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European study group on viral hepatitis

Objective

The specific aims of this European concerted action were the following:
- to assess the natural course and outcomes of patients with chronic HBV infection.
- to construct prognostic indices of chronic hepatitis B aiming for rational application of therapeutical approaches, namely antiviral drugs and/or liver transplantation.
- to study viral antigen expression in liver and serum and relate it to markers of the specific and general immune response in the liver and blood.
- to perform meta-analysis on completed and ongoing clinical trials on antiviral treatment of chronic HBV infection.
- to construct prognostic indices for treatment-induced events in chronic HBV-infection.
- to determine the therapeutic gain in survival after liver transplantation for chronic viral hepatitis.
- to assess the efficacy of hepatitis B immunoglobulin in the prevention of recurrence of viral hepatitis after liver transplantation.
Retrospective data on over 370 liver transplants have been obtained from the European Liver Transplant Registry and from members of the Eurohep programme. A preliminary analysis indicates that survival after liver transplantation is excellent provided that hepatitis B virus (HBV) infection does not recur. The incidence of recurrence is reduced in patients with HBV acute or chronic liver failure who are preoperatively HBV deoxyribonucleic acid (DNA) negative and receive anti-HB immunoprophylaxis postoperatively. Preoperative antiviral therapy may also reduce the likelihood of recurrence.

A European network (Eurohep) has been created, linking expertise on viral hepatitis, and allowing collation of results from individual centres, more precise estimates on the natural history of chronic viral hepatitis and analysis of the effect of antiviral therapy and of the outcome of liver transplantation. Results demonstrated that hepatitis B virus (HBV) related liver cirrhosis is not an unrelenting progressive disease but intervention aimed at inducing viral elimination and biochemical remission can prolong life expectancy significantly.
The clinical relevance of hepatocellular carcinoma (HCC) as a fatal complication of chronic hepatitis B was increased during prolonged follow up. Screening for HCC might become a prerequisite for further improving life expectancy in patients with HBV related compensated cirrhosis of the liver.
Monitoring of hepatitis virus infections and assessment of the effects of intervention therapy has been aided by introduction of European standard samples for nucleic acid measurement.
The efficacy of alpha interferon, which inhibits viral protein synthesis, has been confirmed, although the effect was less than expected. Severe, rare side effects such as fatal hepatic decompensation and suicide following neuropsychiatric disturbances have been observed in European hepatology units, treating patients with chronic hepatitis B and C. It is recommended that patients undergoing this therapy are closely monitored.
Liver transplantation has yielded steadily improved results over the last 5 years, recurrence of the original disease being a main cause of graft or patient loss. Anti hepatitis B immunoglobulin prophylaxis at the time of surgery is effective in reducing the incidence of graft reinfection to less than 30%, thereby limiting graft and patient loss.
Viral hepatitis, in particular chronic viral hepatitis due to hepatitis B and hepatitis C virus, is an important health problem in Europe. In the high-endemic countries like Greece, Italy, Spain and Portugal there are at least 2.5 million virus carriers; in the low-endemic countries of North-Western Europe chronic viral hepatitis predominantly affects haemophiliacs, homosexuals and drug addicts, but 30 percent of virus carriers do not belong to specific risk groups.

Chronic viral hepatitis appears to run a variable natural course. Subjects from North and Central European countries usually become infected during adult life, often through sexual practice, have high levels of hepatitis B virus (HBV) and core protein (HBeAg) in the serum, and after a variable number of years clear HBeAg and HBV from the serum with remission of the inflammation of the liver. In Southern Europe, intrafamilial spread is common giving rise to infection early in life. Clearance of HBeAg occurs frequently, but HBV-replication with active liver disease can persist in antiHBe-positive patients. The existence of an emerging variant strain of the virus has been demonstrated. Moreover, hepatitis D virus (HDV) superinfection is particularly common in Southern Europe both in relation to intrafamiliar spread as well as to drug addiction. Conceivably, the ongoing pandemic of human immuno deficiency virus (HIV) infection, which is spreading predominantly among homosexuals in North-Europe and among drug addicts in Southern countries, might modify the epidemiological, clinical and virologic patterns of the disease. The pathobiology of chronic viraemia is only partly understood and further study of immunology, environmental factors (lifestyle, virus-virus interaction) and molecular biology could elucidate why a small proportion of infected persons develop chronic viral hepatitis.

All types of chronic viral hepatitis are now amenable to treatment by antiviral agents or liver transplantation. Alpha-interferon is being tested widely and will be licensed in Europe. This treatment is costly and only effective in a minority of patients. Similarly, the very costly therapy of liver transplantation is increasingly applied to patients with liver failure due to chronic viral hepatitis, although the effectiveness of this treatment modality appears uncertain. The evaluation of the modification of the natural history by such treatments is impossible by the incomplete knowledge of the prognosis without treatment. Furthermore, indications for intervention should be based on both prognosis and the expected benefits of the treatment. Results of antiviral drugs and liver transplantation vary widely from centre to centre, probably related to different characteristics of the patients and variable modes of treatment. In order to restrict treatment to subgroups of patients with chronic viral hepatitis who are most likely to benefit from it, cooperative research in both assessing prognosis as well as benefits and risks of treatments is mandatory.

In addition to the studies on epidemiology, antiviral therapy and liver transplantation, the Eurohep programme includes a section on pathobiology aiming to diffuse standardized laboratory methodology for measurement of virus or virus antigens, and to facilitate basis research on blood or tissue samples from patients in the clinical research programmes.

Funding Scheme

CON - Coordination of research actions

Coordinator

University Hospital Dijkzigt
Address
Dr Molewaterplein 40
3015 GD Rotterdam
Netherlands