Hepatitis C

Helen S. Te, MD, AGAF

University of Chicago Medical Center, Chicago, Illinois

Helen S. Te, MD, AGAF is an Assistant Professor of Medicine in the Section of Gastroenterology at The University of Chicago Medical Center in Chicago, Illinois. She is the Medical Director of the Adult Liver Transplant Program of the University of Chicago Medical Center. Dr. Te specializes in the diagnosis and management of viral hepatitis, chronic liver disease and liver transplantation. Her research interests include the prevention of post transplant rejection, fatty liver disease, and viral hepatitis. Dr. Te has been involved in several clinical trials studying treatment regimens in patients with chronic hepatitis C, including patients who are nonresponsive to current therapies. Her work has been published in The American Journal of Gastroenterology, Liver Transplantation, Transplantation, and

Gastroenterology and Hepatology. She has served as a reviewer for a number of medical journals, including Archives of Internal Medicine, Digestive Diseases and Sciences, American Journal of Gastroenterology, and Gastroenterology. Certified by the American Board of Internal Medicine, with a subspecialty in gastroenterology as well as transplant hepatology, Dr. Te is a member of the American Association for the Study of Liver Diseases (AASLD) and serves on the Surgery and Liver Transplantation Committee of the AASLD. She is also a Fellow of the American Gastroenterological Association, and is a member of the American Society of Transplant Physicians and the Gastroenterology Research Group.

In this session, we will review the most recent data that was presented at DDW® on the topic of hepatitis C. Most of these are clinical abstracts that were submitted to the AGA. There are other abstracts that have been presented to the other societies participating in this meeting, so I am going to touch on a few that have similar topics as the ones in your handout, and other exciting ones as well if we have enough time. This morning’s session will be divided into these topics 1) non-invasive markers of fibrosis in hepatitis C, 2) hepatitis C and insulin resistance, 3) one abstract that addresses what happens to hepatitis C when the patient is treated with Rituximab (I’m often asked questions by oncology colleagues when they have patients with hepatitis C who need to be given Rituxan for their hematologic malignancies), and 4) three abstracts that highlight some practices regarding hepatitis C screening and management out in the community. In my opinion, the most exciting abstracts this year are those that address updates on the treatment for hepatitis C. Abstract S2069: “Quantitative measure of liver function using 13 C-Galactose (GBT) and 13 C-Methacetin (MBT) breath tests and hyaluronic acid as serum markers in patients with chronic hepatitis B or chronic hepatitis C.” The aim of this study was to determine whether these non-invasive tests (the two kinds of breath tests along with the serum marker hyaluronic acid) would be adequate to diagnose fibrosis of the liver, particularly in the earlier stages of the liver disease. In clinical practice, the currently available serum markers are quite good in distinguishing the two extremes of the whole spectrum; the very early stage (no fibrosis) or the very advanced stage (cirrhosis). In the middle of the whole spectrum, I think there is a big void that has to be filled - how to use non-invasive measurement of those F2-F3 categories. These investigators took 89 patients, about half of whom (41) had hepatitis C. All of these patients had a biopsy within six months. They had the galactose breath test (GBT) and the methacetin breath test (MBT). In addition, they took 31 healthy controls to compare the results. They saw that the controls had essentially the same results with the breath tests (both GBT and MBT) as the people with no fibrosis, which is a good validation. As far as distinguishing between cirrhosis and non-cirrhosis, the GBT and the hyaluronic acid were quite good in distinguishing those patients with a very significant positive correlation in terms of the Metavir scoring with F1-F4. The MBT, however, was not a good test to distinguish that. When looking at early fibrosis, to distinguish F0-F1 versus F2-F3 from the later stages, neither GBT, MBT or hyaluronic acid could distinguish these

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groups. The authors’ conclusion was that the non-invasive GBT and hyaluronic acid was pretty good in distinguishing cirrhosis from non-cirrhosis but MBT was not. None of these three tests were able to distinguish early stages of fibrosis in either hepatitis B or hepatitis C. This is the same problem we have in practice. Abstract S2078: “The APRI and FIB-4 are equivalent in the estimation of fibrosis in chronic hepatitis C.” These authors wanted to compare the accuracy of the AST to platelet ratio index (APRI) and FIB-4 (an inexpensive and accurate marker of fibrosis in HCV infection) in predicting fibrosis. They enrolled about 277 patients and performed biopsies at the time of the blood draw. They utilized the Ludwig criteria in staging liver biopsies where mild fibrosis was assigned as F0-F1 and significant fibrosis was F2-F4. They then used a different category where they combined mild and moderate fibrosis as F0-F2 and advanced fibrosis as F3-F4. When they compared the two tests, FIB-4 and APRI, they had nearly identical area under the curve results with pretty good correlation of 0.85 for each. The tests are similar in terms of predicting mild fibrosis and distinguishing that from significant fibrosis. When looking at mild to moderate fibrosis, to distinguish that from advanced fibrosis, there was a decent negative predictive value but the positive predictive value fell down to relatively lower levels; to 69% for APRI and 77% for FIB-4. The authors concluded that both tests were good at separating mild from significant fibrosis and in predicting the absence of advanced fibrosis, but they were not as accurate in predicting the presence of advanced fibrosis. The APRI and FIB-4 are easier indices to obtain in our day-to-day practice since the labs are typical components of our management of hepatitis C patients. However, we may have to utilize more than one tool if we are aiming for a more accurate non-invasive means of assessing fibrosis. Utilizing a single formula or a particular instrument is probably not going to give us the best result. A problem in this study, as with others, is that they are utilizing liver biopsies as the gold standard. We are all aware that liver biopsy has its own pitfalls in terms of sampling error. We probably have about a 15%, or even up to 30%, sampling error with liver biopsies. When we are comparing a variable against a gold standard that has its own problems, it becomes more difficult to determine which one is the better test. Abstract S2065: “Minimal visceral fat accumulation is a prerequisite for a persistent normal serum ALT level in chronic hepatitis C patients.” The authors wanted to determine if there was any relationship between visceral fat accumulation and the serum ALT of patients with hepatitis C. The study patients had CT scans performed to evaluate the amount of visceral fat in their abdomen. There were two categories - normal ALT (less than 30) or elevated ALT (greater than or equal to 31). The insulin resistance was calculated by the homeostasis model assessment (HOMA) and the quantitative insulin-sensitivity check index (QUICKI). The investigators had a total of 95 patients - 22 had a normal ALT and the rest had an elevated ALT. The patients in the normal group were a little older and they had a lower BMI. Their visceral fat accumulation was lower as well. Investigators found that the HOMA and the QUICKI indices were significantly correlated to the visceral fat area; meaning that visceral fat accumulation was positively correlated with an increased insulin resistance. The more visceral fat, the more likely the patient was insulin resistant, which is expected. They found that the normal ALT patients were also those who had low visceral fat. If a patient had a lean body, they were more likely to have a normal serum ALT compared to someone who has more visceral fat accumulation. Abstract M1771: “The prevalence of insulin resistance in patients with chronic hepatitis C and B.” The authors wanted to assess the prevalence of insulin resistance using the HOMA index among non-cirrhotic, non-diabetic naïve hepatitis B and C patients, and compare the indices between hepatitis B and C patients. The study enrolled 102 hepatitis C patients and 27 hepatitis B patients. The demographic data, the BMI, the waist circumference, the free fatty acid levels, the histological activity index (HAI), and fibrosis and steatosis scores were very similar between the hepatitis B and hepatitis C patients. There was a slight divergence in that there were more males and Asians in the hepatitis B patients and there were surprisingly more patients with elevated serum cholesterol. There was no significant difference in the prevalence of insulin resistance between hepatitis B (30%) and C (38%) patients, although we have to remember that the number of hepatitis B patients is so small (27 patients). The authors did note that BMI a nd the HAI were independent risk factors for insulin resistance in

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hepatitis C patients. We do expect the BMI to be positively correlated with insulin resistance, and the HAI potentially might be a sequela instead of a causative factor in insulin resistance development. I think that insulin resistance, in terms of those who have excessive weight and metabolic syndrome, will remain to be a continuing challenge for us to treat our patients with hepatitis C and get them to respond to treatment. It is so much easier to treat the hepatitis C itself than for them to try to lose the weight. Abstract 383: “Hepatitis C virus (HCV) flares in patients with hematological malignancies treated with anti-CD 20 antibody rituximab including regimens.” The authors evaluated the role of rituximab in inducing significant increases in transaminases in patients with hepatitis C. There were about 104 patients who were treated with rituximab-containing regimens in their institution within a two-year period. Nine of these patients who had hepatitis C were followed for up to twelve months after their chemotherapy ended. A hepatitis flare was defined as an ALT of more than five times normal. The investigators found that among the nine hepatitis C patients, three of them had elevation in ALT to more than five times baseline, whereas there was no elevation at all in non-hepatitis C patients. That is a 33% incidence of a hepatitis flare that occurs while the hepatitis C patient is receiving rituximab. Fortunately, none of these flares ended up in either hepatic failure or death for the patients and they all were able to continue their chemotherapy. This is very helpful information. My oncology colleagues often ask if a patient can receive rituximab for hepatitis C, or would it increase the hepatitis C viral replication. The problem with this abstract is that the hepatitis C diagnosis was made with a hepatitis C antibody rather than hepatitis C RNA, and the authors did not mention what happened to the viral load during the times that patients were given treatment. It would have been very interesting to see if there was also a correlation with the viral load going up during the time of flare. That may be something to monitor during the treatment of patients with rituximab and might help anticipate a flare before it actually happens. I don’t know if they will present this information in their oral presentation tomorrow, but that would be interesting to see. Abstract 380: “Project ECHO (Extension for Community Healthcare Outcomes): Knowledge networks expand access to hepatitis C (HCV) treatment with pegylated interferon and ribavirin in rural areas and prisons. Care is as safe and effective as a university HCV clinic.” Project ECHO (Extension for Community Healthcare Outcomes) is a very elaborate and sophisticated model of an outreach into the underserved rural areas, prisons where hepatitis C patients have not been treated before, by using telemedicine and computer networking. The specialists in the tertiary care center provide the guidance for the primary care physicians, physician’s assistants and nurse practitioners, to allow them to treat the HCV patients. They have treated about 327 hepatitis C patients with this project and the majority of the patients (about two-thirds) are minorities including Hispanic, Native American or African American. About 24% were cirrhotic, which is an expected fraction. Depression was quite high, with a 41% prevalence in this population. There was about 60% genotype 1 with a high viral load. The early virologic response (EVR) was about 85%, 82% and 93% respectively for the university, prison and rural patients. The authors did not report on the sustained virologic response (SVR). The significant adverse event (SAE) rate was about 12% and those who had SAE’s were patients who were older and had a lower serum albumin, probably representing advanced disease. The platelet count was also lower, so these patients were more likely to have cirrhotic livers. They also were the ones who had the history of depression. The authors conclude that hepatitis C treatment delivered to patients in rural areas and prisons using this model was quite safe and as effective as a university clinic treating hepatitis C. Abstract S1058: “Hepatitis A and B immunization practices among community physicians of chronic hepatitis C patients.” The authors wanted to evaluate the frequency of vaccination of hepatitis C patients in the community in accordance with AASLD practice guidelines. They studied patients who were referred to their hepatology practice for a year. Eighty-nine of these patients have been diagnosed with hepatitis C for at least one year, to give the primary care physician and the referring physician time to screen these patients for hepatitis A and B immune status, so they could be vaccinated if they were not immune to hepatitis A and B. When the patients were seen at the referral

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center, they were presumably already vaccinated by their referring physicians, so the authors evaluated the immune status to hepatitis A or hepatitis B in these patients. Of the 89 patients, about 46% were immune to hepatitis A, which could represent either prior exposure or vaccination. Fifty-eight percent had evidence of previous hepatitis B exposure or vaccination as well. The authors tried to compare these incidents of immunity to hepatitis A and B to the number of patients who had a previous screening colonoscopy within five years, to have a comparative gauge of adherence to preventive healthcare practice guidelines. Sixty-five percent of the patients had a screening colonoscopy within five years, which is higher than the prevalence of immunity to hepatitis A or B in these patients. The authors also compared their results with previously published prevalence of hepatitis A and B immunity in hepatitis C patients. In hepatitis A, this is reported to be about 38% and in hepatitis B, 59%. The authors concluded that hepatitis A or B immunity in the patients who were referred to them was very similar to the hepatitis A or B immunity status as previously reported in hepatitis C patients who have not been immunized to hepatitis A or B. This suggests that perhaps none of these referred patients were vaccinated by the referring physicians, as a higher rate of immunity would have been expected if immunization was given. There was a higher compliance with colonoscopy than the vaccination for hepatitis A and B. Patients are screened for colon cancer more commonly because colon cancer has such a high profile. The consequence of colon cancer is also graver than that of lack of immunization to hepatitis A and B. I think the level of awareness on the part of the referring physician regarding hepatitis A and B vaccine is not as high as their level of awareness regarding the need for colonoscopies. I think it is that the gravity of the situation is very different. These results indicate that we have improved the level of awareness in the primary or referring physicians for the need to immunize these patients. There were only 89 patients in this study, and I have heard of adult primary care clinics not necessarily stocking the vaccine because it is not very commonly used in the adult population, unlike in pediatric offices. There are also patients who receive the first dose but then don’t go back for the second and the third dose. Recalling these patients is not likely to always be done by each clinic. Abstract S2079: “The impact of hepatitis B (HBV), hepatitis C (HCV) and non-alcoholic fatty liver disease (NAFLD) guidelines on clinical practices.” These investigators were trying to assess the attitudes of primary care physicians, gastroenterologists and hepatologists regarding hepatitis B, C and NAFLD. They sent out surveys that had specific questions about NAFLD, HBV, and HCV, but the number of surveys sent out was not specified. One hundred sixty-one surveys were returned, but the response rate can not be determined. One hundred one responses came from primary care physicians, 30 from gastroenterologists and 26 from hepatologists, which might reflect a similar proportion of physicians to whom the survey was sent. Most of the physicians practice in urban and suburban settings, with very few in rural areas. When it comes to screening, the primary care physicians considered hepatitis C to be less common in the population than the gastroenterologists and the hepatologists. The primary care physicians also thought NAFLD was more common, which is a realistic perception. The survey results showed that 40% of primary care physicians were not aware of guidelines for any of these diseases compared to about 13% of gastroenterologists and 4% of hepatologists. Most hepatologists were familiar with the AASLD guidelines, although only 40% of gastroenterologists were aware of the AASLD guidelines for HBV, HCV and NAFLD. I would have expected a higher number in this group. Primary care physicians were most likely to follow the United States Preventive Service Task Force guidelines, followed by the American Academy of Family Practice guidelines, followed by the American College of Physicians guidelines and then least, AASLD guidelines. That is not surprising, as most primary care physicians would follow the preventive task force guidelines. The hepatologists or gastroenterologists typically do not follow the American Academy of Family Practice guidelines. The primary care physicians also rated themselves less knowledgeable about hepatitis B guidelines than the gastroenterologists and the hepatologists, as well as less knowledgeable about the hepatitis C guidelines. The primary care physicians have less use of the guidelines when they make a decision to screen for hepatitis B and C. The hepatologists rated effectiveness of hepatitis B treatment higher than the primary care physicians, whereas the primary care physicians rated the effectiveness of treatment for NAFLD higher than the hepatologists. I thought this was quite interesting, considering many hepatologists still find the treatment of NAFLD to be quite lacking. Side effects of hepatitis B and NAFLD treatment were rated to be more harmful by the primary care physicians than the hepatologists. The conclusion is that although there are several practice guidelines available out there, there is still a lack of familiarity and adaptation of these guidelines into clinical practice, particularly in the primary care setting as far as screening

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and treatment for hepatitis B and C. The US Preventive Task Force guidelines for screening for hepatitis C do not advocate screening for hepatitis C in asymptomatic patients or low risk patients and had a neutral stand on screening for hepatitis C in high-risk patients, which is really interesting. This is based on the lack of conviction that screening is going to translate to cost effectiveness in terms of increasing patients’ survival. This is the only set of preventive guidelines that did not take a strong stand for hepatitis C screening in high-risk patients. Abstract S2081: “Peginterferon and ribavirin for treatment of hepatitis C and HIV co-infection: A meta-analysis of randomized controlled trials.” These authors did a meta-analysis of all randomized controlled trials comparing peginterferon and ribavirin versus standard interferon and ribavirin in HIV and hepatitis C infected patients. They had five trials included into their meta-analysis with about 13,000 patients. The majority of these patients (85%) were on highly active anti-retroviral therapy (HAART) therapy. The bottom line is that there was a higher sustained viral response (SVR) with peg-interferon and ribavirin compared to standard interferon, with a very similar side effect profile between the two groups. This is not new news; as we are expecting the pegylated interferon would be a better form of treatment for the co-infected population than the standard interferon.

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Abstracts Discussed TITLE: Quantitative measure of liver function using 13C-Galactose (GBT) and 13C-Methacetin (MBT) breath tests and hyaluronic acid as serum markers in patients with chronic Hepatitis B or chronic Hepatitis C

ABSTRACT FINAL ID: S2069 AUTHORS (FIRST NAME, LAST NAME): Krista Stibbe1, Claudia Verveer1, Jan Francke1, Bettina E. Hansen2, Pieter E. Zondervan3, Ernst J. Kuipers1, Robert J. de Knegt1, Anneke van Vuuren1 ABSTRACT BODY: Background Quantification of fibrosis is essential in chronic hepatitis patients (HBV or HCV) to determine progression of fibrosis or cirrhosis, necessity for treating patients, and efficacy of treatment. Liver biopsy is the golden standard, however the procedure is invasive, with a significant morbidity rate, and problems like sampling error and observer variability. Aims To determine whether non-invasive tests (breath tests and a serum marker) could be used as alternatives for diagnosing liver fibrosis, especially in the earlier stages of liver fibrosis. Methods 89 patients (48 HBV and 41 HCV), who had a liver biopsy within previous 6 months, were included for GBT and/or MBT. Both breath tests were metabolized via different pathways in the liver. Biopsies were classified via Metavir score (F0-F4). In addition, 31 healthy controls (C) with normal liver biochemistry were included for both breath tests. Breath samples were taken frequently up to 3 hours (T=0, 10, 20, 30, 40, 60, 90, 120, 150 and 180 min) to measure the expired 13CO2/12CO2 isotope ratio. Hyaluronic acid (HA) was measured in serum of all participants. Results In Metavir group F0, F1, F2, F3 and F4, resp. 8, 34, 14, 11, 15 patients attended GBT and resp. 9, 32, 14, 11, 15 patients attended MBT. Controls (n=31; mean AUC= 20.4) were not significantly different from patients in F0 (17.8) for GBT, neither for MBT controls vs F0 (68.2 vs.74.3). GBT as well as HA results distinguished between non-cirrhotic and cirrhotic patients. GBT: (C+ F0-3) vs F4 (17.5 vs 14.3, p=0.01) and HA: (36.6 vs 182.3, p<0,001). Linear regression showed a significant positive correlation between Metavir scoring and GBT as well as HA (both p<0.001). However, neither GBT, MBT nor HA could discriminate early fibrosis stages from late stages (F0-1 vs F2-3) (GBT: 16.7 vs 15.2; p=0.113) (MBT: 71.6 vs 66.1; p=0.180) (HA: 38.4 vs 47.0; p=0.544) (T-test). In addition, GBT mean was lower in men compared to women (-0.29, p=0.002) and MBT and BMI of the patients were inversely related (0.24; p=0.011). Both measured by linear regression. Expiration patterns were different: the peak and time of expired 13CO2 in GBT is significantly lower and later in time in F3-4 compared with C+ F0-2 (both p<0,001). In MBT the peak in F3-4 is significantly lower (p=0.037), but not significantly later (p=0.085). Also HA measurement is significantly different between F0-2 vs F3-4 (p=0.03,T-test). Conclusion The non-invasive GBT and HA distinguish reliably between cirrhotic and non-cirrhotic patients, unfortunately MBT cannot. However, GBT, MBT and HA had not enough accuracy to diagnose early stages of fibrosis in patients with HBV or HCV. TITLE: The APRI and FIB-4 Are Equivalent in the Estimation of Fibrosis in Chronic Hepatitis C

ABSTRACT FINAL ID: S2078 AUTHORS (FIRST NAME, LAST NAME): Ned Snyder1, Tony Trang1, Shu-Yuan Xiao2, John R. Petersen2 ABSTRACT BODY: Background: Several hepatic fibrosis markers utilizing simple biochemical tests or components of the hepatic extracellular matrix are useful in predicting broad categories of fibrosis in chronic hepatitis C (HCV). Two tests that can easily be calculated from routine data are the APRI and FIB-4. Aims: We compared the accuracy of the APRI and the FIB 4 in the separation of mild from significant fibrosis, and also mild/moderate fibrosis from advanced fibrosis. Methods: The 277 patients studied were enrolled in a prospective study of hepatic fibrosis markers in chronic HCV. Blood was drawn at the time of staging liver biopsy. The biopsies were staged using Batts Ludwig criteria (F0-F4) by a single pathologist who only knew the patients had HCV. Patients with co-infection, an organ transplant, or HCC were excluded. The APRI and FIB-4 were calculated as below. Mild fibrosis was defined as F0-F1, significant fibrosis: F2-F4, Mild/moderate fibrosis: F0-F2, and advanced fibrosis: F3-F4. Results:Construction of Receiver Operating Characteristic curves revealed that the FIB-4 and APRI had near identical Areas Under the Curve (AUC)of 0.859 and 0.850 respectively for the separation of mild and significant fibrosis. Utilizing cut offs or 0.85 and 1.80, the FIB-4 predicted 68 of 75 for mild fibrosis (NPV=90.7%) and 78 of 86 for significant fibrosis (PPV=90.8%) with an indeterminate zone (0.86-1.79) of 116 patients (41.1%). Using cut-offs of 0.42 and 1.2, the APRI predicted 50 of 56 with mild fibrosis (NPV=89.3%).and 82 of 91 for significant fibrosis (PPV=92%) with an indeterminate zone of 123 patients (45.5%)

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The AUC's for the separation of mild/moderate from advanced fibrosis were 0.810 and 0.798 for the FIB-4 and APRI respectively. Using cut-offs of 0.85 and 1.80, the FIB-4 predicted 127 of 146 for mild/moderate fibrosis (NPV=87%) and 28 of 36 for advanced fibrosis (NPV=77.8%). The indeterminate zone was 88 patients (32.6%). Using cut-offs of 0.75 and 2.05, the APRI predicted 114 of 127 (NPV=89.8%) for mild/moderate fibrosis and 29 of 42 (PPV=69%) for advanced fibrosis. The indeterminate zone was 101 patients (37.4%). Conclusion: The FIB-4 and the APRI are equal in their ability to separate mild from significant fibrosis, and mild/moderate fibrosis from advanced fibrosis since they have near identical predictive values, AUC’s, and indeterminate zones. While both are good at separating mild and significant fibrosis, and negatively predicting advanced fibrosis, neither is very accurate in the positive predictive of advanced fibrosis. FIB-4= Age(years) x AST (U/L)/ Platelets (109/L)xALT(U/L)1/2 APRI= AST/ULN x 100 / Platelets (109//L)

TITLE: Minimal visceral fat accumulation is a prerequisite for a persistent normal serum ALT level in chronic hepatitis C patients.

ABSTRACT FINAL ID: S2065 AUTHORS (FIRST NAME, LAST NAME): Noriko Oza1, Yuichiro Eguchi1, Shunya Nakashita1, 2, Eriko Ishibashi1, 2, Takahisa Eguchi 2, Aki Matsunobu1, 2, Yoichiro Kitajima2, Shigetaka Kuroki 2, Iwata Ozaki 1, Yasunori Kawaguchi1, Yasushi Ide1, Tsutomu Yasutake1, Ryuichi Iwakiri1, Toshihiko Mizuta 1, Naofumi Ono2, Kazuma Fujimoto1 ABSTRACT BODY: Background/aims: Serum ALT level, an indication of the activity of hepatitis, is an important maker in the progression of hepatitis C. Namely, progression of hepatitis C was correlated with the serum ALT level. There might be many factors which regulate serum ALT level of liver diseases and recent study demonstrated visceral fat tissue might influence damage of liver tissues via various adipocytokines. This study aimed to determine an effect of visceral fat accumulation on serum ALT level in patients with chronic hepatitis C. Methods: Patients with chronic hepatitis C were sequentially enrolled in the study during November 2005 to April 2007. After gaining informed consent, the subjects underwentabdominal CT to measure the amount of visceral fat for cross-sectional assessment. Amount of visceral fat was assessed using the visceral fat area (VFA cm2) on the umbilical cross section. Patients were classified into either a normal (serum ALT level�30 IU/L) or increased (serum ALT level�31 IU/L) group. Insulin resistance in the liver was assessed using a homeostasis model of insulin resistance (HOMA-IR). Insulin resistance in skeletal muscle was assessed using the Quantitative Insulin Sensitivity Check Index (QUICKI). Patients of HBs antigen-positive; consumption of greater than 20 g alcohol per day; autoimmune liver disease; and advanced chronic hepatitis (histological stage of fibrosis=F3 or F4 in liver biopsy) were excluded. Correlation was evaluated using Pearson’s correlation coefficient. Results: A total of 95 patients (46 males, 49 females, mean age: 54.6±11.6) were included in the study (22 patients in the ALT normal group, 73 patients in the increased ALT group). Age was significantly higher in the normal group than the increased group (60.6±9.8 vs 52.8±11.5, p<0.05). BMI was significantly lower in the normal group (21.9±2.3 vs 24.6±3.7, p<0.01). VFA was lower in the normal group with no patient with excessive visceral fat (VFA�100 cm2) in this group (normal: 57.3±24.8, increased: 89.0±49, p<0.05). HOMA-IR and QUICKI were significantly correlated with visceral fat area (HOMA-IR: r=0.614, p<0.01; QUICKI: r=-0.558, p<0.01). Serum ALT level was correlated with HOMA-IR and QUICKI (HOMA-IR: r=0.553, p<0.01; QUICKI r=-0.462, p<0.01). Conclusion: Visceral fat accumulation leads to an increase in insulin resistance in the liver and skeletal muscle. To have a persistent normal serum ALT level, patients with chronic hepatitis C must be free from visceral fat obesity. To confirm this hypothesis, it should be evaluated whether visceral fat reduction improves increase in ALT level in chronic hepatitis C. TITLE: The prevalence of insulin resistance in patients with chronic hepatitis C and B

ABSTRACT FINAL ID: M1771 AUTHORS (FIRST NAME, LAST NAME): Wael Soliman1, Magdalena Kuczynski1, I.George Fantus2, Jenny Heathcote1 ABSTRACT BODY: Background: The presence of insulin resistance (IR) may predict the subsequent development of diabetes. Diabetes is associated with chronic hepatitis C (CHC). The prevalence of IR in non-cirrhotic CHC patients has not been well assessed and similarly prevalence of IR in chronic hepatitis B (CHB) remains unknown. Aim: To assess the prevalence of IR defined as [Homeostasis Model assessment (HOMA-IR) ≥ 2.1] among treatment naïve, non-cirrhotic, non-diabetic (fasting serum glucose < 7mmol/l) patients with CHC and CHB (controls). Methods: IR measured by HOMA test [fasting insulin (microunits per milliliter) × fasting glucose (millimoles per liters) / 22.5] was determined in treatment naïve, non-cirrhotic (biopsy proven), non-diabetic patients with CHC and CHB. Patients with

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other diseases or those taking medications or alcohol (> 20 gm /day) were excluded. Demographic data (sex, race, age) and metabolic parameters [body mass index (BMI), waist circumference, lipid profile and free fatty acids] were collected in the patients studied. A series of t-tests (continuous) and chi-square test (categorical) were used to determine the differences between the CHC and CHB patient groups. A series of logistic regression analyses were performed to determine the independent predictors of IR (HOMA ≥ 2.1) among CHC and CHB. This study was approved by our hospital research ethics board. Results: IR status was determined in 102 CHC and 27 CHB patients. BMI, waist circumference, free fatty acids, histological activity index (HAI), hepatic fibrosis and steatosis scores were not significantly different between CHC and CHB patients (p=0.3092, p=0.1587, p=0.9486, p=0.4455, p=0.7871, p=0.4079 respectively).The two groups were different in that male sex (p=0.0247) , Asian race (p<0.0001) and elevated serum cholesterol (p=0.0330) were more common in patients with CHB but there was no significant difference in the prevalence of IR (HOMA ≥ 2.1) among patients with CHC (38%) and CHB (30%) (p=0.4087). Multivariate analysis indicated that the prevalence of IR among patients with CHC was independently associated with BMI [p= 0.0054, overweight odds ratio (OR) = 6.78 & obesity OR = 17.13] and HAI (p=0.0344, activity grade 2 OR = 3.69), which was not the case in CHB. Conclusion: The prevalence of IR was 38% in CHC and 30% in CHB. BMI and HAI are independent risk factors for insulin resistance (HOMA ≥ 2.1) but only in CHC. TITLE: Hepatitis c virus (HCV) flares in patients with hematological malignancies treated with anti-CD 20 antibody (rituximab)-including regimens.

ABSTRACT FINAL ID: 383 AUTHORS (FIRST NAME, LAST NAME): Manuela Mangone1, Stefano Angeletti1, Michela Di Fonzo1, Fabio Attilia1, Sara Gallina1, Marcella Epifani1, Bruno Monarca2, Antonella Ferrari2, Caterina Tatarelli2, Gianfranco Delle Fave1, Massimo Marignani1 ABSTRACT BODY: Background: Limited data are available on transaminases increases in HCV-positive (HCV+) patients affected by haematological malignancies treated with the anti-CD 20 antibody (rituximab)-based regimens. Aim: To evaluate in this group of patients the possible role of rituximab in inducing significant increases in transaminases. Material and methods: the data regarding 104 patients consecutively treated for haematological malignancies at our Institution during the period from January 2004 to December 2006 with anti-CD 20 antibody (rituximab)-including regiments (55M, 49 F, median age 63.6 yrs, range 23-92) were retrospectively evaluated. HCV+ and HCV-negative (HCV-) patients were identified and the trend of serum alanine aminotransferase (ALT) during treatment collected. Patients experiencing an increase in ALT >5times normal value were defined to have an hepatitis flare and followed up to 12 months after completing their chemotherapy treatment. Results: 9 patients were HCV antibody positive before treatment (4M, 5F, median age 62yrs, range 37-72; 8.6% of total). No statistical difference was detected in age and sex distribution between the HCV+ and the HCV- groups. An ALT flare was identified in 3 of the 9 HCV+ patients (33%) and in none of the HCV- (p<0.0005, Fisher test). None of these patients had clinical or histological stigmata of end stage liver disease (ESLD). One of the HCV+ experiencing the increase in ALT evolved to an icteric hepatitis picture. None showed hepatic failure or died because of the hepatitis flare. Chemotherapeutic treatment was continued in all three patients. Conclusions: HCV+ patients undergoing treatment with anti-CD 20 antibody (rituximab)-based regimens may experience significant increases of ALT but this event is to be considered benign in patients without end stage liver disease. TITLE: Project ECHO (Extension for Community Healthcare Outcomes): Knowledge Networks Expand Access to Hepatitis C (HCV) Treatment with Pegylated Interferon and Ribavirin in Rural Areas and Prisons. Care is as Safe and Effective as a University HCV Clinic.

ABSTRACT FINAL ID: 380 AUTHORS (FIRST NAME, LAST NAME): Sanjeev Arora1, Glen H. Murata2, Karla Thornton1, Brooke Parish3, Steven M. Jenkusky3, Jeffrey C. Dunkelberg1, Richard M. Hoffman2, Miriam Komaromy4 ABSTRACT BODY: Objective: To conduct a prospective cohort study to evaluate the safety and efficacy of HCV treatment by primary care providers in rural areas and prisons in comparison to university clinic. Methods: Project ECHO is a new method of healthcare delivery and clinical education for the management of complex, common and chronic diseases, in underserved areas, using HCV as a model. Project ECHO is a partnership of University of New Mexico, eight prisons, and thirteen rural health clinics dedicated to providing best practices and protocol-driven healthcare in rural areas. Telemedicine and internet connections enable specialists to co-manage HCV patients using case-based knowledge networks and to track outcomes. Project ECHO partners (nurse practitioners, primary care physicians, physician assistants) present HCV positive

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patients during weekly 2-hour telemedicine clinics using a standardized, case-based format that includes discussion of history, physical examination and test results. In these case-based learning clinics, partners rapidly gain deep domain expertise in HCV as they collaborate with university specialists in hepatology, psychiatry and substance abuse in co-managing their patients. Results: Since June of 2003, 185 HCV knowledge network clinics have been conducted with 2640 case presentations of HCV patients. Of 327 patients treated via Project ECHO, 63.5% were members of a minority (Hispanic in 53.2%, Native American in 4.4%, and African American in 2.0%). Cirrhosis was present in 24.1% and depression in 41.4%. Genotype 1 was found in 61.1%, while the average log viral load was 5.94 ± 0.94. Early Virological Response was seen in 82/96 (85%), 61/74 (82%) and 105/113 (93%) of university, prison and rural patients. Significant adverse events (SAE) occurred in 24 (11.8%). Compared to patients without SAE, those with events were significantly older (48.7 ± 6.9 vs 43.6 ± 9.3 years; P=0.002); had lower serum albumin (3.69 ± 0.58 vs 4.08 ± 0.49 gm/dl; P=0.009), and platelet count (156 ± 75 vs 190 ± 81 x1000; P=0.047); and more likely to have cirrhosis of liver (50.0% vs 21.0%; P=0.002), and report a history of depression (66.7% vs 38.1%; P=0.008). Logistic regression showed that cirrhosis of liver [adjusted odds ratio (OR) 4.59; 95% confidence interval (CI) 1.66 – 12.7), depression (OR 4.77; 95% CI 1.66 – 13.7), were independent determinants of SAE (Hosmer-Lemeshow P=0.927; ROC area 0.742). No differences in genotype distribution, SAE or response to treatment were found across sites. Conclusions: HCV treatment delivered to patients in rural areas and prisons using the Project ECHO model is as safe and effective as a university HCV clinic.

TITLE: Hepatitis A and B immunization practices among community physicians of chronic hepatitis C patients

ABSTRACT FINAL ID: S1058 AUTHORS (FIRST NAME, LAST NAME): Yasmin Metz1, Ketan Kulkarni2, Maya Gambarin-Gelwan2, Ira M. Jacobson2 ABSTRACT BODY: PURPOSE: We sought to determine if chronic hepatitis C (CHC) patients are being appropriately vaccinated in the community in accordance with AASLD practice guidelines (Strader DB et al. Hepatology 2004; 39: 1147-71). METHODS: Patients with CHC initially seen in our hepatology practice between 7/06-7/07 were identified. Subjects were either self-referred, referred by their primary care provider or gastroenterologist. Charts were reviewed to ascertain date of diagnosis, demographic data, hepatitis serologies and stage of liver disease. Screening colonoscopy status in age-appropriate subjects was also reviewed to assess compliance with another recommended preventive health measure. Patients were only included in the final analysis if they had well-compensated liver disease and had known CHC for at least one year prior to re-ferral to permit time for immunization. RESULTS: One hundred and fifteen consecutive new CHC referrals were identified. 89 of them had been diagnosed at least one year prior to referral with a mean of 6.6±4 years. 41 patients (46%, n=89) were HAV IgG +, suggesting either prior vaccination or natural immunity. Among 86 patients for whom complete HBV serologies were available, 50 (58%) had serum markers of past HBV infection or vaccination (isolated HBcAb+ n=5, HBsAb+ n=45). Of 66 patients over 50 years old for whom colonoscopy history was documented, 43 (65%) had a screening colonoscopy within 5 years. Prior studies have shown the prevalence of natural immunity to HAV and HBV among CHC patients is 38% and 59%, respectively (Siddiqui F et al. Am J Gastroenterol 2001; 96: 858-63). There was no difference between the prevalence of immunity to HAV (p=0.13) or HBV (p=0.91) among our population when compared to the expected prevalence of natural immunity. The prevalence of colonoscopy screening was greater than that of immunity to HAV (p=0.02) but not for HBV (p= 0.41). CONCLUSION: The prevalence of immunity to HAV and HBV among our CHC patients was similar to the prevalence of natural immunity previously reported. Since the immunogenicity of HAV and HBV vaccinations is high in patients with well-compensated disease, ineffective seroconversion could only account for a small percentage of unvaccinated subjects. Hence, immunity to HAV and HBV in our population of HCV-infected subjects was not adequately ensured by referring physicians. Patients were more likely to have undergone colonoscopy than have immunity to HAV. Greater awareness is needed among physicians so that immunization against HAV and HBV becomes part of routine health maintenance for CHC patients.

TITLE: The Impact of Hepatitis B (HBV), Hepatitis C (HCV) and Non-Alcoholic Fatty Liver Disease (NAFLD) Guidelines on Clinical Practices

ABSTRACT FINAL ID: S2079 AUTHORS (FIRST NAME, LAST NAME): Jillian Kallman2, 1, Aimal Arsalla1, 2, Angela M. Wheeler1, Ruben D. Aquino2, Kathy L. Terra1, Rebekah Euliano1, Zobair M. Younossi1, 2 ABSTRACT BODY: Although guidelines for HBV and HCV and position statements for NAFLD have been put forth by different societies, awareness of these guidelines and their impact on the physician practices have not been measured. Aim: To assess the attitudes of primary care physicians (PCP), gastroenterologists (GE), and hepatologists (HEP) regarding HBV, HCV and NAFLD. Design: An in-depth questionnaire was sent to PCP, GE, and HEP, assessing their familiarity with issues related to HBV, HCV and NAFLD. The survey contained 29 NAFLD items, 35 HBV items, and 35 HCV items. Comparisons were

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made between different practice specialties, using one-way ANOVA with Bonferroni adjustments. Results: A total of 161 surveys have been received (101 PCP, 30 GE, 26 HEP). Demographics of survey respondents included age (46.9 years +/- 12.4), gender (Male = 59.9%), practice environment (42.8% Urban, 46.6% Suburban, 3.3% Rural, 7.3% multiple environments), with a median of 60 patients seen per week. The majority of PCP, GE, and HEP agreed on most screening issues related to HBV, HCV and NAFLD. However, some important differences exist. PCP considered HCV to be less common than both GE (p=.0001) and HEP (.001) and NAFLD more common than HEP (.0001). Over 40% of PCP reported being unaware of any official guidelines for HBV, HCV or NAFLD, compared to 13% of GE and 4% of HEP. A majority of HEP (88%) and 40% of GE were familiar with and followed AASLD guidelines. PCPs were most likely to be familiar with and use USPSTF guidelines (24%) followed by AAFP (15%), ACP (14%) and AASLD guidelines (5%). Neither HEP nor GE reported following AAFP guidelines. Further, PCP rated themselves significantly less knowledgeable of HBV guidelines than both GE and HEP (p=.003 and p=.0001, respectively) as well as for HCV guidelines (p=.0001 each). PCP also reported significantly less reliance on guidelines when making a decision to screen for HBV and HCV (P<0.05). Although PCP, GE and HEP did not differ in rating the effectiveness of HCV treatment, HEP rated the effectiveness of HBV treatment higher than PCPs (p=.0001) and PCPs rated the effectiveness of treatment for NAFLD higher than HEP (p=.0001). Furthermore, side effects of HBV and NAFLD treatment were rated as more harmful by PCP than HEP (p=.001) or GE (p=.009). Conclusions: Although practice guidelines for three common liver diseases exist, there continues to be a lack of familiarities and practice variation in clinical practice. As expected, specialists are more aware about these guidelines than primary care physicians. In order to increase knowledge base about important liver diseases, efforts should be focused on primary care practices. TITLE: Peginterferon and Ribavirin for Treatment of Hepatitis C and HIV Co-infection: A Meta-Analysis of Randomized Controlled Trials

ABSTRACT FINAL ID: S2081 AUTHORS (FIRST NAME, LAST NAME): Ajitinder S. Grewal1, Abhishek Choudhary1, Matthew L. Bechtold1, Srinivas R. Puli1, Mohamed O. Othman1, Praveen K. Roy1 ABSTRACT BODY: Background and Purpose: Hepatitis C (HCV) co-infection is a significant contributor of morbidity and mortality among HIV patients. The progression of liver disease is accelerated in these patients. Combined treatment with peginterferon (PEG) and ribavirin (RBV) is the standard treatment for HCV mono-infected patients. Recently, several studies have reported the efficacy and adverse effects of treating the HIV/HCV co-infected patients with peginterferon and ribavirin. We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and side effects of peginterferon and ribavirin versus standard interferon (INF) and ribavirin. Methods: MEDLINE, Cochrane Central Register of Controlled Trials & Database of Systematic Reviews, PubMed, and recent abstracts from major conference proceedings were searched (through 10/07). RCTs enrolling adult subjects and comparing PEG/RBV with INF/RBV were included. Studies were assigned a quality score using Jadad score. Standard forms were used to extract data by two independent reviewers. Pooled estimates of the following outcomes were obtained: End of treatment response (ETR), sustained viral response (SVR), and side effects. Separate analyses were performed for each outcome by using odds ratio (OR). Publication bias was assessed. Heterogeneity among studies was assessed by calculating I2 measure of inconsistency and if noted, a random effects model was performed. Results: Five trials satisfied the inclusion criteria (1,335 patients). The mean age ranged from 37-45 years. 86.2% of patients were on HAART therapy. Two trials used PEG alpha-2a (180 mcg per week) & 3 trials used PEG alpha-2b (2 trials used 1.5 mcg/kg/week & 1 trial used 100-150 mcg/week). Dose of RBV was 800-1,200 mg daily. PEG/RBV achieved a higher SVR compared to INF/RBV (OR 2.94, 95% CI: 1.70–5.08, NNT 5). ETR was also higher with the PEG/RBV (OR 3.17, 95% CI: 1.93–5.17, NNT 5). SVR was significantly higher with PEG/RBV, regardless of the genotype. The side effects profile was similar among the treatment groups (OR 1.04, 95% CI: 0.82–1.32, p=0.73). However, influenza-like symptoms were more common in the INF/RBV group (OR 1.68, 95% CI: 1.06–2.60, NNH 12). No significant publication bias was present. Conclusion: Peginterferon and ribavirin achieves a higher SVR compared to standard interferon and ribavirin therapy in HCV/HIV co-infected patients (NNT=5). Influenza-like symptoms were more common in patients treated with standard interferon and ribavirin. However, other side effects were similar in the two treatment groups.