May 16, 2005

Abstract ID: M965

Long-Term Progression Of Fibrosis in Patients With Chronic Hepatitis C (CHC) Non-Responders To Interferon Therapy (IFN). a Longitudinal Study Of Repeat Liver Biopsies

R. Planas, I. Cirera, I. Ojanguren, M. Giménez, M. Rivera, M. Gimeno, C. Barranco, C. Tural, R. Solà

Introduction

Few studies have examined the degree of fibrosis progression in patients with CHC non-responders to IFN.

Aims

To assess the rate of fibrosis progression in CHC patient’s non-responders to IFN and to identify associated variables.

Patients and methods

84 patients (50.5±1.3 years) with CHC non-responders to IFN, and without cirrhosis in their initial biopsy, followed for 8.1±0.2 years. In 67 of them a second liver biopsy was performed after 8.6±1.7 years. In the remaining 17 cases the second biopsy was not performed because the diagnosis of cirrhosis was established after hepatic decompensation (10) or hepatocellular carcinoma (7). Liver biopsy samples were re-examined blindly by a pathologist who was unaware of the clinical and biochemical data of the patients or the order of the biopsies. Studies on the liver biopsies included assessment of fibrosis (METAVIR), and of steatosis.

Results

In the basal biopsy, fibrosis was F0 in 19 patients, F1 in 19, F2 in 10 and F3 in 36. Steatosis was absent in 40 cases, but was grade I in 36 and grade II in 8 cases. The overall rate of fibrosis progression was 0.104 units per year. Fibrosis progression was found in 52 patients (62%) (13/19 patients with F0 in the basal biopsy, 11/19 F1, 6/10 F2, and 22/36 F3). Variables associated with fibrosis progression were age, HCV-RNA, GGTP, AP, AST/ALT, platelets, cholesterol and steatosis in the initial biopsy. The independent predictors for fibrosis progression were platelet count (OR 0.09; 95%IC: 0.01-0.67) and steatosis (OR 4.96; 5%IC: 1.11-25.5). 27 patients (32%) developed cirrhosis (1 with F0 in the basal biopsy, 3 F1, 1 F2, and 22 F3), and 11 patients (13%) developed hepatocellular carcinoma.

Conclusions

1. The results of this longitudinal study have shown progression of liver fibrosis, cirrhosis and hepatocellular carcinoma development in approximately one half, one third and one tenth, respectively, of CHC patients non-responders to IFN in a median follow-up of 8 years.

2. The variables independently associated with fibrosis progression were thrombocytopenia and steatosis in the initial biopsy.

3. Re-treatment is highly indicated in this subgroup of patients with high risk of fibrosis progression.

Abstract ID: M1031

Regression Of Lymphoproliferative Disorders After Treatment for Hepatitis C Infection? A Systematic Review

Authors: J.P. Gisbert, L. Garcia-Buey, J. Pajares, R. Moreno-Otero

Aim

To systematically review the experience of therapeutic studies where alfa-interferon (IFN) with or without ribavirin (RBV) was administered to patients with lymphoproliferative disorders, in order to evaluate whether eradication of hepatitis C virus (HCV) may induce regression of lymphoproliferative disorders.

Methods

Bibliographical searches were performed in several electronic databases and in the Cochrane Controlled Trials Register, looking for several key words related with “Hepatitis C” and “Lymphoma”. Articles published in any language were included. Patients with only mixed cryoglobulinemia but with no other associated lymphoproliferative disorders were not included.

Results

Sixteen therapeutic studies where antiviral regimen (with IFN with or without RBV) was administered to HCV-infected patients with lymphoproliferative disorders (mainly low-grade, but also intermediate/high grade non-Hodgkin’s lymphomas) have been performed, including a total of 65 patients. Complete remission of the lymphoproliferative disorder was achieved in 75% (95% confidence interval, 64-84%) of the cases. In contrast with infected patients, HCV-negative subjects did not respond to IFN therapy, indicating that the response observed in the HCV-infected patients is not merely due to the antiproliferative effect of IFN. Remission of lymphoproliferative disorders after HCV eradication with IFN was maintained, provided that HCV infection did not reappear; however, viral relapse was usually followed by recurrence of lymphoma. Several studies demonstrated a similar response to chemotherapy in non-Hodgkin’s lymphoma patients infected and non-infected with HCV. It was reported that in HCV-infected patients with non-Hodgkin’s lymphoma treated with corticoids and chemotherapy liver function tests deterioration did not occur, thus indicating that immunosuppressive therapy does not, apparently, increase HCV replication. Some studies suggest that the addition of IFN to standard CHOP may decrease hepatic side effects of chemotherapy.

Conclusion

Although it is evident that larger therapeutical trials of antiviral therapy are needed to determine the role of this strategy in HCV-infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that IFN (plus RBV) is an attractive therapeutic option for some HCV-related low-grade lymphomas. Multicenter controlled studies with pegylated IFN plus RBV are eagerly awaited.

Abstract ID: M1236

Knowledge and Practices Of Internal Medicine Residents in the Management Of Chronic Hepatitis C (HCV) Infection: a Prospective Multicenter Survey

Authors: J.K. Lim, J.S. Ng, D.D. Proctor

BACKGROUND/AIMS

Primary care physicians may be inadequately prepared to evaluate and manage patients with chronic HCV infection. Identification of specific areas of knowledge deficit among internal medicine residents may provide targets for educational intervention.

METHODS

We administered a structured 1-page survey assessing knowledge and practices regarding HCV infection to 251 internal medicine residents at 8 ACGME-accredited U.S. training programs.

RESULTS

Residents were equally distributed among three post-graduate years. 89.6% were U.S. medical graduates, most were enrolled in traditional (64.9%) or primary care (22.7%) programs, and nearly all (98.0%) had seen patients with HCV within the past year, 60.6% of whom had seen >10 patients. Although most screen for HCV in patients with abnormal LFT’s (85.3%), prior needlestick exposure (82.1%), prior IVDU (80.9%), or HIV co-infection (77.7%), few performed screening in other at-risk populations, including individuals with a history of transfusion (59.8%), snorting cocaine (26.7%), or incarceration (21.5%). Only 45.5% and 36.7%, respectively, use the diagnostic tests HCV PCR and genotype appropriately. Only a fraction vaccinate HCV (+) patients for protection against HAV (33.1%) or HBV (61.4%), and few were familiar with recommended vaccination schedules, 19.5% and 64.5%, respectively. Some report they vaccinate HCV (-) individuals with HCV vaccine (20.3%) although it does not exist. Only 25.5% and 22.3%, respectively, correctly identified genotype 1 as the most common in the U.S., and least responsive to antiviral therapy. Only 30.7% named HCV as the #1 indication for liver transplantation. Although most correctly cited EtOH (80.5%), HIV (75.3%), and HBV (64.1%) as risk factors for disease progression, only 10.0% and 14.7%, respectively, correctly estimated the rate of chronic viremia following exposure, and risk for developing cirrhosis at 20 yrs of infection. Only 35.5% identified IFN/RV or PEG-IFN/RV as 1^st line antiviral therapy – 30.7% incorrectly named lamivudine. Few residents feel adequately trained in HCV management (23.9%).

CONCLUSIONS

Many internal medicine residents receive inadequate training in the management of chronic HCV infection. Most lack basic knowledge regarding the epidemiology, natural history, diagnosis, clinical course, and treatment of HCV. Targeted educational interventions are needed to address knowledge deficits among future primary care physicians.

Abstract ID: M1239

Patient Knowledge Of Hepatitis C Virus (HCV) Infection: a Comparison Between HCV-Infected Patients and HCV Negative Subjects

Authors: N.B. Shukla, C. Tenner, A. Aytaman, G. Villanueva, E.J. Bini

BACKGROUND

Knowledge of risk factors for acquiring HCV infection is crucial to reduce transmission. The aim of our study was to assess patient knowledge of modes of HCV infection and long-term health problems.

METHODS

403 patients with chronic HCV infection and 556 HCV negative controls completed a survey at the time of their outpatient clinic visit at 3 study sites. Data collected included patient demographics, knowledge of HCV risk factors, and HCV-associated health problems. Each patient completed anonymous questionnaire of 14 questions. Limited knowledge of participants was defined as less than 25% of correct answers.

RESULTS

· The median patient age was 57 years (HCV + pts, 56.3 ± 9.7; HCV - pts, 56.4 ± 11.1), 87.8% were male,

· The majority were of low socioeconomic status.

· The demographic characteristics of the HCV+ and HCV- patients were similar.

· Ethnic/Racial characteristics:

o Non-Hispanic White- HCV + = 29.3%, HCV – = 45.7%

o Non-Hispanic Black – HCV + = 40.7%, HCV - = 31.7%

o Hispanics – HCV + = 24.6%, HCV - = 17.1

o Other - HCV + = 5.5%, HCV – 5.6%

· Alcohol use:

o None – HCV + = 68.5%, HCV - = 54.9%

o 1-6 drinks/day – HCV + = 22.1%, HCV - = 35.4%

o 7 or more drinks/day – HCV + = 9.4%, HCV - = 9.7%

· HCV+ and HCV- subjects, respectively, agreed/strongly agreed:

o HCV can be transmitted by one-time injection drug use (74.4% vs. 61.9%, P <0.001),

o Blood transfusion (72.7% vs 51.3%, P <0.001),

o Sexual intercourse (65.0% vs 58.8%, P = 0.52),

o Tattoos (72.7% vs 51.3%, P <0.001),

o Body piercing (69.0% vs 48.6%, P <0.001),

o Sharing razors (72.5% vs 51.4%, P <0.001)

o Toothbrushes (58.3% vs 46.4%, P <0.001),

o Holding hands (4.7% vs 9.9%, P <0.003),

o Coughing (59.2% vs 25.2%, P <0.001),

o Eating contaminated food (17.9% vs 31.3%, P <0.001).

o Mother to child (53.3% vs. 56.8%, P=2.8)

HCV+ patients were less likely to think that IV drug use is the only way to get HCV (25.1% vs. 31.7%, P = 0.002) and more likely to know that condoms protect against HCV infection (63.8% vs. 40.5%, P <0.001). Among HCV+ patients, whites were more likely than blacks, Hispanics, or other races to know that one-time injection drug use (94.1% vs 74.6% vs 78.3% vs 71.4%, P = 0.003) and blood transfusions (94.8% vs 74.4%, vs 78.1%, vs 78.6%, P = 0.004) were risk factors for HCV infection and that condoms can prevent HCV transmission (84.4% vs 57.9% vs 56.2% vs 50.0%, P <0.001).

CONCLUSIONS

1. Patient knowledge of risk factors for HCV infection and transmission is limited, especially among those who are not infected.

2. Limited knowledge of risk factors for HCV infection was more common among older patients, those of low socioeconomic status, and racial ethnic minorities.

3. Public health programs to educate patients about HCV risk factors are needed to reduce HCV transmission.

Abstract ID: M1238

Liver Stellate Cell Activation in Chronic Hepatitis C: Correlation With the Fibrogenic Markers Piiip and TGF Beta1. the Effect Of Interferon-Ribavirin Therapy.

Authors: F. Serejo, A. Costa, M.C. Moura, M.J. Lacerda

BACKGROUND

The mechanisms of fibrogenesis in chronic hepatitis C are not well understood. Human liver stellate cells (LSC) express the á-isotype of actine, specific to smooth muscle cell differenciation. Aims: to evaluate the expression of á-smooth muscle actin (á-SMA) in liver stellate cells of chronic hepatitis C patients, to correlate with Histological Activity Index (HAI), with fibrogenic markers (PIIIP and TGF â1) and whether such expression can be modified by anti-viral therapy.

Methods

30 chronic hepatitis C patients (pts) were treated with á-interferon 3MU s.c., tiw, 6 to 12 months + ribavirin (1000-1200 mg/day), 22 male and 8 female, mean age 37.5 ± 12.8 years. HAI before and after therapy, was graded according Knodell / Peter Scheuer (Hepatology 1992;15). Using immunohistochemistry and the semi-quantitative method of Shmith-Graff (Am J Pathol 1991; 138) we evaluated á-SMA expression in liver stellate cells before and after anti-viral therapy (Liver stellate cell index –LSCI in 6 controls= 0.4 ± 0.2). Serum aminoterminal propeptide of procollagen type III (PIIIP) was quantified by RIA (Riagnost PIIIP c.t. Biodesign, 20 controls= 0.4 ± 0.2 U/L). Transforming growth factor â1 (TGFâ1) was quantified by Tsushima method (J Hepatol 1999; 30) (6 controls: plasma= 4.4 ± 0.7 ng/ml; tissue= 3.4 ± 0.6 ng/g protein).

Results

Before therapy, a significantly great numbers of á-SMA reactive LSC were present throughout all acinar zones comparing with controls (LSCI =2.5 ± 1.7 vs 0.4 ± 0.2, p <0.005). A significant reduction in á-SMA reactivity of LSC was noticed in liver biopsies performed 6 months after stop anti-viral therapy (LSCI before= 2.5 ± 1.7; after= 1.5 ± 0.7), p <0.005. A significant correlation was seen between portal á-SMA reactive LSC and fibrosis staging (r= 0.42 p <0.03) but not with grading. Sinusoidal á-SMA reactive LSC correlates with PIIIP (r= 0.39 p =0.04) and TGFâ1 (plasma r= 0.50 p =0.04; tissue r=0.56 p=0.02) but not with the HAI scores. Comparing the different types of response, the drop in the number of á-SMA reactive LSC was only significant in the 10 sustained responders (LSCI before= 1.2 ± 0.6; after= 0.4 ± 0.8, p <0.03) and was associated with a significant improvement of HAI.

Conclusions

The mechanisms of fibrogenesis in chronic hepatitis C may have different pathways involving the activaction of stellate cells, suggesting an anti-fibrotic effect of á-interferon especially on sustained responders.

Abstract ID: M1241

Is Blood Ferritin Levels Useful in Interferon and Ribavirin Therapy for Chronic Hepatitis C ?

Authors: M. Takase, K. Abe, E. Murashima, K. Ueda, K. Maruta, T. Katagami, M. Yamada, S. Sugiki, M. Miyaoka

Introduction

In chronic hepatitis C (CH-C), it is said that the intrahepatic iron volume influences the effects of IFN therapy and liver function stability.

Aims

We examined the significance of measuring blood ferritin levels by measuring dynamics of blood ferritin levels before, during (after 2, 4, and12 weeks), directly after, and more than 6 months after administration of interferon and ribavirin (IFN+Rib) in chronic hepatitis C, and comparing the results of the therapeutic effect, and further by examining the relationships with liver function(ALT), blood platelets (PLT), and host immunocytokines (Th1:IL-18, Th2:IL-10) before and after administration. Subjects were 64 patients (M/F35/29; Mean age: 52.5) who underwent IFN+Rib administration. Those who remained negative for blood HCV-RNA 6 months after the treatment and maintained normal ALT level for at least 6 months were defined as complete response (CR) cases, and all other cases were defined as non-response (NR) cases.

Results

Compared to before IFN + Rib administration, blood ferritin levels significantly increased to a peak after 2 weeks of administration (total: p<0.0001,CR: p=0.0009,NR: p=0.0016), and it was significantly high also after 4 weeks (total: p<0.0001, CR: p<0.0001, NR: p=0.0002) and after 12 weeks (total: p=0.0034,CR: p=0.0283, NR: p=0.0283), but there were no significant differences immediately after the completion of administration. However, after the completion of administration, the level significantly decreased from the pre-administration level in CR cases (p=0.0015). Blood ferritin levels after 4 weeks of administration (p=0.0016) and after the completion of administration (p=0.0011) was shown to significantly decrease more in CR cases than in NR cases. Examination of the correlation with blood ferritin levels before and after administration revealed that before administration, there was a correlation with ALT (r=0.513; p<0.0001) and after administration, there was a correlation with ALT (r=0.488; p=0.0001) and IL-18(r=0.597; p<0.0001).

Conclusions

1. Blood ferritin levels correlated with liver function before and after administration.

2. Blood ferritin levels after 4 weeks of IFN + Rib therapy might act as a predictor of therapy effectiveness.

3. It might be possible to assess the effectiveness of treatment by blood ferritin levels after the completion of administration.

4. Blood ferritin levels were related to the Th1 system immune response caused by IFN + Rib therapy.

Abstract ID: M1233

Specialty Care Of Hepatitis C Infection Of Hispanic Patients in the Continental United States

Authors: J. Uribe, T. Matheus, M. Dejongh, V. Araya, S. Muñoz

BACKGROUND

Emerging data indicates that chronic hepatitis C virus infection (HCV) has a differential impact in Caucasian and African American patients in terms of response to antiviral therapy and possibly natural history. Little is known on the features of HCV infection in Hispanic patients, in spite of the fact that the last population census revealed that Hispanics are one of the largest ethnic groups (12.5 % of U.S. population). It is projected by the year 2010 that Hispanics will comprise 15% of the U.S. population, which will make it the largest minority group in the United States.

AIM

We evaluated the care of HCV in a large cohort of Hispanic patients.

METHODS

Medical records of 150 consecutive Hispanic patients attending an urban academic gastroenterology and hepatology practice in the Mid Atlantic U.S. were carefully reviewed to determine demographics, status of initial evaluation, extent of follow up, viral load, genotype, frequency of liver biopsy and antiviral therapy. As controls, the same variables were also studied in a cohort of 100 randomly selected Caucasian patients.

RESULTS

The proportion of females and the frequency of obesity were similar between Hispanics and controls although the former were somewhat younger (44.7 vs. 47.68 years; p< 0.01). A significantly smaller proportion of Hispanics completed the initial evaluation of HCV compared to controls (56.7% vs. 74%; p< 0.01), but the groups were not different in terms of follow up compliance. Distribution of HCV genotypes were similar in both groups but a significantly greater number of Hispanic patients had low viral loads (< 600,000 U/ml, 70.8% vs. 59.4%; p< 0.01). The proportions of Hispanic patients who had a diagnostic liver biopsy or underwent antiviral therapy with interferon (49.3% and 31.8%, respectively) were significantly lower than the proportions observed in Caucasian controls (81% and 48%, respectively; p< 0.01). This may be due to genetic variation, dietary factors or lifestyle factors.

CONCLUSIONS

Hispanic patients with chronic HCV complete their initial evaluation, undergo liver biopsy and receive interferon treatment less often than Caucasians. However, Hispanics have similar genotype distribution, follow up visits, and are more likely to have low viral levels, a favorable predictor of response to antiviral therapy. Additional studies are necessary to determine the reasons for the lower frequency of completion of evaluation, liver biopsy and therapy in this ethnic group

Abstract ID: M1229

Clinical Features and Natural Course Of Hepatitis C Virus Carriers With Persistently Normal Alanine Aminotransferase Levels in a Hyperendemic Area Of Japan

H. Uto, K. Hayashi, K. Kusumoto, S. Kanmura, H. Abe, M. Numata, S. Hasuike, k. Nagata, A. Ido, S.O. Stuver, H. Tsubouchi

Background

It is important to clarify whether hepatitis C virus (HCV) carriers with persistently normal serum alanine aminotransferase (ALT) levels progress to liver disease, in order to assess the necessity of interferon therapy. We conducted a cohort study in a hyperendemic area of HCV infection in Japan and examined the clinical features and natural course of HCV carriers with persistently normal ALT levels.

Methods and Results

Twenty-one percent of residents were seropositive for anti-HCV antibodies. In 1995, 591 of 836 anti-HCV seropositive residents were positive for HCV core antigen (HCVcAg) (by fluorescence enzyme immunoassay) and/or HCV RNA (by reverse transcription polymerase chain reaction). Of these HCV carriers, 449 had at least four available ALT measurements taken annually between 1993 and 2000 and did not report receiving interferon therapy. One hundred sixty-two residents had persistently normal ALT levels (<35 IU/L) (group N), and 287 had abnormal levels (group A). Although there was no difference in HCVcAg levels between the two groups in 1995, the frequency of infection in females and serologically-defined (serotype) II infections was significantly higher in group N (75.9 and 40.3%, respectively) than in group A (56.4 and 29.3%, respectively) (P<0.001 and P=0.03, respectively). Furthermore, spontaneous elimination of serum HCV RNA was observed in three residents in group N and two in group A between 1996 and 2002. Although there was a significant relationship between the loss of HCV RNA and low levels of HCVcAg (<20 pg/ml) (P=0.03), this elimination was not related to ALT status, gender, or serotype. Hepatocellular carcinoma (HCC) was observed in seven residents in group A subjects, but none in group N, between January 2001 and September 2004.

Conclusions

HCV-infected residents with persistently normal ALT are not rare in this community-based population and are more likely to be female or to have serotype II infections. Furthermore, the spontaneous elimination of HCV RNA is highly unusual and unrelated to ALT status, while occurrence of HCC may be associated with ALT status. Based on the findings of our study, treatment of HCV carriers with stable, normal ALT levels may not be necessary.

Abstract ID: M1219

Accuracy Of APRI in Predicting Significant Hepatic Fibrosis and Cirrhosis in Patients With Chronic Hepatitis C and HIV Co-Infection

B. Danesh, J. Kim, D.A. Labowitz, A. Davatgarzadeh, P. Suwandhi, A. Walfish, I.M. Grosman, D. Clain, H.C. Bodenheimer, Jr., A.D. Min

Introduction

The aspartate aminotransferase-to-platelet ratio index (APRI) has been developed as a simple, non-invasive, inexpensive predictor of significant fibrosis and cirrhosis in patients with chronic hepatitis C (CHC). Since patients infected with the human immunodeficiency virus (HIV) often have aspartate aminotransferase (AST) and platelet (PLT) abnormalities, this index may not be as accurate in patients co-infected with HIV. We sought to determine the accuracy of the APRI in patients with CHC and HIV co-infection.

Methods

56 CHC patients co-infected with HIV who had undergone liver biopsies were identified, and compared with 56 age- and gender-matched non-HIV CHC patients with available liver histology. Hepatitis C viral load, AST value and its upper limit of normal (ULN), PLT count, and modified Ishak fibrosis stage (FS) were obtained. 4 HIV patients and 3 non-HIV patients were excluded because of missing lab values. All lab data were within 6 months of the liver biopsy date. The APRI was calculated using the formula: (AST / ULN) / PLT count) x 100. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the APRI in predicting significant fibrosis (FS³2) and cirrhosis (FS=4) were then calculated.

Results

The mean age of the 52 patients with HIV (46.4 ± 6.7) was similar to that of the 53 patients without HIV (48.5 ± 8.4). The mean FS (2.4 ± 1 vs. 2.1 ± 1.1) and the gender of the patients were also similar (82% vs. 82.5% male). The data on accuracy of the APRI in predicting significant fibrosis or cirrhosis are presented in the table 1.

Table 1.

	APRI	Sensitivity (%)		Specificity (%)		PPV (%)		NPV (%)
		HIV+	HIV-	HIV+	HIV-	HIV+	HIV-	HIV+	HIV-
Prediction of significant fibrosis	> 0.50	86	69	56	43	90	77	45	33
	> 1.50	33	10	100	100	100	100	24	29
Prediction of cirrhosis	> 1.00	60	100	53	81	12	36	92	100
	> 2.00	40	40	83	98	20	67	93	94

Accuracy of APCI in predicting significant fibrosis and cirrhosis in HCV mono-infected patients presented by Berg et al and Wai et. al

	APRI	Sensitivity (%)		Specificity (%)		PPV (%)		NPV (%)
		Berg	Wai	Berg	Wai	Berg	Wai	Berg	Wai
Prediction of significant fibrosis	> 0.50	89	91	53	47	66	61	73	86
	> 1.50	37	41	93	95	85	88	57	64
Prediction of cirrhosis	> 1.00	76	89	74	75	30	38	95	98
	> 2.00	48	57	89	93	40	57	92	93

Conclusions

In comparing CHC patients co-infected with HIV to those without HIV, the APRI was more accurate in predicting significant fibrosis but markedly less accurate in predicting cirrhosis. In patients without HIV, the accuracy of the APRI in predicting cirrhosis was similar to that of previous studies (Wai et al. Hepatology 2003;38:518-526).

Abstract ID: M1230

The Clinical Characteristics, Management and Outcomes Of Patients 65 and Over With Chronic Hepatitis C in An Integrated Health Care System.

Authors: R. Vachhani, L. Lamerato, E. Quraishi, K. Brown, D. Moonka

Background

Little is known about the presentation, outcomes and response to therapy of older patients (>65) with chronic hepatitis C (HCV). Our current study is designed to look at how patients over the age of 65 present and are managed when compared to a younger cohort.

Method

Our health system datastore was queried to identify patients who were HCV Ab positive between 1997 to 2002. 7588 patients were identified of which 758 were > 65. A random sample of 424 older patients was compared to a random sample of 276 patients <65. The groups were compared for clinical course, management and response to therapy. Patients were followed for a median of 48.9 + 21 months after diagnosis.

Results

Older patients (>65) who were HCV Ab positive were more likely to be HCV RNA negative. Older patients were as likely to be seen by a gastroenterologist, however, they were less likely to undergo biopsy and less likely to receive treatment. Older patients who underwent biopsy were more likely to have advanced fibrosis. Those who did receive therapy had a sustained response rate of 25%. Older patients were more likely to present with hepatic decompensation (p = 0.051) but no patient developed decompensation during follow-up.

Findings	Patients < 65	Patients >65	P value
Negative HCV RNA	19.56%	30.18%	0.065
GI consult	39.62%	44.89%	0.361
Among patients seen in the Gastroenterology Clinic, the following patterns were seen:
Pt refused treatment or didn’t come back for f/u appointment	44.89%	32.5%	0.046
Observation recommended by Gastroenterologist	1.02%	21.87%	<0.001
Medical Contraindication to treatment	10.2%	16.25%	0.174
Decompensated liver disease on presentation	10.2%	19.37%	0.051
Decompensation during follow-up	0%	0%	1
Biopsy done	35.71%	14.37%	<0.001
No or mild fibrosis on biopsy	54.27%	26.08%	0.034
Bridging fibrosis or cirrhosis on biopsy	20%	52.17%	0.011
Received Treatment	33.67%	9.37%	<0.001
Sustained response to therapy	41.4%	25%	0.398

Conclusion

Older patients with HCV were as likely to be referred for evaluation as younger patients, but there is a tendency toward conservative management in this group. Less than 10% of patients over 65 seen by a gastroenterologist received therapy. Older patients had more advanced fibrosis on biopsy and higher rates of hepatic decompensation. However, patients who did not present with signs of hepatic decompensation did well in the follow-up period. The overall sustained response to therapy in older patients receiving combination therapy was 25% and improved therapies are needed.

Abstract ID: M1220

Relationship Between Body Mass Index and Diabetes Mellitus in African American and Hispanic Patients With Chronic Hepatitis C

A.K. DEV, M.S. PADDA, D.S. RHEEM, C. ANYADIKE, A. SANDERSON, R. RAYMUNDO, M. SHAHEEN, A. AKHTAR, I. GIANNIKOPOULOS

BACKGROUND AND PURPOSE

There is controversial data regarding the association of body mass index (BMI) with diabetes mellitus (DM) in chronic hepatitis C (CHC) patients. Our aim is to investigate the relationship between BMI and DM in African American and Hispanic patients with CHC.

METHODS

Medical records of 268 patients (age range: 20 to 70 years), who were diagnosed with CHC from 1999 to 2003, were reviewed retrospectively. Data related to age, gender, race/ethnicity, height, weight and diagnosis of DM was abstracted and analyzed. The BMI was calculated using the formula Weight (in kg)/Height ² (in meters). Logistic regression analysis was used to assess the relationship between diabetic status and BMI values controlling for the age, gender, and race/ethnicity.

RESULTS

Of the 268 patients, 175 (65%) were African-Americans (111 Male, 64 female) and 93 (35%) were Hispanics (45 Male, 48 female). Of the 268 patients, 78 patients were diabetics (29%). Among the 78 diabetic patients, 43 (55%) were African-Americans and 35 (45%) were Hispanics. DM was significantly more prevalent among Hispanics (37.6%) compared to African American (24.6%) (p=0.03). Among the 268 patients, the BMI range was 17.6 to 62 with an average of 29.8 ± 6.3 (mean ± SD). The BMI varied significantly by gender where it was higher among female 31 ± 7 compared to male 29 ± 5 (mean ± SD, p=0.008). There was no difference in the BMI by age, race/ethnicity or diabetic status (p>0.05). The logistic regression analysis showed that there was no association between diabetic status and BMI even after controlling for age, gender, and race/ethnicity (30.5 ± 7 in DM, 29.6 ± 6 in non DM, P = 0.3). Hispanic patients with CHC were at higher odds of having DM as compared to African-Americans (OR=2.3, p=0.009).

CONCLUSION

Among our patient population, there was no association between diabetic status and BMI. Hispanic patients with chronic hepatitis C are at higher odds of having DM as compared to the African-Americans. There is a need for better diabetic education for Hispanic population with HCV infection to prevent the development of related complications. More studies are needed to test this relationship in a prospective way.

Abstract ID: M1227

Keratin Variants As Markers Of Fibrosis Progression in Patients With Hepatitis C

P. Strnad, G. Tao, N. Ku, F. Stickel, D. Schuppan, M.B. Omary

Background

Keratins 8 and 18 (K8/K18) protect the liver from stress of multiple etiologies. K8/K18 mutations have been found in 58 of 467 liver explants obtained from a US cohort of patients who have undergone liver transplantation and 13 of 349 controls (12.4% vs 3.7%; p<0.0001). The two most common variants are K8 G61C and K8 R340H. However, there appears to be population-related differences in the frequency of K8/K18 variants in German, British and Italian population cohorts. For example, a recent study did not detect any keratin mutations in 256 German patients with various liver disorders (J Med Genet 41:e42, 2004).

Aims

We tested the hypothesis that K8/K18 variants are associated with liver disease in German patients with hepatitis C, and that these variants correlate with progression of fibrosis. Methods: The presence of K8/K18 variants was examined in a German cohort of 254 patients who carried the diagnosis of hepatitis C. All patients have undergone liver biopsy and were staged for disease duration, histologic inflammation and fibrosis. Genomic DNA was isolated from peripheral blood, and exonic regions were PCR-amplified and analyzed using a WaveSystem and DNA sequencing.

Results

Our analysis showed: (i) exonic keratin variants in 18 of 254 patients (7.1% for the common K8 L227L polymorphism) and intronic variants in 10 of 254 patients (3.9%), (ii) two novel K8 T25R and K8 G54A exonic variants that have not been previously described, (iii) the K8 R340H variant in 4 patients (1.6%), as contrasted with the observed frequency of 6.4% in the 467-patient US liver disease cohort, (iv) K8 G61C as the most common variant in the analyzed cohort, and (v) the overall frequency of likely relevant variants (ie after exclusion of variants that are likely to be simple polymorphisms due to the nature of the amino acid substitution) is 5.1%. Notably there is a lower frequency of exonic keratin variants in patients with mild liver fibrosis [3 variants in 133 patients (2.3%) with fibrosis stage 0-2 versus 13 variants in 78 patients (16.7%) with fibrosis stage 3-4, p<0.001].

Conclusion

The overall frequency of specific K8/K18 variants may differ among populations. Keratin variants do occur in a German cohort of patients with hepatitis C, and their presence appears to correlate with fibrosis progression.

Abstract ID: M1218

Excessive Alcohol Consumption Is Associated With High Viral Load in Patients With Chronic Hepatitis C Infection

K. Cesario, K. Edwards, N. Zein

Background/Aims

High baseline hepatitis C (HCV) viral load has been associated with poor response to antiviral therapy. However, the relationship of HCV viral load to stage of liver disease and to host-related characteristics is not fully understood. Our aim was to determine host and environmental features associated with high viral load in patients with chronic HCV. Understanding these associations may support the development of novel approaches to lower viral load and improve therapeutic response.

Methods

We performed a historical cohort study examining chronic HCV patients who were seen at the Cleveland Clinic Foundation between 2001 and 2004. Those who had received previous interferon-based therapy or liver transplantation were excluded. Subjects were classified by HCV RNA levels as “high viral load” (>800,000 IU/ml) or “low viral load” (<800,000 IU/ml). Demographics features and histologic profile on liver biopsy were compared. Excessive alcohol consumption was defined as one alcoholic drink daily or greater than 5 drinks weekly. For those who had completed therapy with pegylated interferon (PEG) and ribavirin (RBV) at our institution, sustained virologic response (SVR) rates were examined.

Results

200 subjects, 100 successive patients in each group, were enrolled. Mean viral load in the high group was 1.92 x 106 IU/ml compared to 3.85 x 105 IU/ml in the low group. High viral load patients were more likely to be male (70% vs. 53%, p=0.02) and have a history of frequent alcohol consumption (59% vs. 42%, p=0.02). Both groups were similar in terms of age, race, gender, genotype, body mass index and baseline ALT. Similarly, there was no significant difference in presence of steatosis, marked fibrosis or inflammation on baseline liver biopsy. SVR data was available in 43 patients in the high viral load group and 58 patients in the low viral load group. As anticipated, SVR was more common in patients with low viral load 39% SVR compared to 20% SVR in patients with high viral load.

Conclusions

High HCV viral load appears to be associated with male gender and excessive alcohol intake. These findings may help understand the mechanism of treatment failure associated with excessive alcohol consumption in HCV patients. Whether complete cessation of alcohol intake in HCV patients leads to decrease viral load and improved outcome of therapy remains to be addressed in future studies.

Abstract ID: M1237

Prediction Of Outcome in Chronic Hepatitis C (HCV) Treatment by Creatinine, Genotype, and Ethnicity in HIV/HCV-Coinfected Patients

J. Park, L. Moorehead, A. Uriel, D. Carriero, M. Sulkowski, D.T. Dieterich

Introduction

Serum creatinine (creat) is a reflection of renal function, nutritional status, and total muscle mass, and varies between sexes and different ethnic groups. Human Immunodeficiency virus (HIV)-infected patients (pts) often suffer lipodystrophy and loss of muscle mass. Current recommendations for doses of ribavirin (RBV) and pegylated interferon (Peg-IFN) do not factor in renal function, lean muscle mass and lipodystrophy in HIV-coinfected pts. This may impact on response to anti HCV therapy.

Objectives

To determine the influence of creat and ethnicity on HCV treatment response in pts with HIV/HCV treated with Peg-IFN and RBV.

Methods: The clinical data were obtained on 308 pts enrolled in 2 prospective, HCV treatment trials, HRN 004 and 005, evaluating weight based Peg-IFN and RBV in previous non-responders and naïve pts respectively. After review, 214 patients remained and selected for analysis.

Results

Baseline characteristics were 76% male, 39% Caucasian, 37% African-American (AA), 22% Hispanic, 1% Asian, and with a mean age of 48.1 years ( +/- 6.6SD) and a median BMI of 26.0 (IQR 23.5 - 30.0). 79% had HCV genotype (GT) 1 with a median HCVRNA of 601,190 IU/mL (IQR 465,000 - 4,169,512). 85% of pts were on HIV antiretroviral (ART). The median CD4 count and HIVRNA were 499 cells/mm3 (IQR 360-737) and 400 copies/ml (IQR 82 - 985), respectively. EVR was achieved by 51% of the study cohort, by 55.0% (189) of pts with normal creat (0.7-1.2), 14.3% (14) of pts with low creat (<0.7) and 30.0% (10) of pts with elevated creat (>1.3). In a basic logistic regression model, normal creat was a significant linear positive predictor of EVR (p = 0.0295) and pts with normal creat were 4.1 times more likely to have EVR than pts with abnormal creat. These findings held when adjusted for age, gender, HCVRNA, GT and ART. 68.6% Caucasian, 30.4% AA, and 53.1% Hispanic pts had EVR. In pts with GT 1 & 4, there was a strong negative relationship between ethnicity and EVR (p = 0.0191). HCV GT 2 & 3, was a strong predictor of EVR, regardless of ethnicity (p = 0.0018). The combination of AA ethnicity with GT1 and abnormal creat was the stronger negative predictor for EVR.

Conclusions

Our data demonstrate that serum creat, GT, and ethnicity are important predictors of EVR in HIV/HCV-coinfected pts.

Abstract ID: M1713

African Americans and Less Educated Patients With Chronic Hepatitis C Are Less Likely To Be Tested for Hepatitis a Immunity and Hepatitis B Infectivity

H.S. Yee, S.L. Currie, M.C. Pedrosa, B.S. Anand, H. Shen, E.J. Bini, L.J. Jeffers, T.L. Wright, F. VA-HCV-001 Study Group

Background

Superinfection with hepatitis A virus (HAV) and/or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) infection can increase morbidity and mortality. The NIH Consensus panel recommends vaccinating against hepatitis A and B in chronic HCV-infected patients who lack immunity. However, limited data on provider practices with HAV and HBV screening exists. The aims of this study were to determine the proportion of HCV-infected veterans tested for HAV immunity or HBV infectivity, and to compare factors in those tested versus those not tested.

Methods:

Data were prospectively collected in 4,338 U.S. veterans at 24 VA medical centers over a 15-month period. All subjects were HCV antibody positive. Information collected included demographics, comorbid diseases, social habits, HAV antibody status, and HBV surface antigen status.

Results

The mean age of patients was 50.3 ±7.6 years, 97.2% were male, 57.2% Caucasian, and 29.5% African American. The majority of patients had a history of ³3 alcoholic drinks/day within the past year (75.2%), injection drug use (60%), intranasal cocaine use (67.6%), and incarceration for ³48 hours (61.4%). There were 21.4% who had >50 sexual partners and 8.1% with HIV coinfection. Of the 4,338 patients, HAV antibodies were not performed in 2,104 (48.5%) and HBV surface antigen were not performed in 1,192 (27.5%). Multivariate logistic regression analysis identified age ³50 (OR 1.3; 95% CI, 1.1 – 1.4), African American (OR 1.3; 95% CI, 1.1 – 1.6), and £12 years of education (OR 1.4; 95% CI, 1.2 – 1.6) as independent predictors for not testing for HAV antibodies. Multivariate logistic regression analysis identified age ³50 (OR 1.2; 95% CI, 1.0 – 1.5), African American (OR 1.5; 95% CI, 1.2 – 1.8), £12 years of education (OR 1.4; 95% CI, 1.2 – 1.8), and cardiac disease (OR 1.6; 95% CI, 1.0 – 2.7) as independent predictors for not testing for HBV surface antigen; those that were more likely to be tested were HIV coinfected (OR 2.1; p<0.05) or snorted cocaine (OR 1.2; p<0.05).

Conclusions

· Over 48% of chronic HCV-infected veterans were not tested for hepatitis A immunity.

· Over 27% of chronic HCV-infected veterans were not tested for hepatitis B infection.

· Chronic HCV-infected veterans with HIV coinfection or who snorted cocaine were more likely to be tested for hepatitis B infection.

· Being African American, older or less educated was independently associated with not testing for HAV immunity and HBV infection.

· Increased HAV and HBV screening efforts should be made in patients to identify those that need vaccination or those coinfected with HBV.

Abstract ID: M1679

Recipients With Cryoglobulinemia Both Before and After Liver Transplantation for Hepatitis C Are At Greatest Risk for Severe Activity, Severe Fibrosis, and Early Graft Loss

S.C. Rayhill, M. Voigt, D. Katz, P. Kirby, D. Labrecque, Y. Wu, W. Schmidt

Positive cryoglobulin (CG) levels are associated with poor outcome in the non-transplant population. We have demonstrated a strong relationship between CG and poor outcome after txp. The kinetics of CG in HCV infection remains unknown, especially with immunosupression after liver txp. Therefore, we examined txp outcome based on pre and post-txp CG status.

Methods:

Using our longitudinal database, survival for all recipients of liver transplants for cirrhosis due to HCV was analyzed (1991 onward) based on the presence or absence of CG. Any of the 97 patients (105 grafts) with a cryocrit > trace was defined as CG positive. All liver transplant biopsies were analyzed (in a blinded fashion) and activity and fibrosis were graded using the Batts-Ludwig scale. Severe activity was defined as moderate or worse activity, including fibrosing cholestatic hepatitis, and severe fibrosis was defined as bridging fibrosis or cirrhosis. Graft survival, and survival until the onset of severe activity and fibrosis were determined using Kaplan Meier estimates. Survival analyses were performed for the entire population (overall survival) and after censoring patients who died or lost their grafts for reasons other than recurrent HCV (HCV specific survival). The log rank test was used to compare survival and Cox multivariate analysis was used to determine relative risks (RR).

Results:

Forty-five patients had both pre and post-transplant CG levels. Twenty-two were pre and post-txp CG negative, 16 converted from CG positive to CG negative, and 6 remained CG positive. Compared to pre negative – post negative:

Pre Positive - Post Negative
	Severe	Activity			Severe	Fibrosis
Overall	Survival	HCV Specific	Survival	Overall	Survival	HCV Specific	Survival
RR	p	RR	p	RR	p	RR	p
1.2	0.7	1.0	1.0	1.3	0.7	1.3	0.7

Pre Positive - Post Positive
	Severe	Activity			Severe	Fibrosis
Overall	Survival	HCV Specific	Survival	Overall	Survival	HCV Specific	Survival
RR	p	RR	p	RR	p	RR	p
3.9	0.05	4.2	0.04	5.8	0.02	5.2	0.02

In addition, p values for overall and HCV specific graft survival were 0.05, indicating that survival was significantly worse for the Pre+Post+ patients.

Conclusions:

Liver txp recipients with detectable CG both pre and post liver txp are at greater risk for graft loss, severe early activity, and severe early fibrosis. Recipients CG positive pre-txp who become CG negative post-txp, may be at a similar lower risk as those consistently CG negative.

Abstract ID: M1704

The Relationship Of Race, Hepatic Steatosis, and Insulin Resistance in Patients With HIV and Chronic Hepatitis C (HCV)

J. Park, L. Moorehead, D. Carriero, A. Uriel, M. Fiel, M. Sulkowski, D.T. Dieterich

Introduction

Hepatic steatosis (HS) is commonly seen in patients (pts) with HCV. Its association with obesity, insulin resistance (IR) and hyperlipidemia suggests an underlying metabolic dysfunction similar to that found in pts with nonalcoholic fatty liver disease (NAFLD). Superimposed NAFLD may affect HCV-related disease progression. Possible ethnic differences were suggested in NAFLD recently.

Objective

To assess the frequency, severity and clinical correlates of steatosis and IR in a cohort of different ethnic groups.

Methods

Baseline characteristics of 102 coinfected individuals in a re-treatment study (HRN004) were assessed. After review 73 pts entered in the study. IR was calculated utilizing the homeostasis model assessment (HOMA-IR). Liver histology was scored using the modified HAI for HCV disease. A novel scoring system was devised to assess histological damage related to NAFLD, and degree and distribution of steatosis (grade 0-3, modified Brunt score).

Results

Baseline characteristics: 84% were male, 29% Caucasian (C), 40% Hispanic (H), 29% African-American (A), and 1% Asian with a mean age of 48.5 years (± 6.4SD) and a median BMI of 25.8 (IQR 24.1 - 30.1). 82% were HCV genotype (GT) 1 with a median HCVRNA of 657,931 IU/mL (IQR 438,790 - 5,011,414). The median CD4 count was 564 (IQR 378 - 788). 74% had undetectable HIV viral load. On liver biopsy 73 (76%) pts had mild or no (grade 0 – 1) HS, and 23 (24%) had moderate/severe steatosis (grade 2-3). 51 (55%) had HAI stage 1 - 3 fibrosis. In univariate analysis, HS was strongly related to ethnicity, 66% of C vs 96% of AA vs 72 % of H had grade 0 - 1; whilst 34% of C vs 4% of AA vs 28% of H had grade 2-3, (p = 0.01). Necroinflammatory (NI) grade and fibrosis were not significantly related to ethnicity; 90% of C vs 93 % of AA vs 74 % of H had HAI scores between 0-8; 10% of C vs 7% of AA vs 26% of C had scores between 9-18; (p = 0.053). Fibrosis stage: 69% of C vs 53% of AA vs 52% of H had scores between 0 - 3; 31% of C vs 47 % vs 48% had scores between 4 - 6; (p = 0.333). In univariate analysis, ethnicity was not related to IR. Gender was not related to HS or IR. Once GT 3 was excluded, GT did not correlate with HS (p = 0.61).

Conclusions

Our data demonstrate that ethnicity is an important factor in NAFLD. Caucasians had more fatty liver disease and this may contribute to more accelerated progression of disease observed in this group.

Abstract ID: M1705

Steatosis Is More Frequent in Hepatitis C Compared To Other Liver Diseases, But Less Prevalent Than in Healthy Controls.

F. Poordad, T.T. Tran, W. Ayoub, Y. Patel, L. Chan, S.A. Geller

Background

Several reports have indicated a frequency of steatosis in Hepatitits C (HCV) of 30-70%. The mechanism for this is not known. The presumed incidence of fatty liver in the general US population is 15-25%.

Aim

To evaluate the prevalence and severity of steatosis in HCV compared to healthy adults and other forms of liver disease.

Patients and Methods

215 patient biopsies performed between 1/02 and 4/04 were reviewed and evaluated for steatosis using a scoring system of mild, moderate and severe to correspond with < 30%, 30-60%, and > 60% steatosis, respectively. All biopsies were read by a single pathologist. 100 patients had HCV (gp 1), 64 patients were healthy prospective living donors with normal cell counts, liver chemistries and electrolytes, normal CT or MRI imaging (gp 2), 20 patients had hepatitis B (HBV) (gp 3), 13 patients had primary biliary cirrhosis (PBC, gp 4), and 18 patients had other forms of liver disease, predominantly primary sclerosing cholangitis (PSC), autoimmune hepatitis and hemochromatosis (gp 5).

Results

See Table 1. The prevalence of steatosis by genotype was as follows: Genotype-1=17%, Genotype 2=33%, Genotype 3 =50%, Genotype 4= 20%.

· The prevalence of steatosis was highest in the door group

o Donors = 37%, p = 0.052

o HCV = 23%, p = 0.052

o Other = 8%, p = 024.

· BMI > 25 was associated with steatosis in the donor group (p=0.043). In the HCV group gender, age race BMI, advanced fibrosis or viral load were not associated with steatosis.

· Diabetes was associated with steatosis and compared to genotype 1 (p=0.048)

Conclusion

· Steatosis is seen in nearly ¼ of HCV infected individuals, but no more common than the general population.

· Steatosis in genotype 3 is significantly more common than in genotype 1

· Steatosis in HCV is associated with the presence of diabetes

· BMI correlates with steatosis in healthy adults.

Table 1	Gp-1 HCV	Gp 2-Donors	Gp 3- HBV	Gp 4-PBC	Gp 5-others
Mean age	48	42	43	52	46
Mean BMI	27	26	25	27	27
% Caucasian	74	80	40	69	90
% Male	54	55	70	15	67
% with DM	7	2	5	15	22
Mean Cholesterol (mg/dL)	178	205	197	251	208
Mean TG (mg/dL)	147	184	85	136	110
% with HTN	16	9	10	8	39

Abstract ID: M1670

Clinical Utility Of Alpha Fetoprotein (AFP) L3 and Des-Gamma Carboxy Prothrombin (DCP) in Patients (pts) With Hepatitis C (HCV) and Advanced Fibrosis At Risk for Hepatocellular Carcinoma (HCC): Results From the Lead in Phase Of the HALT-C Trial.

R.K. Sterling, A.S. Lok, L.B. Seeff, J.C. Hoefs, E.C. Wright, a. the HALT-C Trial Clinical Investigators

Background & Aims

The risk of HCC is increased in pts with HCV and advanced fibrosis. Current screening methods include AFP and ultrasound (US). However, elevations in AFP are common in the absence of HCC, resulting in the performance of additional and unnecessary tests. The aims of the current study were to determine if 2 additional markers, AFP-L3 and DCP, will help in excluding HCC among HCV pts with elevated AFP.

Methods

We analyzed the baseline clinical and biochemical features of 936 pts entering the lead in phase of the HALT-C trial followed for a minimum of 12 months. All pts had Ishak fibrosis 3-6, 36% had cirrhosis, and all were nonresponders to prior interferon therapy. Pts with total AFP >200 ng/mL at screening and/or suspected HCC on imaging were excluded. Total AFP, AFP-L3% (Wako Diagnostics, cutoff >10%), DCP (Eisai, cutoff >150 mAU/mL), and US were performed at baseline and every 6 months. Pts with elevations in total AFP (>20 ng/ml) and/or abnormal US were evaluated with additional imaging (CT/MRI) without knowledge of AFP-L3 or DCP results.

Results

Of the 936 pts, 794 had an AFP <20 ng/ml. Of these, 23 (2.9%) had an AFP-L3 >10% while 20 (2.5%) had a DCP >150 mAU/ml (table 1): HCC was diagnosed in 3 (0.4%). Of the 142 (15%) that had an AFP > 20 ng/ml (mean 62.0, SD 52, range 20-263) at baseline, 13 (9%) had an elevated AFP-L3% and 3 (2%) had elevated DCP: HCC was diagnosed in 4 (2.8%). Patients with AFP >20 and AFP L3 >10% or DCP >150 were significantly more likely to have HCC than those with AFP >20 alone (p=.049).

Table 1
N (# HCC)	Total AFP	AFP L3% <10		AFPL3% >10
		DCP <150	DCP >150	DCP <150	DCP >150
794 (3)	<20	752 (1)	19 (1)	22 (1)	1
142 (4)	>20	128 (2)	1	11	2 (2)

The sensitivity, specificity, PPV and NPV for developing HCC within 1 year of enrollment for elevated AFP alone and for AFP-L3% and/or DCP in those with AFP >20 are shown in table 2.

Table 2
	N	Sensitivity %	Specificity %	PPV %	NPV %
AFP >20	936	57	85	3	99
AFP >20 + AFP L3>10%/DCP>150	142	50	91	14	98

The likelihood of HCC correlated with the number of abnormal test results: 0.1% with none, 2.4% with 1 test and 13.3% with >1 test (p<.0001).

Conclusions

AFPL3% and DCP increased the specificity for HCC in pts with HCV and advanced fibrosis compared to total AFP alone. Further studies are needed to determine if AFPL3% and DCP may reduce the need for additional imaging studies in the majority of pts with elevated AFP levels and the impact on sensitivity.

Abstract ID: M950

Factors Predicting Degree Of Liver Fibrosis Among Patients With Chronic Hepatitis C (CHC) in An Ethnically Diverse Population.

D. Basu, A.A. Modi, C.H. Clark

Purpose

Evaluation of the degree of liver fibrosis in patients with CHC is valuable for prognostication prior to starting antiviral therapy. The gold standard for assessing fibrosis is liver biopsy that is costly and has complications. Hence, there is a need to develop some reliable yet noninvasive methods to enumerate the severity of liver fibrosis in patients with CHC. Wai et al suggested a noninvasive technique called AST to platelet ratio index (APRI) to predict the presence or absence of significant fibrosis. We tested this hypothesis along with other factors in our CHC population having more ethnic diversity.

Methods

Secondary analysis of data was collected prior to starting antiviral therapy from two county clinics and one tertiary clinic located in Houston. Patients with diabetes, alcoholism or any cause of chronic liver disease other than CHC were excluded. Platelet count (10⁹/L) and AST (mg/dl) were obtained and APRI was calculated. The upper limit of normal for AST was taken as 45. APRI £ 0.5 or > 1.50 were taken as markers for absence or presence of significant fibrosis, respectively. Ishak fibrosis scores (stage 1 through 6) from liver histology prior to antiviral therapy were obtained. Stages between 0 to 2 and those between 3 to 6 were taken as absence and presence of significant fibrosis, respectively. Ordinal logistic regression using MINITAB 12 was used to establish a predictive model for fibrosis in our CHC patients. The factors used in this analysis were APRI, age, gender, ethnicity and clinic site (tertiary vs. county).

Results

Of 302 initially evaluated, 189 patients were used in the analysis. There were 121(64%) Whites, 34(18%) Blacks, 26(14%) Hispanics and 8(4%) Asians. There were 102(54%) males and 87(46%) females. 119(63%) patients were from tertiary clinic and 70(37%) from county clinics. APRI did not predict the presence or absence of significant fibrosis nor did age, gender or ethnicity. But it was found that patients from county clinics had more significant fibrosis when compared to tertiary clinic [CI(0.06,0.53), OR=0.18, p=0.003] probably reflecting a delayed treatment seeking behavior due to disease unawareness, more severe disease among the minority county residents or nondisclosure of prior alcohol use.

Conclusion

More investigations are required to establish the validity of APRI in minority cohort. Studies attempting to identify the relationship between liver fibrosis and HCV genotypes in minorities are also needed.

Abstract ID: M951

Hepatitis C Knowledge and Attitudes Among Methadone Maintenance Patients: a Brief, Educational Inservice Makes a Positive Difference

T. Belville-Robertson, A. Eshelman, G. Mahr, D. Moonka, K. Brown

Background

· Hepatitis C is the most common blood-borne disease in the United States, with 2.7 million people chronically infected.

o Individuals with a history of intravenous drug abuse (IVDA) are at highest risk, with 60-90% infected.

o Most individuals with a history of IVDA are infected during the first year of needle use

· Surveys of former IVDA prior to 2001 indicate poor knowledge of HCV.

· In 2001, the US Centers for Disease Control and Prevention (CDC) issued the “National Hepatitis C Prevention Strategy” which promotes HCV prevention and control

o Targets “at-risk” populations such as substance abusers in treatment and outreach programs

o Recommends HCV education be integrated into all substance abuse treatment programs.

AIM

· Assess HCV knowledge and attitudes among community-based methadone maintenance patients subsequent to the 2001 CDC recommendations.

· Evaluate whether a brief patient educational program on HCV improved high-risk patients’ disease-related knowledge and attitudes.

Methods

· Subjects (number 203) were 18 years or older and receiving methadone maintenance for opiate addiction.

· Subjects were recruited from local, licensed methadone maintenance clinics between June 2003 and August 2004

o Paticipantion was voluntary

o Received $5 food gift certificate if attended educational program and completed pre-post surveys

o Data collection and educational intervention occurred in a group format, during a regularly schedule group time

§ Group size ranged from 3 to 20

o Design: pre-post survey

o Intervention: 45-minute educational program on HCV utilizing a slide presentation and opportunity for questions and discussion

o Survey: 17 items assessing knowledge of HCV transmission risk factors, testing procedures, treatment, treatment efficacy, and general attitudes toward HCV and treatment.

Patient Characteristics (203 People)

Male	45
Female	55
African-American	53
Caucasian	39
Other	8
Age, years (mean ± SD)	47.58 ± 7.4
Methadone duration, months (mean ± SD)	49 ± 59
Methadone dose, mg (mean ± SD)	76 ± 30
Employed	35
Unemployed	65
Medicaid Insurance	45
Private Insurance	19
Medicare	7
Uninsured	29

Note: 16% failed to report age

RESULTS
Overall, 74% of subjects had been tested for HCV, with 51% being HCV-positive. Of those not tested, 56% did not know where to go for testing. Most HCV subjects had seen a doctor (64%), but only 26% had a liver biopsy. While 42% with HCV were offered treatment, only 13% had undergone it. On pre-survey, only 6% of the sample got all 9 HCV knowledge questions correct. Except for needle sharing, transmission risk factors were poorly understood in over 30% of subjects. Intranasal cocaine use as a possible route of transmission was unknown to 58% of subjects. Eighty percent of subjects were concerned about HCV and 25% felt they lacked adequate information to protect themselves. Most subjects wanted more treatment information (86%) and were willing to try treatment (76%). Pre-post survey comparisons showed significant (p< .05), positive treatment effects for 7 of the 9 HCV knowledge items. On post-survey, 36% of subjects answered all HCV knowledge items correctly. There was also a significant (p< .05) intervention effect for 2 of the attitude questions, in that subjects felt more able to protect themselves from HCV, but also felt stronger that HCV treatment had potential side effects. Thus, there was a mixed treatment effect on changing HCV attitudes. Gender, hepatitis C status, and length of time on methadone all failed to influence the intervention effects.

CONCLUSION

· Despite the CDC’s 2001 recommendations for targeting HCV education for “at-risk” populations, such as former or current substance abusers, knowledge of HCV among methadone maintenance clinics in a large, urban area was poor.

o HCV is a continuing health concern for this population

· An HCV educational program for methadone maintenance patients was shown to significantly improve HCV knowledge and impact on disease-specific attitudes.

· Immediate improvements suggest that this may be a cost-effective method for educating this high-risk population

· Whether these improvements are sustained over time could not be ascertained in this study due to the poor response to the optional, 1-month follow-up survey.

· Future research needs to assess longer term benefits of this brief intervention, such as impact on infection rates and barriers to testing and treatment.

Abstract ID: M968

The Impact Of Hepatitis C on Health Related Quality Of Life: a Systematic Review and Quantitative Assessment

B.M. Spiegel, Z.M. Younossi, R.D. Hays, D. Revicki, S. Robbins, F. Kanwal

Background

Hepatitis C virus (HCV) negatively impacts health related quality of life (HRQOL), and it is now common to measure HRQOL in clinical trials. However, there has been no attempt to systematically review the HRQOL literature in HCV. We therefore sought to summarize and present the HRQOL data in HCV stratified by clinically relevant anchors, and to establish the “minimally clinically important difference” (MCID) in HRQOL scores in HCV.

Methods

We performed a systematic review to identify relevant English-language studies from MEDLINE and EMBASE published since 1990. We abstracted data from each study according to a conceptual model regarding the measurement of HRQOL differences, and converted HRQOL data to clinically interpretable statistics, including cross-sectional mean difference and the effect size (ES). Interpretation of the ES has been previously standardized as follows: <0.2=“small” clinical effect; 0.5=“medium” effect; >0.8=“large” effect. The results of the systematic review were presented to an expert panel that then used a modified Delphi technique to estimate the MCID in HCV.

Results

Patients with HCV scored 7-13 points lower than matched controls across all scales of the SF-36, corresponding with a medium to large ES range of 0.3-1.0. Patients achieving sustained virologic response (SVR) scored higher across all scales versus patients without SVR, especially in the physical health domains (7-10 point difference, ES=0.4). HRQOL differences did not correspond with differences in liver histology or ALT levels. Based upon a priori hypotheses and data from the systematic review, the expert panel concluded that the SF-36 vitality scale was most relevant in patients with HCV, and generated a mean MCID of 4.2 points (range 3-5) on this scale.

Conclusions

Patients with HCV have a clinically significant decrement in HRQOL versus matched controls. Physical HRQOL improves in patients achieving SVR but not in those without SVR. Traditional outcomes may fail to capture the full spectrum of illness related to chronic HCV. A difference of 4.2 points on the SF-36 vitality scale can be used as an estimate of the “minimally clinically important difference” in HCV. This value may be used to monitor patient outcomes in clinical practice as well as clinical trials. Moreover, this value may serve as the basis for power calculations in HCV clinical trials employing the SF-36 as an outcome.

Abstract ID: M959

A Stratification Of Risk Factors for Fibrosis in United States Veterans Vs Non-Veterans With Chronic Hepatitis C: a Prospective Study From a Non-Urban Medical Center.

Z. Kayali

Introduction

Chronic HCV causes progressive fibrotic liver disease and major risk factors include male sex, excessive alcohol use, age and obesity. Limited data have evaluated risk factors in special high HCV prevalence groups such as US veterans nor directly compared these factors with non-veterans.

Aim

To compare the demographic, clinical characteristics and risk factors for advanced fibrosis in US veterans and non-veterans with chronic HCV.

Methods

HCV seropositive US veterans (n=459) and non-veterans (n=395) were prospectively administered a detailed medical, social and occupational questionnaire at the VAMC and UIHC in Iowa City, IA, respectively. Liver biopsies were obtained on 208 non-veterans and 167 veterans and scored using Metavir analysis for fibrosis as well as standard grading methods for NIA, steatosis, and iron deposition. Sixteen risk factors for fibrosis [age, BMI, ALT, disease duration, ethanol (alcohol) use*. cryoglobulins, gender, HCV RNA, steatosis, iron deposition, NIA, genotype and rheumatoid factor] were compared by uni- and multivariate analysis. Fibrosis was analyzed as both a progressive and a multi-level categorical outcome. Linear and logistic regression was used to determine independent risk factors for fibrosis within each group.

Alcohol Use defined:

· Unit of alcohol- 10-12 grams (12 oz beer, 8oz wine or one oz spirits)

Significant consumption:

· Men greater than 150 kg lifetime consumption (4-5 drinks a day over 10 years)

· Women greater than 100 kg (3 drinks per day over 10 years)

Temperate consumption:

· Men less than 150 kg men (less than 3 drinks per day over 10 years)

· Women les than 100 kg (less than 2 drinks per day over 10 years)

Results

On univariate analysis, veterans were significantly older, had higher lifetime alcohol consumption, and had detectable cryoglobulins less frequently than non-veterans, however, there was no difference in fibrotic scores between the two groups. ALT, NIA and cryoglobulin positivity were the only factors that were significant for fibrosis within both groups. On multivariate analysis, veterans showed NIA and ALT to be independent risk factors for fibrosis (p<0.005). In contrast, non-veterans showed NIA (p =0.0001), steatosis (p=0.0003), alcohol intake (p=0.005) and age (p=0.02,) to be independent factors for fibrosis. There was no independent effect of viral load or male gender in either group.

Conclusion

1. Independent risk factors for HCV fibrosis are different in veterans compared to non-veterans when evaluated cross-sectionally using identical methodology;
2. Necroinflammatory is the major risk factor for fibrosis in both veterans and non-veterans. Although veterans are overwhelmingly males, tend to be older, and consume more alcohol than non-veterans, they do not show significantly higher fibrotic scores than non-veterans;
3. Veterans represent a special population with increased accepted risk factors for HCV disease, yet the veterans in our study did not have increased levels of fibrosis or cirrhosis;
4. The lack of more advanced liver disease in veterans, despite increase age and lifetime alcohol consumption, may be due to a survival cohort effect. Veterans now using VHA facilities may be stratified group of survivors of extended HCV infection and excessive alcohol use. Many HCV positive veterans may have already developed decompensated liver disease, received liver transplant, or have expired and were unavailable for study;
5. Additional studies are needed to determine the relationship between risk factors and HCV liver disease progression in special high risk patient populations such as U.S. veterans.

Abstract ID: M957

Aspartate To Alanine Aminotransferase Ratio (AAAR) and Aspartate Aminotransferase To Platelets Ratio Index (APRI) As Non-Invasive Parameters for Predicting the Presence Of Significant Fibrosis in Patients With Chronic Hepatitis C. a Multi-Center Study.

E. Giannini, A. Zaman, L. Mastracci, P. Ceppa, R. Testa

Background

The presence of significant fibrosis is an important diagnostic and prognostic histological hallmark in patients with chronic hepatitis C (CHC). The AAR proved to be an easy and validated tool for non-invasively assessing cirrhosis in patients with CHC, although its diagnostic accuracy for significant fibrosis has never been assessed. The APRI was recently proposed for identifying significant fibrosis in patients with CHC.

Aim

To assess the diagnostic accuracy of the AAR and APRI for the diagnosis of significant fibrosis in a large cohort of patients with CHC evaluated at two Academic referral centers.

Patients and Methods: Three-hundred-nineteen patients made up the Italian cohort and 90 patients made-up the US cohort. Histopathological evaluation was carried out by means of the Ishak score (Fibrosis score range 0-6, Italian cohort) and METAVIR score (Fibrosis score range 0-4, US cohort). A fibrosis score >2 (Ishak) or >1 (METAVIR) was considered significant fibrosis. Biochemical data of the patients were collected within one week of liver biopsy. APRI was calculated according to original formula. ROC curves were used to assess the accuracy (c-index) of the AST/ALT Ratio and APRI for the diagnosis of significant fibrosis.

Results

In both cohorts, patients with as fibrosis scores increased the AST/ALT Ratios and APRI increased as well. Prevalence of significant fibrosis was no differently distributed in the two cohorts (43% vs 38%). The AST/ALT Ratio (n=409, 0.89±0.35 vs 0.62±0.21, p<0.0001) and APRI (1.97±1.61 vs 1.03±0.96, p<0.0001) were significantly higher in patients with significant fibrosis. A ROC curve-generated AST/ALT Ratio cut-off of 0.66 had 74% sensitivity, 66% specificity, and 0.747 (0.701-0.788, 95% confidence interval) accuracy for identifying significant fibrosis. An APRI cut-off of 1.22 had 59% sensitivity, 77% specificity, and 0.720 (0.674-0.763) accuracy for identifying significant fibrosis.

Conclusions

We have shown that simple and readily available parameters such as the AST/ALT Ratio and APRI are able to identify non-invasively the presence of significant fibrosis in CHC patients. These results seem to be of particular importance since two different fibrosis scoring systems were used. There was no significant difference between the two non-invasive parameters regarding accuracy for identifying significant fibrosis. Both AST/ALT Ratio and APRI can be proposed as alternative tools for non-invasively stage CHC.

Abstract ID: M956

Health-Related Quality Of Life (HRQL) in Chronic Hepatitis C (CHC) Patients With Elevated Vs Persistently ‘normal’ ALT Levels (PNALT): Comparison Of Data From Patients Treated With Peginterferon Alfa-2a (40KD) Plus Ribavirin in Two Multinational Trials

E. Gane, M. Diago, MD, A. Mohankumar, N. Wintfeld, Ph.D., K. Patel, PharmD, MBA, S. Zeuzem, MD, M. Shiffman, R. Reindollar, MD

Introduction

Patients with CHC and elevated ALT levels have impaired HRQL compared with healthy individuals, but less is known about the HRQL of persons with PNALT. We compared HRQL at baseline in patients from these two populations who were enrolled in phase III, multinational clinical studies evaluating peginterferon alfa-2a (40KD) plus ribavirin.

Methods

Patients included in this analysis were enrolled in one of two randomized trials assessing the efficacy of peginterferon alfa-2a (40KD) plus ribavirin in patients with CHC. One trial (Fried NEJM 2002;347:975-82) included patients with elevated ALT levels; the other (Zeuzem Gastroenterology 2004;127:1724-32) included patients with PNALT (defined as three normal ALT levels within the preceding 6-18 months). Pretreatment HRQL was measured with the Short Form 36 (SF-36) and Fatigue Severity Scale (FSS). Analysis of covariance was used to compare baseline HRQL scores between the two groups, adjusting for gender and weight.

Results

Baseline HRQL scores for all randomized patients are presented in the table. Two of the eight SF-36 scale scores (‘Mental Health’ and ‘Role Emotional’) were significantly higher for the PNALT group than the elevated ALT group (p<0.05). The remaining six SF-36 scale scores and two FSS scores did not differ significantly. Of the two domains displaying statistically significant score differences, only ‘Role Emotional,’ with a 6.1 point difference, was clinically significant.

Conclusion

Baseline HQOL in treatment-naïve patients with chronic hepatitis C is not influenced substantially by serum ALT activity. Thus patients with persistently ‘normal’ ALT activity experience impairment of HRQOL similar to that in patients with elevated ALT activity.

The only clinically and statistically significant difference in HRQOL scores between patients with elevated and persistently ‘normal’ ALT activity was on the SF-36 Role Emotional domain, for which scores were significantly higher in patients with persistently ‘normal’ ALT activity. We speculate that this may reflect that patients with elevated ALT levels are aware of the status of their liver disease and perceive themselves to be more seriously ‘ill’ than patients with persistently ‘normal’ ALT levels.

Improvements in HRQOL should be considered to be a goal of therapy in all patients with chronic hepatitis C, irrespective of baseline ALT activity.

Baseline adjusted HRQL scores for patients with PNALT and elevated ALT
SF-36 domain^a	PNALT (n=491)	Elevated ALT (n=1121)	Difference
Pain index	76.3	77.5	-1.2
General health	66.5	64.6	1.9
Mental health	73.9	71.9	2.0^*
Physical functioning	83.8	84.3	-0.3
Role emotional	85.2	79.1	6.1^**
Role physical	77.5	74.7	2.8
Social functioning	82.4	80.4	2.0
Vitality	59.3	58.6	0.7
FSS Scales^b
FSS total Score	31.3	31.8	0.5
FSS VAS Score	31.0	32.1	1.1
^aHigher scores indicate better HRQL;^bLower FSS scores indicate less fatigue and better HRQL.*p<0.05; **p<0.0001

Abstract ID: M932

Serum Hepatitis B Virus Markers (HBVm) in Postransfusional Chronic Hepatitis C (pt Chc)

M. MARTIN ARRANZ, R. BARCENA MARUGAN, G. MORALEDA, S. DEL CAMPO, J. MORENO, J. SEGURA CABRAL

BACKGROUND

The prevalence of past infection by HBV in the population is high, especially among those patients with CHC.

AIMS

To analyze the incidence and influence of HBV markers in patients with post-transfusional CHC and verify whether latent HBV infection is still present.

PATIENTS AND METHODS

203 patients (>18 years) with PT CHC, without previous antiviral treatment were studied. The exclusion criteria were: intravenous drug abuse, HIV infection, history of liver disease previous to the transfusion, two or more major surgeries prior to transfusion and positive HBsAg. Liver biopsy was obtained. HBsAg, anti-HBs, anti-HBc and HBV-DNA were analyzed (ELISA and nested PCR). Relaxed circular (RC) and covalently closed circular (ccc) HBV-DNA was analysed in liver by nested-PCR.HCV-RNA was analyzed by qualitative and quantitative PCR assay.

RESULTS

Anti-HBc was detected in 41/203 patients (20.2%) with or without anti-HBs (Group I); 28/41 (68.3%) were anti-HBs positive.162 patients were anti-HBc negative (group II).There were no significant differences in demographic and clinical characteristics between both groups, except age (Group I: 51.9 ± 11.7 vs Group II: 46.15±13.9; p<.005).Group I had more fibrosis (2.26 ± 1.56 vs 1.49 ± 1.18; p<.005).51.4% in group I had fibrosis III or IV (34% cirrhosis) vs 9.4% in group II (p<.001). No significant differences in inflammatory activity were observed. Finally, 71.4% of the patients with fibrosis III-IV/IV had anti-HBc vs 28.6% of patients with fibrosis 0-II/IV (p<.001).The multivariate analysis showed that the age ( p=.002, OR 1.045), male sex (p=.028, OR 2.203) and anti-HBc (p=.003, OR 3.107) were 3 independent factors associated with higher fibrosis. Serum HBV-DNA was negative in patients from group I and in 40 analyzed patients from group II.HBV-DNA in liver was observed in 10% of patients from group I (20 liver samples were analyzed) and in any patient from group II (25 liver biopsies were analyzed). No differences between both groups regarding to the HCV viremia were found. In the two patients with DNA-HBV in liver, HCV viral load was nearest the media of population.

CONCLUSION

Prevalence of serum HBVm in PT CHC patients was 20.2%.Presence of anti-HBc had a relationship with fibrosis and were more frequent in patients with severe fibrosis or cirrhosis. HBV latent infection is still present in the 10% of them. Serum HBVm do not seem to influence HCV viral replication or necroinflammatory activity.

Abstract ID: M963

Assessment Of Mutations in Hepatitis C Virus (HCV) Core Protein Associated With Progression To End-Stage Liver Disease

E. Mann, S. Stanford, K. Sherman

BACKGROUND

The mechanisms of progression to end-stage liver disease (ESLD) due to chronic HCV infection are not fully known, but are thought to include damage from oxidative injury and may reflect variations in the effectiveness of hepato-protective NF-κB signaling. Rates of progression are highly variable and reflect a combination of both patient and viral factors. In a longitudinal study of viral quasispecies variation in HCV-infected hemophilic patients, we analyzed sequences from multiple subclones of core amplified from 10 patients with progression to ESLD versus matched non-progressing control patients. Quasispecies evolution between early (first available) and late (average 9 years later) time points differed significantly between index and control subjects. We hypothesized that specific motifs might influence NF-κB signaling.

METHODS

To study the functional significance of these divergent core proteins, we used primers to directionally clone the sequences into an expression vector. As controls, a core sequence from the early time point of each case patient was also cloned. Huh-7 cells were transiently co-transfected with core expression vector and an NF-κB luciferase reporter vector. Luciferase activity was measured after 48 hours and normalized to the protein content of the cell lysate.

RESULTS

In 2 cases there were multiple clones at the late time point that exhibited a single amino acid change in the RKT sequence (amino acids 9-11) of core. This motif has been previously identified as a modulator of NF-κB activation. No alterations in this sequence were observed in the non-progressor controls. For one index subject, 6 of 19 clones had the sequence RKP while in the other subject all 12 clones encoded RQT. Both control core sequences activated the NF-κB reporter approximately 2-fold compared to results with transfection of the empty expression vector. The RQT core motif demonstrated a similar activation. In contrast, RKP core failed to activate the NF-κB promoter (P<0.001, n = 4). Western blot analysis confirmed equivalent levels of expression of the variant core proteins (21 kDa).

CONCLUSION

Analysis of HCV core amplicons from a well characterized cohort of ESLD progressor subjects and matched non-progressor controls led to identification of a mutational variant present only in progressors that was associated with loss of NF-κB activation. Emergence of virus with altered regulatory motifs may play a role in disease progression.

Abstract ID: M1675

Steroid-Free Induction, and Pre-Emptive Antiviral Therapy for Liver Transplant Recipients With Hepatitis C

T. Kato, H. Yoshida, J. Gaynor, E. Martinez, S. Nishida, J. Moon, J. Madariaga, E. Schiff, A. Tzakis

Background

Recurrence of Hepatitis C (HCV) has been a most difficult dilemma in liver transplantation (OLT). Effects of immunosuppresion including use of steroids, mycofenolate mofetil(MMF), and anti IL-2 antibody, and the role of pre-emptive antiviral therapy have not been determined.

Methods

Patients andOLT recipients with HCV were randomized to receive one of 2 different types of immunosupression during two separate time periods. Period 1 Between December, 1999 and June, 2001, patients were randomized to receive: tacrolimus + daclizumab (group 1) or tacrolimus + corticosteroids (group 2). Antiviral therapy was only given to patients having recurrent disease. Period2 Starting in September, 2002, patients were randomized to receive: tacrolimus + daclizumab + MMF (group 3), or tacrolimus + Steroids + MMF (group 4). All patients in period 2 received pre-emptive anti-viral therapy with Pegasys ® and ribavirin. In both periods, patients in the steroid-free arm received no steroids except for the treatment of biopsy-proven rejection.

Results

Patients who completed 1 year of follow-up include a total of 34 patients in period 1 (median f/u 1271 days) and 23 so far in period 2 (median f/u 458 days). The distributions of baseline variables such as patient age, donor age, pretransplant creatinine, pretransplant bilirubin, and pretransplant MELD score, were similar among 4 groups. The 1 year protocol biopsy showed mean fibrosis score (+ SE)of 2.1 + 0.4 in group 1, 1.6 + 0.3 in group 2, 0.7 + 0.4 in group 3, and 1.1 + 0.3 in group 4. Stepwise regression showed that among the variables including pre-transplant operative and treatment variables, only one variable, the use of MMF and/or use of pre-emptive antiviral therapy showed a significantly favorable impact on fibrosis score at 1 year (p=.01). No other variables, including the use of steroid-free induction (p=.49), showed a significant impact on fibrosis score. Comparing the common side effects of steroids in patients who received steroid-free induction vs steroid induction, all of these side effects were lower in patients who received steroid-free induction: hypertension (28% vs 45%, p=0.10), PTDM (13% vs 35%, p=0.018), and wound infection (10% vs 25%, p=0.078).

Conclusions

OLT recipients with HCV tolerated the steroid-free protocol with lower steroid-related side effects. Use of MMF and/or pre-emptive antiviral therapy significantly reduced the progression of hepatic fibrosis in the first year after OLT.

Abstract ID: M1711

Barriers To Vaccination Against Hepatitis A and Hepatitis B in Patients With Chronic Hepatitis C Virus Infection: a National Survey Of U.S. Physicians

S. Chaudhari, C.T. Tenner, E.H. Weinshel, E.J. Bini

BACKGROUND

Although vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for all patients with chronic hepatitis C virus (HCV) infection, physicians often do not follow these recommendations. The aim of this study was to determine physician practices and barriers to vaccination against HAV and HBV in this population.

METHODS

A 2-page questionnaire was mailed to 3000 primary care (PC), 1000 gastroenterology (GI), and 1000 infectious diseases (ID) physicians randomly selected from the AMA Physician Masterfile. The survey was pre-tested prior to mailing and included questions about physician demographics, practices (scored on a 5-point Likert scale), and barriers (yes/no).

RESULTS

Among the 5000 physicians surveyed, 115 were undeliverable, 89 were not in practice, and 2038 (42.5%) of the 4796 eligible physicians returned completed surveys. There were no differences between respondents and non-respondents with regard to age, sex, geographic location, or specialty. Of the 2038 respondents, 56.4% usually/always tested HCV(+) patients for immunity against HAV, 61.1% vaccinated susceptible patients against HAV, and 56.6% tested for HAV antibody prior to vaccination. Overall, 70.4% usually/always tested HCV(+) patients for immunity against HBV, 69.7% vaccinated susceptible patients against HBV, and 70.3% tested for HBV antibody prior to vaccination. For all 6 of these questions on vaccination practices, there were significant differences (P <0.001) between specialties in the proportion of physicians who tested and vaccinated HCV(+) patients for HAV and HBV, and these were substantially higher in GI (80.9% - 87.4%) and ID (72.9% - 87.0%) than in PC physicians (41.8% - 60.2%). There were many barriers to HAV and HBV vaccination, including patient refusal (41.4%), cost (36.8%), lack of reimbursement (34.7%), compliance issues (27.1%), time constraints (20.4%), staffing issues (10.7%), uncomfortable with vaccination (11.0%), and lack of evidence regarding efficacy (8.3%) and safety (7.2%) of vaccination. The prevalence and type of barriers differed significantly between specialties.

CONCLUSIONS

Despite published recommendations for vaccination against HAV and HBV in patients with chronic HCV infection, physicians often do not test or vaccinate susceptible individuals. There is wide variability in vaccination practices and barriers to vaccination among specialties, and interventions are needed to improve vaccination rates.

Abstract ID: M1674

Recurrence Of Hepatitis C Virus-Associated Hepatocellular Carcinoma After Complete Tumor Ablation: An Analysis With Mathematical Model

H. Yoshida, R. Tateishi, N. Yamashiki, y. Kondo, N. Mine, M. Akamatsu, T. Fujishima, T. Teratani, S. Shiina, T. Kawabe, M. Omata

Background & Aims

Recurrence of hepatocellular carcinoma (HCC) is very frequent even after complete removal of primary tumor. We constructed a mathematical model for HCC recurrence consisting of two components, multicentric carcinogenesis (MC) and intrahepatic metastasis (IM).

Methods

Assuming constant hazard for MC and log-logistically distributed probability density for IM detection, on-computer simulation was plotted and fitted to the observed recurrence-free survival among 623 consecutive HCV-associated HCC patients after complete ablation.

Results

The hazard of MC was estimated to be 18% per year. The comparison between the simulated plots and observed data (Fig.) indicated the prevalence of IM to be 10% when the primary tumor was uninodular and smaller than 20 mm in diameter (A), 30% when the number of nodules was three or less with the maximum diameter smaller than 30 mm (B), and 50% or greater if more advanced (C).

Conclusions

MC plays a major role in the recurrence of HCV-associated HCC while IM is also important when the size of primary tumor exceeds 20 mm in diameter. Each mode of recurrence may require distinct strategy for prevention.

Abstract ID: M960

Is Hepatitis C Virus Infection a Risk Factor for Diabetes Mellitus? Half a Million Us Veterans' Case-Control Study

V. Khurana, L. Hagood, W. Cassidy, G. Caldito, C. Fort

Aim

To investigate the statistical association between diagnosis of HCV (HCV) infection & the risk of developing Diabetes Mellitus (DM) in the US veterans’ population using the VISN 16 VA database.

Design

VISN 16 data warehouse, which contains clinical & demographic information about all veterans (>1.4 million patients) cared for at the 10 VA Medical Centers in 4 states comprising the South Central VA health Care Network in the mid-south region of the US, was queried from Oct 1998 to June 2004. Retrospective case control design was used. Multiple logistic regression analysis was used with calculation of odds ratios & 95% confidence intervals were used universally. Statistical analysis was performed using SAS software version 9.0 (Chicago, IL).

Result

A total of 480,306 patients were studied. Males constituted 91.7% of the sample. Average age was 61.1±14.8 years. A total of 103,256 (21.5%) patients had DM (ICD-9 code: 250) and 14,021 (2.92%) patients had HCV infection (ICD-9 codes: 070.51, 070.41, 070.54 or 070.44). The data was adjusted for age and body mass index (BMI) (missing values=89,141, mean 28.57±5.45). HCV infection was a significant risk factor for the DM (OR 1.48, 95% CI for OR 1.41, 1.54, p <0.0001). Other significant covariates for DM include age (OR 1.035, 95% CI for OR 1.034, 1,036, p <0.0001) and BMI (OR 1.114, 95% CI for OR 1.113, 1.116, p<0.0001).

Discussion

Association between HCV infection and DM has been studied before but the results are confounded by a synergistic interaction between increasing age, obesity and HCV infection. The strengths of the database allow us to study the effect of these factors independently. An internal consistency of the database is reflected by an increased risk associated with documented risk factors. The prevalence of HCV (2.92%) & DM (21.5%) in this population is greater than in the general population (1.8% & 6.3% respectively) but is explained by a relatively older veteran population. The results should be interpreted with caution given the limitations of population, the database and retrospective design. However, the large number of patients should potentially overcome some of these limitations.

Conclusion

HCV infection is associated with 48% increased risk of DM after controlling for age and BMI.

Abstract ID: M955

Role Of CYP2D6 Polymorphism in Predicting Liver Fibrosis Progression Rate in Caucasian Patients With Chronic Hepatitis C .

S. Fishman, Y. Lurie, H. Peretz, T. Morad, E. Grinberg, L. Blendis, M. Leshno, E. Brazovsky, Z. Halpern, R. Oren

Introduction

Fifteen to twenty percent of chronic hepatitis C (HCV) patients progress during their life time to end stage liver disease. However, markers of fibrosis progression rate are yet to be defined. Recent studies have demonstrated that cytochrome P450-2D6 (CYP2D6) polymorphism is associated with liver cirrhosis. The aim of our study was to find out whether CYP2D6*4, the poor metabolizer allele can predict fibrosis progression rate. METHODS: Fifty caucasian patients with chronic HCV were recruited. They were divided to "fast fibrosers" and "slow fibrosers" according to Poynard's fibrosis progression curves, based on age of exposure and duration of infection. Thirty six underwent liver biopsy. Blood of 20 neonates served as a control. DNA was extracted from peripheral blood and CYP2D6*4 was tested by polymerase chain reaction (PCR) method, using fluorecent hybridization probes in a lightcycler instrument. RESULTS: Thirty three patients were classified as "fast fibrosers" and 17 patients as "slow fibrosers". The prevalence of CYP2D6*4 in the "fast fibrosers" (37.8%) was significantly higher than its prevalence in the "slow fibrosers" (P-value=0.0166). There was no significant difference between the prevalence of CYP2D6*4 in the "slow fibrosers" (14.7%) compared to the controls (11%). Carrier state of CYP2D6*4 was the only covariate that was significantly directed associated with fast progression to cirrhosis (OR=11.7 P= 0.022) CONCLUSIONS: This study indicates for the first time, that CYP2D6 genotype is a significant predictor of liver fibrosis progression rate in HCV patients. Prospective studies are needed to further validate the data that bear significant therapeutic importance .

Abstract ID: M1677

Long-Term Follow Up Of Patients With Recurrent Hepatitis C Intolerant To Interferon and Ribavirin -A Single Center Experience

S. Mukherjee, J. Rogge, L. Weaver, D.F. Schafer

BACKGROUND

Patients with recurrent hepatitis C (HCV) after liver transplantation are treated with interferon-based therapy to prevent cirrhosis requiring retransplanatation. These medications are poorly tolerated leading to premature treatment discontinuation.We describe the natural history of patients with recurrent HCV intolerant to anti-viral treatment from a single liver transplant program.

METHODS

Between October 2000 and November 2001, consecutive patients with recurrent HCV were screened to determine if they were eligible for treatment. Recurrent HCV was defined as the presence of HCV viremia (HCVRNA) in the presence of elevated liver tests and a biopsy demonstrating recurrent hepatitis or fat. This cohort was followed prospectively after starting interferon alpha-2b 3 million units tiw and ribavirin 1000-1200mg qd (Schering-Plough, Kenilworth, NJ). Patients were treated for 6-12 months depending on genotype. Steroids were discontinued in all patients prior to treatment. Complete blood counts were performed weekly for the first month and monthly thereafter with liver function tests.

RESULTS

45 patients were screened and 38 eligible for treatment. 14 were intolerant to treatment and followed up until death, retransplantation or December 2004. There were 9 males and 5 females with an average age of 49 years. 11 patients were genotype 1. Median treatment duration was 3 months. Indications for discontinuation were anemia (n=1), leucopenia (n=2), fatigue(n=9), depression (n=1), and nausea (n=1). 10 patients (71.4%) have died after a median survival of 15 months following treatment discontinuation. Median Ludwig and Batts fibrosis score in these 10 patients was 2. Causes of death were decompensated cirrhosis from recurrent HCV in 9 patients (retransplantation was performed in two patients) and lymphoma (n=1). 4 patients (28.6%) are currently alive with a median survival of 44 months of whom 3 are genotype 1.

CONCLUSIONS

Decompensated cirrhosis from recurrent HCV is a common cause of death in patients with recurrent HCV intolerant to interferon alpha-2b and ribavirin. Strategies targeted at minimizing side effects and improved patient tolerance to anti-viral therapy are urgently required to prevent premature discontinuation of treatment.

Abstract ID: M953

Impact Of Obesity on Degree Of Liver Disease and Response To Therapy in Patients With Chronic Hepatitis C Genotype 1 Infection

K. Cesario, F. Khandwala, K. Edwards, W. Carey, D. Barnes, N. Zein

Introduction

Obese patients with hepatitis C virus (HCV) may have more rapid progression of liver disease and lower rates of response to antiviral therapy than non-obese patients.

AIMS

Assess the association between obesity and histologic stage of liver disease and determine if weight-based dosing with peginterferon alfa-2b (PEG2b) and ribavirin (RBV) is more likely to result in a sustained virologic response (SVR) than standard dosing with peginterferon alfa-2a (PEG2a) and RBV in obese HCV patients.

METHODS

Treatment-naïve, Caucasian patients with chronic HCV genotype 1 at The Cleveland Clinic Foundation between 2001 and 2004 were identified. Those who received ≥1 dose of PEG with RBV were included and liver transplant recipients or patients coinfected with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) were excluded. Patients were classified by body mass index (BMI) as obese (>30kg/m²) or nonobese (<30kg/m²) and demographic and histologic features on pretreatment liver biopsy were compared. SVR—absence of HCV-RNA 6 months after therapy discontinuation—was determined overall, based on type of therapy received.

RESULTS

Mean BMI of the obese group was 35kg/m² (n=41) compared with 25kg/m² in the nonobese group (n=91; p<0.001), and there were no statistical differences in age, gender, baseline ALT or HCV RNA. Steatosis was more likely in obese (40%) than nonobese (16%) patients (p=0.02), but frequency of advanced fibrosis (60% obese vs 44% nonobese) or marked inflammation (11% both groups) were not significantly different. SVR data were available in 35 obese and 61 nonobese patients. Multivariate logistical analysis showed that mild hepatic fibrosis (OR 2.70, p=0.063), lower pretreatment HCV-RNA (OR 0.93, p=0.052) and weight-based dosing (OR 4.76, p=0.003) were independently associated with attainment of SVR. SVR in patients who received weight-based doses of PEG2b and RBV (n=46) was similar in obese (9/17, 52%) and nonobese (14/29, 48%) patients. However, SVR in those treated with standard-dosed PEG2a and RBV (n=40) was lower in obese (2/11, 18%) than nonobese (8/29, 28%) patients.

CONCLUSIONS

The obese and nonobese patients were demographically and histologically similar. Obese and nonobese patients have equal SVR when treated with weight-based doses of PEG2b in combination with RBV. However, when treated with standard-dosed PEG2a and RBV, obese patients are less likely to attain SVR. A randomized clinical trial is needed to confirm these findings.

Abstract ID: M1423

Regulation Of Heme Oxygenase-1 Gene Expression in End-Stage Cirrhosis Due To Chronic Hepatitis C

Y. Shan, R.W. Lambrecht, T. Ghaziani, H.L. Bonkovsky

Background

Hepatitis C virus is a leading cause of chronic hepatitis. Recent studies implicate increased oxidative stress as an important pathogenetic mechanism in chronic hepatitis C (CHC). Heme oxygenase (HO)-1 is a key cytoprotective enzyme and up-regulated by numerous stressful stimuli. Hepatocytes respond to acute injury with increased expression of HO-1. We found that expression of HO-1 was up-regulated in HCV replicon Huh-7 cells, compared with wild-type cells (Hepatology 2004;40:453). In contrast, Abdalla et al reported that the HO-1 gene expression was down-regulated in liver-biopsy samples from chronic HCV patients and in HCV core expressing HepG2 cells (J Infect Dis 2004;190:1109). The Aim of this study was to study the regulation of HO-1 gene expression in the livers of patients with end-stage CHC.

Methods

We extracted total RNA and proteins from the explanted livers of 5 end-stage CHC patients and 5 controls, quantified HO-1 mRNA and protein levels by quantitative RT-PCR and western blotting, respectively. We performed immunohistochemical (IH) staining to visualize HO-1 protein in the liver samples.

Results

We found that hepatic HO-1 protein levels in all five livers from the CHC patients were significantly down-regulated, compared to controls. Compared with normal controls, hepatic HO-1 mRNA levels were significantly lower in CHC patients (P<0.01). To locate the HO-1 protein, we performed IH staining on sections of liver tissue from control and CHC patients. Interestingly, in normal controls, HO-1 staining was limited to Kupffer cells and to hepatocytes located near the portal area, whereas in CHC livers, HO-1 was located in hepatocytes throughout the liver lobule. Intensity of HO-1 staining was markedly increased in the hepatocytes from patients with CHC compared to controls. However, there were fewer hepatocytes in the sections from cirrhotic CHC patients than controls, because of hepatocyte death, increased hepatic fibrosis, nodule formation, and inflammation due to end-stage CHC.

Conclusion

Although expression of HO-1 mRNA and protein (per g of liver) is decreased significantly, expression of the HO-1 gene is up-regulated and relocated in hepatocytes in end-stage CHC. (Supported by grants and contracts from NIH RO1-DK 38825, NO1-DK 92326, and UO1-DK 065193.)

Abstract ID: 413

Immune Response To Hepatitis C Virus: a Comparison Between Ns5 Protein-Transduced Dendritic Cells and Dna-Based Vaccination

N. Kuzushita, M.D., N.A. Monti

Introduction

We have recently shown that dendritic cells (DCs) transduced with hepatitis C virus (HCV) NS5 (but not Core) protein elicits sustained CTL activity and T_H1 type immune responses in vitro using a murine model. However, the potency of an NS5-transduced DC vaccine in vivo is unknown. The aim of this study was to assess the efficacy of vaccination with NS5-transduced DCs in vivo, and to compare this method to previously established DNA-based vaccination techniques.

METHODS

The DC population in BALB/c mice was expanded in vivo by hydrodynamic delivery of naked DNA encoded Flt3L. The DC population obtained from the spleen was transduced in vitro with recombinant NS5 protein using a macromolecular-based protein delivery system. For DC vaccination, each animal was inoculated subcutaneously three times at 2-weeks intervals with either medium only, DCs (1x10⁶ cells) transduced with NS5, or non-transduced DCs (1x10⁶ cells). For DNA-based vaccination, 100µg NS5-expressing plasmid DNA or 100µg empty plasmid vector was inoculated into the muscle three times at 2-weeks intervals. Vaccine efficacy was assessed using an in vivo tumor challenge model. To assess sustained vaccine efficacy, vaccinated mice were then challenged in parallel with NS5-expressing myeloma cells or non-expressing parental cells at 10 weeks following the final inoculation. Tumor size was measured daily starting on day 7.

RESULTS

At 10 weeks post vaccination, no suppression of NS5-specific tumor growth was observed in mice vaccinated with NS5-DNA plasmids. However, mice vaccinated with NS5-transduced DCs and challenged with NS5-expressing myeloma cells had significantly reduced tumor growth compared to controls (P<0.05). Notably, tumor growth suppression was not evident among mice vaccinated with NS5-transduced DCs when challenged with NS5 non-expressing parental cells, thus demonstrating NS5-specific anti-tumor immunity. To confirm the sustained in vivo vaccination response of NS5-transduced DCs, tumors were dissected and weighed on day 15 and compared to those of the NS5-DNA vaccination group. The mean tumor weight among mice vaccinated with NS5-transduced DCs was significantly less than that in the NS5-DNA vaccination group (P<0.01).

CONCLUSION

Mice immunized with NS5-transduced DCs exhibited strong, sustained HCV antigen-specific vaccine efficacy in vivo compared with those receiving DNA-based vaccination.