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  NIH consensus development conference updates HCV management
Gastroenterology Aug 2002 Vol 123 Number 2
A statement issued by a Consensus Development Conference convened by the National Institutes of Health, June 10-12, highlighted progress in the treatment for chronic hepatitis C and a decline in the number of new infections.
However, the conference panel noted that the number of people with hepatitis C infection is expected to increase 4-fold over the next decade as a result of unsuspected infection from contaminated blood and blood products, occupational exposure, and injection drug use before the advent of routine screening in the early 1990s.
Currently, more than 4 million people in the United States are infected with hepatitis C. Approximately 36,000 cases of acute hepatitis C infection occur each year in the United States and 85% of those with acute hepatitis C develop a chronic infection. Chronic hepatitis C is often asymptomatic but may lead to cirrhosis of the liver, as well as hepatocellular carcinoma. The most common blood-borne infection, HCV transmission now occurs primarily by injection drug use, high-risk sexual behaviors, occupational exposures such as accidental needle stick, and maternal-infant transmission.
The 12-member independent, nonadvocate, non-Federal panel also noted that chronic HCV infections are now associated with significant increases in cirrhosis, end-stage liver disease, liver cancer, and are the most common cause of liver transplant.
Panel chairman Dr. James Boyer, Ensign Professor of Medicine and Director of the Liver Center at Yale University School of Medicine said "the good news is that new combination therapies are having a beneficial impact on this disease. In addition, preliminary research indicates that this approach may prove useful in treating important subgroups of patients including children and injection drug users [who were] previously ineligible for treatment."
In that regard, the panel broke from its 1997 HCV management consensus conference predecessors by expanding the scope of patients eligible for treatment. Panel members cautioned against the exclusion of children and older adults from treatment and further research. It expanded the scope of patients to include users of intravenous drugs, alcohol consumers, people with comorbid conditions such as depression, or those who are coinfected with HIV.
Boyer said the majority of studies have largely focused on what is actually a narrow segment of the patient population-young white males. "There is enough experience with some of the groups for which treatment was not previously recommended to indicate they can respond to combination therapy as well or almost as well," Boyer stated.
During the 2-and-a-half day meeting, panel members heard presentations from 28 hepatitis C experts and reviewed an extensive body of medical literature. Among its recommendations for future research, the panel gave priority to the development of reliable and reproducible HCV cultures, which would enhance the understanding of HCV biology, mechanisms of drug resistance, and aid vaccine development. The panel urged the establishment of a hepatitis research network that would study the natural history, prevention, and treatment of hepatitis C. Panel members also recommended the development of improved strategies for prevention, diagnosis, and treatment of intravenous drug users and the incarcerated population.
See NATAP website Conference Reports http://www.natap.org for detailed review & report of the proceedings.

Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy
Gastrenterology, September 2002 Volume 123 Number 3
"...These data demonstrate that in decompensated chronic hepatitis B patients treated with lamivudine, the pretreatment severity of liver disease is a more important predictor of early mortality than antiviral responseŠ..2 other factors influence survival during the early months of antiviral therapy, i.e., renal function and the pretreatment level of HBV replication...Presumably, patients with detectable HBV DNA have a greater burden of infected hepatocytes and are at increased risk of experiencing progressive liver disease.
Chronic hepatitis B is a leading cause of death worldwide. To identify patients who might require urgent liver transplantation despite antiviral therapy, we investigated the determinants of early mortality in a large cohort of patients with decompensated chronic hepatitis B treated with lamivudine. One hundred fifty-four North American patients with decompensated chronic hepatitis B received lamivudine for a median of 16 months. Univariate and multivariate Cox regression modeling was used to develop a model of 6-month mortality. A biphasic survival pattern was observed, with most deaths occurring within the first 6 months of treatment (25 of 32, 78%) because of complications of liver failure. The estimated actuarial 3-year survival of patients who survived at least 6 months was 88% on continued treatment. This high rate of patient survival is significantly greater than the 40% reported in untreated patients with decompensated HBV-related cirrhosis
In multivariate modeling, elevated pretreatment serum bilirubin and creatinine levels as well as the presence of detectable hepatitis B virus (HBV) DNA (by the bDNA assay) pretreatment were significantly associated with 6-month mortality. An equation approximating the probability of early mortality was developed from these variables. Our data demonstrate a distinct alteration in the slope of the survival curve after 6 months of lamivudine treatment for decompensated chronic hepatitis B. An equation consisting of 3 widely available pretreatment laboratory parameters was developed that can be used to predict the likelihood of early death in patients receiving lamivudine for decompensated chronic hepatitis B. These observations may help identify patients who can be stabilized with suppressive antiviral therapy vs. those who require urgent liver transplantation.
The 154 patients with HBV-related cirrhosis received lamivudine for a median of 16 months (range, 0.5-37) and had baseline characteristics consistent with varying degrees of hepatic decompensation. Patients were predominantly male (80%) and either white (56%) or Asian (36%). None of the patients had HIV coinfection, whereas 9 (6%) had hepatitis C virus (HCV) and 6 (4%) had hepatitis D virus (HDV) coinfection. During study observation, 32 of the 154 (21%) patients died, with most of the deaths (25 of 32, 78%) occurring within the first 6 months. Although 7 patients died after the first 6 months, the estimated actuarial 3-year survival of patients who survived at least 6 months was remarkably good (88%). The mean patient death rate during the first 6 months of treatment was 0.42 deaths per patient year of follow-up compared with 0.04 deaths per patient year of follow-up after 6 months of treatment. As expected, most of the 32 patient deaths were due to complications of advanced HBV-related cirrhosis. The reported causes of the 25 early deaths in the NS group included complications of liver failure (22), suicide (1), intracranial hemorrhage (1), and cardiac arrest (1). The reported causes of the 7 later deaths in the SURV group included complications of liver failure (6) and metastatic lung cancer (1).
Inspection of the pretreatment data indicated that the patients in the NS group appeared to have evidence of more advanced liver failure at study entry than the SURV group. Specifically, the NS group tended to have higher pretreatment serum bilirubin, lower serum albumin, and higher serum creatinine levels than SURV patients. In addition, the CTP scores in evaluable NS patients tended to be higher than in the SURV patients.
Univariate Cox regression analyses were undertaken to examine pretreatment clinical and laboratory characteristics for associations with early mortality. There were strong univariate associations of elevated serum bilirubin, low serum albumin, and elevated serum creatinine levels with early mortality. In addition, the presence of detectable HBV DNA at baseline was associated with early mortality. In a multivariate Cox regression model using backwards elimination of variables, the features that remained significantly associated with early mortality were elevated serum bilirubin, elevated serum creatinine, and detectable HBV DNA. Of note, serum albumin levels were not a significant independent predictor of survival because its effects were accounted for by the other variables, primarily because of its correlation with serum bilirubin.
Because pretreatment serum creatinine and bilirubin levels and detectable HBV DNA were strongly associated with 6-month mortality, we derived a predictive model of 6-month survival in patients with HBV-related cirrhosis receiving suppressive antiviral therapy (lamivudine). A variable called Index was created as follows: Index = 0.5 ? bili + 1.7 ? creatinine + 1.8 ? HBV DNA (0 or 1). For example, a subject with a serum bilirubin of 2.0 mg/dL, creatinine of 1.2 mg/dL, and undetectable HBV DNA (coded as 0) has an index score of 3 and a 5% probability of 6-month mortality while receiving lamivudine. Similarly, a patient with more advanced liver failure at presentation with a serum bilirubin of 6.0 mg/dL, a serum creatinine of 2.0 mg/dL, and detectable HBV DNA with an index score of 8.2 would have a 95% probability of death within 6 months while receiving lamivudine.
More than 80% of patients in both groups had suppression of HBV DNA to undetectable levels by the bDNA assay within 8 weeks of initiating lamivudine treatment. Therefore, the early antiviral response to lamivudine does not appear to predict patients who will survive 6 months. There was also no consistent difference in serum ALT levels between the 2 groups of patients (data not shown). Among the patients that were HBeAg positive at baseline, 15 of 16 (94%) NS patients remained HBeAg positive, whereas 51 of 78 (65%) SURV patients were HBeAg positive at last available follow-up. Only 1 of the 12 (8%) NS patients acquired HbeAb during follow-up, whereas 17 of the 83 (20%) SURV patients had acquired HBeAb at last follow-up. Virologic breakthrough was observed in 22 of the 81(27%) patients who were HBV DNA positive at baseline and who had adequate follow-up evaluation. Confirmatory PCR-based genotype testing performed in 11 of these 22 cases demonstrated the presence of YMDD variants with mutations in the B and C domains of the HBV genome in 10 patients. In 1 patient, only wild-type HBV was detected, suggesting patient noncompliance. The median time to development of breakthrough infection was 13 months.

NIH set to expand digestive diseases study section
Gastroenterology News, September 2002 Volume 123 Number 3
Largely driven by recommendations of the Panel on Scientific Boundaries, the National Institutes of Health (NIH) proposes creating 5 new study sections in digestive diseases. Currently, GMA-2 is the major NIH study section that reviews research grant applications for scientists in digestive and liver diseases.
The 5 proposed study sections are: Gastrointestinal Cell and Molecular Biology Study Section (GCMB); Hepatobiliary Pathophysiology Study Section (HBPP); Immunology, Microbiology and Inflammation Study Section (IMI); Integrative Physiology and Pathobiology Study Section (IPP); and Xenobiotic and Nutrient Disposition and Action Study Section (XNDA).
"The workload assigned to GMA-2 has expanded so dramatically over the last few years that the review process is significantly burdened because there are just too many grants to review," said Dr. Nicholas O. Davidson, gastroenterology head at Washington University St. Louis and chairman of the Research Committee for AGA.
According to Davidson, optimal numbers of grants per study section are in the range of 60 to 70 per cycle. While the average for GMA-2 is about 90, the last few grant cycles have seen between 120 and 140. "So it's just an overwhelming volume of research applications," Davidson said. "On the one hand, that's a surrogate reflection of the health and vigor of the academic community. On the other hand, there are just not enough reviewers and the study section has a broad range of expertise, that it becomes incredibly burdensome and overwhelming."
Davidson said, "intense discussion" is underway at NIH and among members of the AGA Research Committee and PhD-DDM Committee as to the formulation of these new study sections, the research base they will attract, and their staffing. Additional issues under consideration are "implications for GI research in terms of how grants that are currently assigned to a GMA-2 study section will be distributed over 5 study sections, and whether the judging - the scoring patterns - of those different sections will be normalized between the 5 study sections. All of those issues have to be discussed."
NIH has solicited feedback and they encourage all individuals in the gastroenterology community to post their comments on the Website below. A draft document that summarizes the AGA's position is under preparation by the Research Policy Committee, Davidson said. "All the constituent members of the AGA are encouraged to voice their opinions, concerns, thoughts and feedback to the Website." Send responses to: http://www.csr.nih.gov/PSBR/DIG/DIG_Intro.htm
As an interim measure, the GMA-2 study section will be divided into 2 review groups beginning September 25, 2002. GMA-2 will review applications related to cell and molecular biology and physiology of the GI tract including GI immunology, microbiology, and inflammation. A new GMA-3 study section will review clinically oriented and basic research related to gastrointestinal, hepatobiliary and pancreatic physiology, and pathobiology. Further details regarding these changes in review of NIH grant applications can be found at the Center for Scientific Review Website:

Hepatotoxicity Clinical Research Network
Hepatology August 2002 Volume 36 Number 2
Liver injury due to medications is one of the most common causes of acute liver disease and jaundice. Importantly, the mortality rate of hepatic idiosyncratic drug reactions is quite high, and over half of the cases of acute liver failure in the United States are due to medications. Elucidation of the mechanisms of hepatic drug injury, however, is often difficult. Drug-induced liver disease is typically unpredictable, idiosyncratic, and rare. Most of the medications that cause acute liver injury in humans do not produce injury in experimental animals. Attribution of acute liver injury to a medication is frequently difficult: the patient with hepatotoxicity often has multiple other risk factors for liver disease, may be on many potentially hepatotoxic drugs, and may not present until the injury is resolved. Drug-induced liver injury is also quite variable in clinical expression. Patterns of injury mimic virtually all other forms of liver disease, including acute viral hepatitis, autoimmune liver disease, bland cholestasis, mixed cholestatic-hepatic syndromes, acute cholangitis, microvesicular steatosis with lactic acidosis, alcohol-like steatohepatitis, and veno-occlusive disease. Finally, drugs that cause hepatotoxicity are usually withdrawn from use, and the mechanism of injury remains unknown and no longer available for study.
Despite the clinical significance of drug-induced liver injury, this form of liver disease is a relatively unstudied area of research. In October 2000, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the National Institute of General Medical Sciences (NIGMS) and the National Institute of Environmental Health Sciences (NIEHS) sponsored a 2-day workshop on the issue of "Drug-Induced Liver Injury: Mechanisms and Test Systems" which has been summarized as a Meeting Report in this journal (HEPATOLOGY 2001;33:1009-1013). A major conclusion and recommendation of that conference was the creation of "a rigorous, multicenter, active, and prospective database on drug-related hepatotoxicity" that would help promote basic and clinical research on hepatotoxicity and provide materials for the evolving powerful field of pharmacogenomics, using the most modern genetic approaches to investigate the role of inherited factors in pharmacokinetics and toxicology.
Toward this end, the Division of Digestive Diseases and Nutrition of NIDDK has recently published a request for applications (RFA) to establish a multicenter "Hepatotoxicity Clinical Research Network" (RFA-DK-02-033). The text of the RFA and information on how to apply are available at
and search for RFA-DK-02-033. The announcement requests grant applications to support 3 to 5 interactive clinical centers and a data coordinating center. The objective of the Network is to develop standardized definitions and instruments to identify and characterize bona fide cases of drug-induced liver injury to allow for analysis of the epidemiology and clinical spectrum of hepatotoxicity and to identify cases of medication-induced liver disease prospectively, which will allow for collection of biological samples that can be used for the study of the pathogenesis of hepatotoxicity using biochemical, serologic, and genetic techniques. The Network will be funded as interactive cooperative agreements (U01s), a mechanism that allows for substantial involvement of NIH staff in the establishment and conduct of the Network. The Network will be expected to collaborate with other investigators in the areas of hepatocyte biology and cell injury, as well as pharmacokinetics and pharmacogenetics. A respository will be established for storage of serum, tissue, and DNA samples. The Network will be funded as a pilot phase (3 years) which, if successful, will be extended by future RFAs.

Hepatitis C and renal disease
Hepatology July 2002 Vol 36 Num 1
Hepatitis C is both an important cause and an important complication of chronic renal disease in the United States. The hepatitis C virus (HCV) has been implicated as a cause of chronic glomerular disease. In addition, hepatitis C is common in patients with other forms of renal disease and is a major cause of morbidity and mortality in patients on dialysis and after renal transplantation. At present, the pathogenesis of HCV-related glomerulonephritis is not well defined. Furthermore, the management of HCV-related renal disease as well as the complications of hepatitis C in dialysis patients and renal transplantation patients is difficult and has not been systematically studied.
As a part of a long-term initiative on hepatitis C, the Division of Digestive Diseases and Nutrition in collaboration with the Division of Kidney, Urologic, and Hematologic Diseases have organized a one-and-a-half-day workshop on "Hepatitis C and Renal Disease" to be held on October 21-22, 2002, at the Lister Hill Auditorium on the campus of the National Institutes of Health. The purpose of the workshop is to bring together clinical and basic laboratory investigators in the areas of HCV virology, hepatitis epidemiology, chronic liver and renal disease natural history and treatment, cryoglobulinemia, hepatitis C-related glomerulonephritis, renal dialysis, and kidney transplantation and to address the following issues:
-- What is the frequency, natural history, and pathogenesis of HCV-related glomerular disease, with or without accompanying cryoglobulinemia?
-- What is the prevalence and incidence of hepatitis C in patients with end-stage renal disease and in renal transplantation patients?
-- What are the optimal approaches to prevent spread of hepatitis C in dialysis units and transplant centers?
-- What is the natural history of hepatitis C in patients with end-stage renal disease and in patients after kidney transplantation?
-- What is the role of liver biopsy in managing chronic hepatitis C in the patient with renal disease?
-- What are the options, risks, and benefits of antiviral therapy of hepatitis C in patients with renal disease, on dialysis, and after renal transplantation?
-- What future research studies are needed to best address gaps in our knowledge of these issues surrounding hepatitis C and renal disease?
Further information on the meeting can be found at
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