 1. Platelet count ranged from 48,000-402,000 with a mean of 161,000 and mean viral load was 664395 I.U. Dosage reduction was required in 9 (15%) patients and erythropoietin was required in 2 patients. Two (3%) of patients did not complete the study due to adverse events. ETR was seen in 24 (39%) with SVR in 13 (23%). SVR in previous non responders was 61% as compared with 16% in naive patients.

Summary/Conclusions:

  • Male gender and African American race were associated with poor sustained response rates.
  • SVR in patients previously treated with interferon was higher than the total group.
  • Sustained response, discontinuation and dose reduction rates compare favorably with published literature.
  • Combination therapy in patients with advanced fibrosis appears safe and well tolerated
  • Prospective controlled trials are needed to establish the long term benefits in patients with viral clearance.

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Abstract 1614
Severity of Liver Disease in HCV Infected Dialysis Patients Awaiting Renal Transplantation

Renee Pozza, Else Albanese, Karel Biando, Erik Wahlstrom, Tarek Hassanein

Background:

Hepatitis C viral infection (HCV) is common in patients with end stage renal disease. 20-40% of patients on hemodialysis are infected with HCV. In 1997, 0.7% of patients receiving renal transplantation in the U.S. were positive for HCV antibodies. HCV viremia and disease activity is expected to increase as a result of immune suppression post-renal transplantation. Liver histology is crucial in evaluating patients for transplantation to avoid post-transplantation liver decompensation and failure.

Aim:

The aim of this study is to identify severity of liver disease in HCV infected patients undergoing evaluation for renal transplant. Additionally this study will determine if HCV infected patients are candidates for renal transplantation by identifying the extent of their liver disease.

Methods:

  • Studied subjects with ESRD who were on dialysis undergoing evaluation for renal transplantation. All subjects were seropositive for anti-HCV
  • Livery injury test, viral load by PCR and HCV genotype were obtained for all patients during the transplant evaluation
  • Liver biopsies were scored for degree of fibrosis and extent of inflammation using the Metavir score
    • Stage 0 – No fibrosis
    • Stage 1 – Mild fibrosis (fibrous portal tracts)
    • Stage 2 – Moderate fibrosis (early septa)
    • Stage 3 – Severe fibrosis (portal-portal or portal-central bridging)
    • Stage 4 – Cirrhosis (bridging fibrosis/regenerative nodule formation)
Results:
  • 25(57%) were males and 19(43%) were female.
  • Mean age was 52.4 years (range 24-72 years).
  • 25% Caucasian, 34% Hispanic, 21% African American, 11% Asian, 7% Native American and 2% other.
  • 84% were on hemodialysis while 16% were on peritoneal dialysis.
  • 72% of patients have a viral titer <1 million copies/ml and 17% >1 million copies/ml using the superquant assay.
  • 11% of the patients were HCV-RNA negative by PCR. 72% were genotype 1a/1b, 12% 2b, 12% 3a and 4% were genotype 4.
  • The mean ALT and AST levels were 61 and 40 iu/dl respectively.
  • Histologically 3% had severe inflammation, 40% had moderate inflammation and 57% had mild inflammation.
  • Fibrosis scores were 0,1,2,3,4, in 31%, 36%, 11%, 17% and 5% respectively.
  • Iron staining was positive in 89% of the biopsies. Severe iron deposition was seen in only 14% of the patients.
  • All patients were considered candidates for renal transplantation.
Conclusion:

Patients with ESRD on dialysis have mild histological disease. 0% of our cohort had advanced disease while 71% had mild and 29% had moderate disease. Therefore a liver biopsy is essential in evaluating HCV infected patients for renal transplantation. Since HCV disease progression is relatively slow even with immunosuppression, the majority of HCV-infected patients in our cohort were candidates for renal transplantation.

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Abstract 1616
The ?32 Mutation of the Chemokine-receptor 5 Gene is Neither Correlated with Chronic Hepatitis C nor Does it Predict Response to Therapy with Interferon-a and Ribavirin

Juergen Glas, Helga-Paula Torok, Christian Simperl, August Koenig, Katja Martin, Folkhard Schmidt, Martin Schaefer, Christian Folwaczny

Background:

As opposed to patients infected with HIV, homozygosity for a 32 bp deletion (?32) of the chemokine-receptor 5 (CCR5) gene was recently described in increased frequency in patients with chronic hepatitis C. Thus, it was speculated that this mutation might be relevant for disease susceptibility and influence the response to antiviral therapy. While a protective effect of this homozygous mutation against HIV infection is widely accepted, its role in hepatitis C is not yet clear.

Aim:

The present study sought to confirm the association between chronic hepatitis C and the ?32 mutation of the CCR5 gene and to correlate it with the response to therapy with interferon-a-2a and ribavirin.

Methods:

62 patients with chronic hepatitis C and 119 healthy unrelated controls were genotyped for the ?32 mutation by PCR and agarose gel electrophoresis. For the correlation between the ?32 mutation and response to therapy only patients (n=59) who completed six months of combination therapy as part of a prospective study were evaluated.

Results:

The ?32 mutation was not observed in increased frequency in chronic hepatitis C. Furthermore, a significant difference concerning the viral load or aminotransferase values was not observed in carriers versus non-carriers of the ?32 mutation. After stratification for potentially confounding factors such as gender or HCV-genotype a significant difference was also not detected with respect to treatment outcome.

Conclusions/Comments:

These observations argue strongly against a role of CCR5 for susceptibility to chronic infection with HCV or response to combination therapy with interferon-a-2a and ribavirin. However it has to be taken into account that our results are solely based on viral load and ALT value whereas data concerning histopathology and sustained virological response rates are lacking.

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Abstract 1618
Effect of a Low Iron Diet in Chronic Hepatitis C

Tomoko Katoh, Kazutomo Suzuki, Hiroshi Takada, Gordon Luk, Hajime Kuwayama

Background and Aims:

Excessive hepatic iron deposition contributes to the progression of liver disease in hemochromatosis; and plasmapheresis or iron chelation are the mainstay of therapy. It is unclear whether excessive iron deposition may also contribute to progression of other chronic liver diseases, such as hepatitis C, and whether a low iron diet alone may be therapeutic. We therefore investigated the effect of a low iron diet in chronic hepatitis C.

Methods:

In a preliminary study, we measured serum alanine transaminase (ALT) and ferritin levels in 111 patients with chronic hepatitis C. The effect of a low iron diet was studied in 23 of these patients who did not use alcohol and did not have previous gastric surgery (8 male and 15 female, 62+/-10 years old); and compared to 53 patients not on a special diet. Individual patient consulted their nutritional status for 6 months. By face to face interview patients were asked to change iron-rich food to another one. We measured serum ALT and ferritin levels, albumin (ALB), hemoglobin (Hgb), and red blood cell count (RBC).

Results:

  1. Serum ferritin levels in chronic hepatitis patients were significantly higher than those in the health subjects
  2. Serum ALT was higher in patients with high ferritin levels than those with normal or low ferritin levels
  3. Serum ALT levels were decreased by a low iron diet
  4. Serum ferritin levels were decreased by a low iron diet
  5. Low iron diet was very useful in 40% of patients (normalized ALTs) in chronic hepatitis C
  6. No remarkable changes were noted in nutritional parameters such as hemogoblin and albumin
Conclusion:

A low iron diet appears to be safe and effective in patients with chronic hepatitis C, and may be an alternative treatment option in patients who do not respond to or are not candidates for interferon therapy.

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Abstract 1621
Prevalence of Hepatitis C Virus (HCV) Infection in Non-Hodgkin's Lymphoma (NHL). Systematic Review and Meta-analysis

Javier P. Gisbert, Ml Garcia-Buey, Jm Pajares, R. Moreno-Otero

Aim:

To conduct a systematic review of studies evaluating HCV prevalence in B-cell NHL (B-NHL), and to perform a meta-analysis of case-control studies comparing this prevalence with a reference group.

Methods:

All studies evaluating HCV prevalence in patients with B-NHL were considered. Studies comparing HCV prevalence in B-NHL (cases) and in a reference group (controls) were included in the meta-analysis. Bibliographical searches were conducted in several electronic databases. Prevalence (weighted mean) of HCV infection was calculated. Meta-analysis was performed combining the Odds Ratios (OR).

Results:

Fifty studies (including 5,632 patients) evaluating HCV were identified, with 13% mean prevalence of infection (95%CI: 12-14%). This figure was higher in countries as Italy (20%) and Japan (16%). Ten studies compared HCV prevalence in B-NHL (17%) and in blood donors or healthy subjects (1.5%) (OR: 10.8; 95%CI: 7.3-16), results being homogeneous. OR increased up to 14.1 when only Italian and Japanese studies were considered. Sixteen studies compared HCV prevalence in B-NHL (13%) and other haematological malignancies different from B-cell NHL (2.9%) (OR: 4.2; 95%CI: 2.5-7), also without heterogeneity. This figure increased up to 7.5 when sub-analysis included only the Italian studies.

Conclusion:

HCV prevalence in patients with B-NHL is approximately 15%, higher than that reported not only in general population (1.5%) but also in patients with other haematological malignancies (2.5%), suggesting a role of the virus in the aetiology of B-NHL. The striking geographical variation in this association suggests that genetic and/or environmental factors are also involved in the pathogenesis of this disorder.

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Abstract 1622
Racial Differences in Treatment Response to Hepatitis C Virus in a Large Urban Health System

John Riopelle, Lisa Forman, Sharon Bahrych, Katherine Doll, Neil Toribara

Background:

Minority populations are disproportionately affected by hepatitis C virus (HCV), with estimated seroprevalences of 2.1% in Hispanics, 3.2% in African-Americans, and 1.3% in whites. Several studies have reported that African-Americans do not respond to treatment of chronic HCV infection with the same efficacy as Whites. To our knowledge no published study has evaluated the response rate of Hispanics to HCV treatment. Because our institution (Denver Health Medical Center, Denver, CO) serves a predominantly minority population - 52% Hispanic, 13% African-American and 25% white - we are uniquely positioned to investigate this question.

Methods:

We retrospectively reviewed all patients who completed treatment for HCV in our institution from January 1, 2000 until October 31, 2002. Data regarding self-reported demographics and virologic response were obtained via retrospective electronic chart review. HIV-positive patients and those with Childs class B or C were either not treated or excluded from analysis. Patients received several different regimens of interferon and ribavirin for either 24 weeks (non-genotype 1) or 48 weeks (genotype 1). Those with an end treatment sustained virologic response (SVR) returned at 6 months for follow-up viral load.

Results:

Fifty of 68 patients who began treatment finished the intended duration of therapy. The racial distribution of this group was 57.4% white, 30.9% Hispanic, and 7.4% African-American.

White and Hispanic groups had similar age and genotype 1 distribution (63% v. 61.1%). Gender distribution revealed a male:female ratio of 2:1 in whites and 1:2 in Hispanics.

Sustained virological response rates

  • Total – (25/68) – 36.8%
    • White (16/39) – 41%
    • Hispanic (8/21) – 38.1%
    • There were no sustained responders in the African American group
Conclusion:
  • The preliminary data suggests that, in our patient population, Hispanic and white patients have similar rates to HCV treatment.
  • Minority populations are underrepresented in HCV diagnosis and treatment groups compared to Denver Health’s racial distribution and the expected prevalence of HCV from large population studies like NHANES
  • Prospective studies with standard treatment regimes are necessary to assess present standard of care and treatment response.

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Abstract 1625
The Rate of Treatment of Hepatitis C in Patients Co-infected With HIV in an Urban Medical Center

Alexander Restrepo, Timothy C. Johnson, David Widjaja, Lonny Yarmus, Kevin Meyer, Henry C. Bodenheimer Jr., Albert D. Min

Introduction:

Hepatitis C virus (HCV) and HIV co-infection is a common clinical scenario because of shared risk factors. HIV significantly worsens liver disease in HCV infected patients, with a higher rate of progression and shorter time interval to development of cirrhosis than in patients without HIV. Successful treatment and eradication of the virus with interferon-based therapy reduces the morbidity and mortality of HCV infection. However, the applicability of the currently available treatment in the co-infected population in a community setting is unknown.

Objective:

Our objective was to determine the rate of treatment of hepatitis C in a HCV/HIV co-infected population in an urban medical center. Methods: We conducted a retrospective study of HCV/HIV co-infected patients consecutively evaluated at the liver/GI clinics at Beth Israel Medical Center for treatment of HCV during a 12 month period from July 2001 to June 2002. The patient characteristics and the decision to treat or not were recorded. Reasons for non-treatment were noted.

Results:

One hundred four co-infected patients were identified. Of these, 77 (73%) patients were males. The mean age was 48 years (range 32-72). Seventy-four of the 83 (89%) patients whose risk factor for HCV infection was known had a history of intravenous drug use. Overall, 21 (20%) patients had liver biopsy performed. Fourteen (67%) of those who had a liver biopsy were treated.

  • Of the total group, 16 (15%) patients were treated.
  • Ninety three patients were not treated for the following reasons:
    • 13 refused treatment
    • 30 were non-compliant with visits during the evaluation period
    • 11 were actively abusing alcohol and/or intravenous drugs
    • 10 had decompensated cirrhosis
    • 6 had a significant active psychiatric condition precluding treatment
    • 23 had significant co-morbid disease precluding treatment.
Conclusions:

A majority of patients co-infected with HCV/HIV seen at out urban liver/GI clinics had a history of intravenous drug use. Most co-infected patients were not considered to be candidates for interferon-based treatment of HCV. Educating patients about the importance of treatment and improving patient compliance during the pretreatment evaluation period may have a significant impact on the rate of treatment in these co-infected patients.

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Abstract 1626
The Role of Helicobacter Pylori Infection on the Natural History of HCV and the Impact on the Response toTherapy

Maher Azzouz, Christopher J. Christensen, Gagan Sood

Introduction:

Helicobacter Pylori infection (H. Pylori) plays an established role in both peptic ulcer disease and lymphoma. Many recent studies have implicated chronic infections with organisms such as H. Pylori, Chlamydia, and CMV on many chronic inflammatory states and neoplastic processes. Patients with chronic hepatitis C Virus (HCV) infection have increased prevalence of H.Pylori infection.

Objective:

The possibility of an abnormal immune state due to chronic H. Pylori could theoretically impact the natural history of HCV and response to treatment.

Methods:

We retrospectively evaluated a group of patients with chronic HCV from our clinic from July 1999 to June 2002 with and without H. Pylori in regards immune status, liver pathology and response to treatment. Seventy-five patients with chronic HCV infection were enrolled in the study. 56% of these patients were H. Pylori serum antibody negative and 44% were positive. Sixty of the total patients underwent treatment with antiviral therapy. Data collected and compared on the two groups included race, sex, age, BMI, serum ferritin level, Immunoglobin G (humeral immunity) and response to PPD. Each patient also underwent liver biopsy and the two groups were compared regarding degree of inflammation and fibrosis on biopsy.

Results:

H. Pylori infection was found to be more prevalent in African American patients with HCV with a probability of p=0.0004. Also of statistical significance, it was discovered that the patients with chronic HCV who were serum H. Pylori positive had a lesser degree of fibrosis (mean 1.27 ± 1.2) versus H. Pylori negative ( 1.95± 1.48). There was no statistically significant difference in mean IgG levels, PPD response, age, sex, or ferritin level in the two groups. Response to antiviral therapy was also not impacted by the H. Pylori status.

Conclusions:

Our preliminary findings suggest a decreased degree of fibrosis in HCV patients co-infected with H. Pylori and show no association with co-infection and response to antiviral therapy. A larger sample size and further studies involving other inflammatory and immune markers may reveal the role H. Pylori infection has in chronic HCV infection and its treatment.

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Abstract 1628
Is Hepatitis C Genotype a Major Determinant in The Decision to Perform Liver Biopsy in Patients with Chronic Hepatitis C?

David Stokesberry, Muhammad K. Hasan, David M. Thompson, Aura Parra, Sikandar A. Mesiya

Purpose:

Appropriate clinical practice regarding management of chronic hepatitis C continues to evolve. Pre-treatment hepatitis C genotype determines treatment duration and predicts response rate. Liver biopsy is the most reliable test to assess the disease activity and prognosis. However, recent National Institute of Health recommendations have questioned the routine need for liver biopsy in patients with genotypes other than type 1.

This study surveyed gastroenterologists and hepatologists to establish the relative importance and weight given to hepatitis C genotype in formulating the decision to recommend liver biopsy.

Methods:

A 15 question, two-page questionnaire was mailed to 3891 randomly selected members of the clinical practice section of the American Gastroenterology Association. Differences in means and response proportions were analyzed with t-tests and chi-square tests, respectively.

Results:

311 of 3891 (34%) surveys were returned. Ninety-three percent of the respondents were general gastroenterologists and 7% were hepatologists. Seventy one percent were in private practice, 16% in academics and 13% were both. Eighty percent of the respondents surveyed advocate liver biopsy for patients with chronic hepatitis C. Seventy six percent of them recommend biopsy regardless of the genotype. The presence of non-1 genotype prompted 18% of respondents to be negatively disposed to recommend liver biopsy while 6% of respondents viewed this result as a positive factor in recommending liver biopsy.

Academic gastroenterologists were more likely than private practice gastroenterologists to defer liver biopsy in patients with non-1 genotype (26% versus 17% p=0.0071). Similarly, hepatologists recommend fewer liver biopsies in patients with non-1 genotype as compared to general gastroenterologists (30% versus 19% p=0.0046). Practices that see greater numbers of patients with hepatitis C are strongly associated with a decreased likelihood to advise biopsy in non-1 genotype patients (p<0.0001).

Conclusions:

The majority of surveyed private gastroenterologists currently advise liver biopsy for chronic hepatitis C regardless of the genotype. The decision not to recommend liver biopsy in non-1 genotype subjects was significantly higher in respondents who had an academic affiliation, sub specialized in hepatology or devoted a large proportion of their practice to treat hepatitis C.

It is unclear if those that don’t recommend liver biopsy changing practice patterns based in genotype or simply clinical preference. Future studies may be needed to determine the necessity of liver biopsy in various subsets of patients with chronic hepatitis C.

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Abstract 12603
Combining INF alfa 2b with PEG-INF alfa-2b and Ribavirin in the treatment of Non-responders to previous therapy and Nieve Genotype 1 patients with Chronic Active Hepatitis C.

Scott M. Gioe

Introduction:

PEG-INF alfa 2b(Peg Intron) and Ribavirin (RBV) has recently been shown to have an improved sustained response rate over IFN alfa 2b(INF) and ribavirin. The improved response is related to the sustained levels of interferon and the weight basing of PEG. Protein pegylation does come with a price as the viral activity of PEG is only 35% that of INF. It is hypothesized that a combination of the two drugs may offer high viral activity as well as sustained pressure on the virus and improve sustain response rates.

Aim:

The aim of this study is to prospectively evaluate the use of a combination of PEG and INF, along with RBV in the treatment of patients with Chronic active hepatitis C in naive genotype 1 patients and non-responders to at least six months of interferon plus ribavirin therapy.

Methods:

Patients eligible for the study receive PEG at 1.0ug /kg SQ every Saturday. Interferon is dosed at 3mu or 5 mu SQ every Monday, Wednesday, and Friday (0.5ug/kg/wk) and ribavirin is given at doses of 12-15 mg/kg/day.

Treatment duration is for 48 weeks unless HCV RNA is detectable at 24 weeks.

Results:

A total of 35 patients (10 non-responders and 25 Naive) have been enrolled in the study thus far and 29 patients have HCV RNA levels that are available for analysis. HCV RNA is undetectable in 25/29 (86%) patients. Of the non-responders, 8/10 (80%) became HCV RNA negative on treatment. Nineteen of the twenty-five naive genotype 1 patients have completed at least 12 weeks and 17/19 (89%) have undetectable HCV RNA.

Dose reductions of PEG/INF were required in 2/35 (6%) patients. Six patients out of 35 (17%) have required dose reductions in RBV. No serious adverse events have been noted so far.

Conclusion:

The combination of PEG/INF/RBV in the schedule and doses outlined above can be given safely. Initial response rates to PEG/INF/RBV combination therapy in this difficult to treat patient population are very good and are better than those reported for PEG/RBV.

Initial response rates do not insure sustained response rates (SVR). More patients need to be enrolled and sustained response rates need to be obtained in order to draw firm conclusions on its superiority. If these results persist and SVR are high, this could be a method to maximize the effects of interferon in the treatment of this difficult patient population. A large multicenter prospective randomized controlled study comparing PEG/RBV with PEG/INF/RBV in the above patient populations should be performed to see if there is a clinically significant difference in response rates.

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Hepatitis C Support Project

(C) 2004. Hepatitis C Support Project

Medical  Writers' Circle
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