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InterMune announced this week that a Phase II clinical trial of Actimmune (interferon gamma) for treatment of advanced cirrhosis had failed to meet a primary endpoint.

The study evaluated the drug for use in patients with chronic hepatitis C with cirrhosis who had failed standard treatment (interferon alfa plus ribavirin).

The objectives of the study were to evaluate safety and the ability of Actimmune treatment to reverse fibrosis in chronic hepatitis C patients with advanced liver disease when administered for 48 weeks. The primary endpoint of the study, reversal of liver fibrosis as determined by the Ishak histology scoring system, was not met.

Interferon gamma was generally well tolerated and side effects were consistent with those seen in previous experiences.

“We have learned from this study that interferon gamma-1b is generally well tolerated in this patient population," said James Pennington, M.D., Executive Vice President of Medical and Scientific Affairs at InterMune. "We believe that earlier intervention in milder patients over a longer period of time may be necessary to demonstrate efficacy."

About Actimmune

Actimmune (Interferon gamma 1b) is a naturally occurring protein that stimulates the immune system. InterMune markets Actimmune for the treatment of two life-threatening congenital diseases: chronic granulomatous disease and severe, malignant osteopetrosis.

Presently, InterMune is conducting a Phase III study of interferon gamma-1b in idiopathic pulmonary fibrosis (IPF), and a Phase III study of interferon gamma-1b in ovarian cancer.

The most commonly observed side effects are flu-like symptoms, including fever, headache and chills.

Physicians and patients can obtain additional prescribing information regarding Actimmune, including the product's safety profile, at www.actimmune.com.

About InterMune

InterMune is a biopharmaceutical company focused on the applied research, development and marketing of life-saving therapies for pulmonary and hepatic diseases. For additional information about InterMune, visit www.intermune.com.

Source
InterMune, Inc. www.intermune.com.

Public release date: 8-Mar-2004
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Contact: Prof. Roland Contreras
Roland.Contreras@dmbr.UGent.be
32-9-331-36-31
VIB, Flanders Interuniversity Institute of Biotechnology
 

New test detects cirrhosis of the liver in an early stage

Ghent researchers have developed a new and easy method of detecting cirrhosis of the liver. This major finding helps predict the evolution of chronic liver disease, allowing physicians to start proper treatment early on. Patients suffering from this serious, progressive disease in its cirrhosis stage have a high chance of developing liver cancer. The test developed in Ghent permits frequent, non-invasive analyses to be carried out, through which the critical stages of the disease can be closely monitored.

Chronic liver disease: life-threatening and progressive

Millions of people worldwide suffer from chronic liver disease. The major causes are infection by one of the hepatitis viruses and excessive use of alcohol. The liver is a very complex organ, where more than 500 metabolic functions take place, including clearing toxic substances from our body and producing proteins that coagulate the blood following wounds. Liver problems have a high rate of incidence and - after cancer and cardiovascular disorders - they are the third cause of death among people between 40 and 65.

The most problematic aspect of chronic liver disease is liver fibrosis, in which connective tissue grows throughout the liver, disrupting the composition of this complex organ and, in time, its functioning as well. Depending on its cause and on the patient, liver fibrosis can evolve rapidly or slowly. There are several distinct stages. One of the final stages is cirrhosis of the liver. When a patient develops cirrhosis, the chance of liver cancer rises sharply (25 to 40 times higher than normal) and in a very advanced stage the liver is no longer able to function. The only possibility at that point is a liver transplant - an extremely complicated intervention.

Current treatment is problematic

In order to decide which treatment is appropriate for a particular patient with liver fibrosis, doctors need to know which stage the liver disease is in. As soon as cirrhosis has set in, they will want to start tracking the possible development of liver cancer, which can occur at any moment. Of course, early detection and appropriate treatment is vital. But this is precisely the problem. Today, the only way to detect cirrhosis is through a biopsy - where a tissue sample is taken by injecting a needle through the skin into the liver. Biopsy is not entirely risk-free and is very expensive (about 1500 euro per patient).

Ghent discovery enables quick, inexpensive test

VIB researcher Nico Callewaert and his colleagues in the team of Roland Contreras (Dept. for Molecular Biomedical Research, Ghent University) have developed a new method that only requires a little blood in order to detect the cirrhosis stage reliably. In a test group of patients, the researchers succeeded in detecting 70 – 80% of the early liver cirrhoses. Not a single patient was diagnosed incorrectly. The new test detects changes in the quantities of the various sugars that are produced by the liver, which occur in the transition from fibrosis to cirrhosis. The researchers have been able to measure the sugar changes quite accurately with advanced instrumentation that is already being used in clinical laboratories, but for genetic tests.

A hopeful future

The test is now being perfected. Through future collaborations with industry, the researchers hope to arrive at a test that is easy to use and that shows 100% specificity for cirrhosis of the liver. The test could then be used to follow people with chronic hepatitis C viral infection. Often, 10 years can pass between the first diagnosis and the development of cirrhosis of the liver. An annual test could quickly detect a change and be able to predict an early stage of cirrhosis. Nico Callewaert comments: 'We hope to be able to alert patients when the chance of liver cancer increases sharply. At that moment, the doctor can test frequently for the presence of cancer cells and detect the cancer early enough so that the patient can quite possibly be helped.'

Note to the Editor:
VIB, the Flanders Interuniversity Institute for Biotechnology, is a research institute where 800 scientists conduct gene technological research in a number of life-science domains, such as human health care and plant systems biology. Through a joint venture with four Flemish universities (Ghent University, the Catholic University of Leuven, the University of Antwerp, and the Free University of Brussels) and a solid funding program for strategic basic research, VIB unites the forces of nine university science departments in a single institute. VIB also manages an extensive patent portfolio and distributes scientifically substantiated information about all aspects of biotechnology to a broad public.
 

Diabetes raises risk of serious liver problems

Last Updated: 2004-02-25 16:53:54 -0400 (Reuters Health)

By Megan Rauscher

NEW YORK (Reuters Health) - Men with diabetes have about a two-fold greater risk of developing liver cancer and other chronic liver diseases compared with nondiabetic men, new research suggests.

The same may hold true in women, but the study did not have enough women to reach firm conclusions.

"Our study provides evidence that diabetes is an important risk factor for chronic liver disease including (liver cancer)," Dr. Hashem B. El-Serag from the Houston VA Medical Center in Texas told Reuters Health. The study is also the first to show that diabetes precedes, rather than follows, the development of these diseases, he added.

Using the computerized records of the Department of Veterans Affairs, investigators studied all patients with a hospital diagnosis of diabetes between 1985 and 1990. They matched each diabetic patient to three nondiabetic patients and tracked them through 2000. Nearly all of the subjects were men and most had type 2 diabetes. None of the subjects had liver disease when first diagnosed with diabetes.

As reported in the medical journal Gastroenterology, the rates of chronic non-alcohol related liver disease and liver cancer were significantly higher in diabetic than in the nondiabetic patients.

The increased risk "seems to be independent of age, gender, ethnicity, or (other) illnesses," El-Serag noted, and is higher in patients with diabetes for 10 years or more.

This study, Dr. Adrian M. Di Bisceglie from Saint Louis University School of Medicine points out in an editorial, "provides evidence that long-standing diabetes is followed by the development of liver disease and (liver cancer), suggesting a causative role for diabetes mellitus."

The current study supports the team's earlier findings from the same group of patients in which diabetes raised the risk of acute liver failure by 44 percent.

In light of the present findings, El-Serag and colleagues recommend regular liver blood tests in diabetic patients. Further studies are needed to examine the association between diabetes and liver disease in women and to clarify the mechanisms behind the link, the authors note.

SOURCE: Gastroenterology, February 2004.

Copyright © 2004 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

Treatment Considerations in Patients with Hepatitis C and Cirrhosis
 

Patients with cirrhosis due to hepatitis C have a high chance of dying from progressive liver disease and thus have much to gain from successful antiviral therapy.

The highest sustained virologic responses in patients with cirrhosis have been achieved using pegylated interferon alfa plus ribavirin; 43% or more remain with undetectable virus 6 months after the cessation of 48 weeks of treatment.

In those who achieve a sustained virologic response, the degree of fibrosis is less as judged on post-treatment liver biopsy; cirrhosis may even regress. In those individuals with cirrhosis who achieve a sustained virologic response, the risk of developing hepatocellular carcinoma is significantly reduced and it is likely that their chance of developing liver failure is less.

Patients who do not achieve sustained virologic response can still show histologic improvement as demonstrated on liver biopsy post-therapy as compared to baseline.

Patients with compensated cirrhosis can benefit from therapy while those who are decompensated are prone to more safety issues.

Thus, individuals with any evidence of hepatic decompensation should generally not be given interferon-based antiviral therapy, but treatment should be encouraged for those whose status is Child Class A.

02/04/04

Reference
E J Heathcote. Treatment Considerations in Patients with Hepatitis C and Cirrhosis. Journal of Clinical Gastroenterology 2003; 37(5): 395-398. November /December 2003.
 

The Relationship of Chronic Viral Hepatitis, Alcoholism, and Cirrhosis to Liver Cancer

Liver cancer can start within the liver (primary liver cancer or hepatocellular cancer) or spread to the liver (metastatic liver cancer) from other sites, such as the colon. Cancer that starts in the liver, which I will refer to simply as liver cancer, is the fifth most common cancer in the world. In the US, it is among the ten most common cancers. This cancer is more frequent among Native Americans, Asians and Pacific Islanders, and Hispanics than among whites.

Liver cancer is a bad cancer. It has frequently spread beyond the liver by the time it is discovered, and only 5% of patients with liver cancer survive even five years. The only hope for patients who are at risk for liver cancer is regular surveillance so that the cancers can be found early. Early cancers can be treated by surgical removal (resected) or liver transplantation. Although the current techniques for surveillance are not very good at detecting early liver cancer, newer techniques are being tested and may be better.

The most common diseases associated with liver cancer are chronic viral hepatitis, alcoholism, and cirrhosis (scarring of the liver). Moreover, chronic viral hepatitis is common in alcoholism, and both viral hepatitis and alcoholism cause cirrhosis. Therefore, the contributions and interrelationships of alcohol abuse, viral hepatitis, and cirrhosis in the development of liver cancer are complex. Despite the complexity, it is important to try to understand the contributions of each disease so that patients at highest risk for liver cancer can be targeted for surveillance. Theoretically, they also might be targeted with treatments that prevent the development of liver cancer, when such treatments are developed.

Many studies have estimated how frequently patients with alcoholism and chronic viral hepatitis go on to develop cirrhosis and liver cancer. These studies, for the most part, have used small or selected populations to study, and there is disagreement as to whether their findings can be applied to general populations, especially in Europe and the United States.

A scientific study published in October 2001 has added important information about the relationship of liver cancer to chronic viral hepatitis, alcoholism, and cirrhosis. This is a strong study because it used the records of Swedish health registries to identify patients for inclusion in the study. The Swedish registries contain information on the entire population of Sweden. They are large and complete registries and have been in use for many years. In fact, they have provided a wealth of information about many diseases.

An analysis of the Swedish data demonstrated that among patients with alcoholism there was slightly more than a two-fold increase in the risk of liver cancer as compared with the general population. This small increase suggests that alcoholism alone is not strongly related to the development of liver cancer. On the other hand, patients who were alcoholics but also developed cirrhosis, presumably as a result of their alcoholism, had a 22-fold increase in the risk of liver cancer as compared with the general population. Clearly, the development of cirrhosis in alcoholics substantially increases the risk for liver cancer.

Patients with chronic viral hepatitis had a 34-fold greater risk for liver cancer as compared with the general population. Patients with both chronic viral hepatitis and cirrhosis, however, had a much greater increase in the development of liver cancer--118-fold. (Presumably the cirrhosis was caused by the chronic hepatitis.) Clearly, the combination of chronic viral hepatitis and cirrhosis has a very strong association with the development of liver cancer. This association is much stronger than the association of the combination of alcoholism and cirrhosis with liver cancer. The stronger association with viral hepatitis than alcohol supports a greater role for the hepatitis viruses as compared with alcohol in promoting liver cancer.

What can we conclude from this study? First, the risk of liver cancer is markedly increased in patients with chronic viral hepatitis and cirrhosis. The risk also is increased in patients who are alcoholic and have cirrhosis, although the risk is less. Second, if we want to substantially prevent the development of liver cancer, we must identify patients before they develop cirrhosis and then prevent cirrhosis. Third, existing and newer techniques for liver cancer surveillance probably should be applied to all patients with both chronic viral hepatitis and cirrhosis and possibly to patients with both alcoholism and cirrhosis. Fourth, we need to develop better techniques for liver cancer surveillance. A satisfactory solution to the problem of liver cancer in chronic viral hepatitis and alcoholism will not be quick or easy.

Medical Author: Jay W. Marks, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.

For additional Doctor's Views written by Dr. Marks, please visit the Doctor's Views Library at www.FocusOnDigestion.com.

Last Editorial Review: 4/3/02

A Sustained Viral Response Predicts a Significant Decrease in Clinical Complications Among Patients with Advanced Fibrosis or Cirrhosis

In patients with chronic hepatitis C, sustained virological response (SVR) seems to be associated with a significant decrease in the occurrence of clinical complications. Such an effect has not yet been demonstrated in patients with cirrhosis or advanced fibrosis, as SVR in patients treated with interferon (IFN) monotherapy was very low.

The aim of the present study at the Hopital Jean Verdier in Bondy, France was  to assess the occurrence of clinical events according to virological response in a homogeneous cohort of patients with HCV-related cirrhosis or severe fibrosis treated with antivirals.

Consecutive patients with the following criteria were retrospectively included:

)     HCV-related cirrhosis or advanced fibrosis (Metavir score F3 ou F4);

(2)     Absence of clinical complication or HCC previously or at inclusion;

(3)     Absence of HBV or HIV coinfection or alcohol consumption > 80 g/d;

(4)     No contraindication to antiviral treatment;

(5)     Treated by at least one course of antiviral treatment = 3 mo; and

(6)     Regular follow-up = 18 months (US/6 months). (1

Results

138 patients (mean age: 54±11 years, males: 59%, Metavir F4: 83%, genotype 1: 54%) were included. Treatment courses were performed 1, 2, 3 and 4 times in 45%, 38%, 14% et 3% respectively.

IFN-ribavirin combination therapy was administered in 70%. SVR (negative HCV RNA 6 mos after the end of treatment) was obtained in 53 patients (38%).

SVR and non SVR (NSVR) patients did not differ either in term of follow-up (5.6±2.3 vs 5.7±3.0 years) or of cumulated duration of antiviral treatment (14±6 vs 14±8 months).

Nevertheless, SVR patients were younger (50±11 vs 57±11 yrs, p=0.003), more often belonging to Metavir F3 (28% vs 10%, p<0.01), and less often infected with genotype 1 HCV (41% vs 76%, p<0.0001).

During the follow-up, clinical events occurred in NSVR group but were virtually absent in SVR group (HCC: 22/85 (26%) vs 0/53, p<0.0001 ; decompensation: 10/85 (12%) vs 1/53 (2%), p<0.01).

No patient died in SVR group vs 14/85 in NSVR group (16%, p<0.001); in the latter group, HCC was the cause of death in 43%.

Conclusions

Combination antiviral therapy results in SVR in 38% of patients with HCV-related cirrhosis or advanced fibrosis. Virological cure seems to be associated with a dramatic decrease in the incidence of clinical complications during a mean follow-up period of about 6 years.

“These results are a strong argument for treating and re-treating patients with severe compensated liver disease,” conclude the authors.

04/28/04

Reference
R El Braks and others. EFFECT OF VIRAL CLEARANCE ON CLINICAL OUTCOME IN PATIENTS WITH HCV-RELATED CIRRHOSIS OR ADVANCED FIBROSIS. A RETROSPECTIVE STUDY IN 138 PATIENTS. Abstract 211. 39^th EASL. April 14-18, 2004. Berlin, Germany.

  http://www.hivandhepatitis.com/2004icr/39easl/documents/0428/042804_hcv_h.html

Internet Conference Report
39th EASL - April 14 - 18, 2004, Berlin Germany

Future Trends of HCV-related Cirrhosis and Hepatocellular Carcinoma in Greece after Adjusting for Access to Peginterferon and Ribavirin

Greek researchers conducted a comprehensive analysis to estimate future HCV-related mortality in Greece, using a model that is the first to take into account currently available treatments (pegylated interferon and ribavirin).

The investigators reconstructed the incident infections per year in the past that progressed to chronic hepatitis C (CHC). Then, the natural history of the disease was simulated in sub-cohorts of newly infected subjects in the presence or absence of treatment using a Markov model.

Annual estimates of the incidence and prevalence of CHC by fibrosis stage, hepatocellular carcinoma (HCC) and mortality in Greece were obtained up to 2030.

Results

Treatment of 1%-10% of CHC patients per year would reduce the cumulative number of incident cirrhosis and HCC cases from 2002-2030 by 9.2%-39.4% and 10.9%-39.8%, respectively and decrease the number of prevalent cirrhosis and HCC cases in 2020 by an estimated 12%-42% compared to the number estimated under the assumption of no treatment.

Approximately 18 cirrhosis cases or 6 HCC cases or 10 premature deaths would be prevented for every 100 treated patients. However, the prevalent cirrhotic/HCC cases and HCV-related deaths would not plateau until 2030 even with treatment of 10% of CHC patients per year.

The authors conclude, “Despite the introduction of effective treatment, HCV-related morbidity and mortality will likely increase during the next 20-30 years in Greece. Intensive primary prevention efforts coupled with increased access to the currently available treatments are necessary to control the chronic consequences of HCV epidemic.”

05/05/04

Reference
FUTURE TRENDS OF HCV-RELATED CIRRHOSIS AND HEPATOCELLULAR CARCINOMA UNDER THE CURRENTLY AVAILABLE TREATMENTS. Abstract 270. 39^th EASL. April 14-18, 2004. Berlin, Germany.

www.hivandhepatitis.com