The hepatitis C link: Diagnose, treat, transplant

WASHINGTON, D.C. (May 20, 2007) -- Hepatitis C not only affects more than 3.9 million Americans, but continues to impact and influence the occurrence of related inflammatory conditions. Research presented today at Digestive Disease Week® 2007 (DDW®) analyzes advancements in the diagnosis of hepatitis C and therapies available to patients who suffer from the disease. DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

"Almost four million Americans have chronic hepatitis C infections and are at risk for of cirrhosis, liver failure, liver cancer and transplantation," said John Vierling, M.D., Baylor College of Medicine. "These studies advance our understanding for the potential for developing markers to detect liver cancer, to increase our capacity to treat hepatitis C and provide evidence that livers from persons with hepatitis C can be successfully used for transplantation."

Chronic active hepatitis C (HCV) remains the strongest connection to the development of hepatocellular carcinoma (HCC, liver cancer). Unfortunately, the mechanism behind hepatitis-associated cancer remains puzzling. Such effects as oxidative stress and DNA damage are known to occur in hepatitis, through which the role of the liver in nucleic acid metabolism may be impacted. This study evaluated the key elements in nucleic acid metabolism that might account for the biologic behavior of hepatitis-associated cancer.

Autotaxin (ENPP2) is a tumor cell motility-stimulating factor and has been linked to tumor invasion and cancer growth in several human cancers, such as breast cancer and non-small-cell lung cancer. ENPP2 has also been linked to adenosine triphosphate (ATP) and purinergenic pathways, chemical reactions occurring within a cell to maintain homeostasis. To assess the key elements in nucleic acid metabolism, researchers looked at liver tissue collected prospectively from three patient subtypes: 1) patients undergoing liver resection for non-hepatitis related diseases; 2) HCV cancer-free transplant patients; and 3) HCV patients with biopsy-confirmed HCC.

Using microarray analysis, the group sought to profile patients with respect to cancer risk. The goal of the study was to determine whether one could identify patients at high risk for the development of cancer. Differences between groups were tested by ANOVA, a statistical test that determines the significance of any given observation.

Within purine metabolism, several genes were expressed between normal liver and both HCV groups. Of these, autotaxin was significantly elevated in patients with cancer compared to HCV patients without cancer or normal liver. In addition, genes associated with autotaxin, such as the lypophosphatidic acid receptor (LPA), a potent signaling molecule, were also over-expressed in HCV patients.

"Early detection of liver cancer is crucial. For patients eligible for liver transplant, early detection is associated with excellent long term cancer survival," said Mary Maluccio, M.D., of Indiana University in Indianapolis, Ind., and senior author of the study. "Autotaxin is one of the few genes within the purine metabolic pathway that is up-regulated in the liver of cancer patients versus their non-tumor bearing counterparts, and therefore may be a novel and important marker for early stage HCC in the hepatitis C-infected liver."

Dr. Maluccio will present this study on Tuesday, May 22, at 3:00 p.m. in Hall E.

Celgosivir is a new class of antiviral medicine in clinical development for the treatment of chronic hepatitis C virus (HCV) infection. Researchers tested this new antiviral medicine and measured its potential to offer improved treatment outcomes when combined with other anti-HCV drugs.

The current study evaluated 57 chronic HCV genotype-1 patients, separated by prior treatment status into non-responders or partial responders and randomized to three treatment groups: 1) celgosivir 400 mg once daily in combination with peginterferon alfa-2b and ribavirin (PRC); 2) celgosivir 400 mg once daily in combination with peginterferon alfa-2b (PC); or 3) placebo with peginterferon alfa-2b and ribavirin (PR, active control). All patients were treated for 12 weeks. The non-responders cohort enrolled 36 patients (PRC: 15; PC: 11; PR: 10) and the partial responder cohort had 21 patients (PRC: 3; PC: 9; PR: 9).

For prior non-responder patients, an Early Viral Response (EVR) was achieved in 42 percent (5/12) of those in which celgosivir was added to the standard peginterferon alfa-2b and ribavirin therapy compared with only 10 percent (1/10) of patients receiving just peginterferon alfa-2b and ribavirin. Non-responder patient study results also demonstrate an improved mean decrease in HCV viral loads when celgosivir is added to peginterferon alfa-2b and ribavirin of 1.63 log10 IU/mL versus 0.92 log10 IU/mL in patients treated with peginterferon alfa-2b and ribavirin alone. Eleven of the 36 non-responder patients were classified as a very difficult-to-treat patient subgroup (null responders) as they were shown to have a prior HCV treatment response of ≤0.4log10 to optimized therapy. In the present study, the mean decrease in HCV viral loads in these null responder patients was 1.86 log10 IU/mL with celgosivir plus peginterferon alfa-2b and ribavirin while the two null responder patients treated with peginterferon alfa-2b and ribavirin was 0.32 log10 IU/mL. The observed difference in mean viral load between the PRC and PR treatment groups provides evidence that the combined effect of celgosivir with peginterferon alfa-2b and ribavirin provides a clinically significant treatment benefit for difficult-to-treat chronic HCV infected patients.

"This study is the first demonstration that celgosivir in combination with peginterferon alfa-2b and ribavirin results in a clinically significant decrease in HCV viral loads in patients highly resistant to current standard treatment," said Kelly D. Kaita, M.D., of the University of Manitoba in Canada, and lead author of this study. "Further clinical research on the best dosing regimen and combinations is warranted to optimize the potential of this innovative combination for chronic HCV patients."

Dr. Kaita will present this study on Monday, May 21, at 2:45 p.m. in Room 206.

To meet the increasing demand for donor livers, researchers are searching for opportunities to utilize non-optimal livers to offer some improvement to severely ill patients. Some centers are now transplanting livers from hepatitis C (HCV)-infected donors into recipients with HCV-related cirrhosis. This study compared transplant outcomes for liver recipients from HCV-infected donors to those for standard, non-extended criteria (ECD) donors to determine the possible benefits or consequences of this practice.

Researchers examined 37 recipients of livers and 76 ECD donors. Thirty percent of all donors met non-ECD criteria (standard donors) and were included as potential matches for the case-control study. Each HCV-positive liver donor recipient was matched to two standard donor recipients as matched standard donor controls (MSDC). MSDC were classified by recipient age, primary diagnosis, cancer stage for those with HCC, recipient MELD (Model for End-Stage Liver Disease system used to prioritize waitlist patients) and donor age. Patients were monitored for graft and patient survival at three months, one year and two years; perioperative death; and HCV recurrence by four-month and one-year fibrosis (F0-F4).

In this study, researchers note that when hepatitis C positive donors were used, no difference in survival was observed. However, the rate of fibrosis appeared to be slower in those receiving HCV-infected livers. These preliminary results suggest that HCV-infected liver transplant recipients receiving livers from HCV-infected donors may have a slower rate of fibrosis progression at one year.

"This is a trend we're seeing in survival advantage for those receiving HCV-donor grafts compared to standard donor controls," says Paul Kwo, M.D., of Indiana University in Indianapolis, Ind., and lead author of this study. "The use of HCV positive donors may be considered as a first line therapy to increase the available donor pool of organs in those undergoing OLT for HCV-related cirrhosis, which is the most common cause of cirrhosis leading to orthotopic liver transplantation. We hope to further extend this research to understand how we can maximize the use of extended criteria donor organs. This includes hepatitis C positive graft that may benefit HCV-infected individuals who require orthotopic liver transplantation, as well as gain insight as to why these organs may have a slower rate of fibrosis than non-HCV infected donor organs."

Dr. Kwo will present this study on Sunday, May 20, at 8:45 a.m. in Room 207.

Digestive Disease Week® (DDW®) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 19-24, 2007 in Washington, D.C. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.