41st Annual Meeting of the European Association for the Study of the Liver

Vienna, Austria, April 26-30 2006

Prof. Dr. C.Verslype, University Hospital Gasthuisberg, Leuven,

Summary

In this summary we review the clinical papers presented at the EASL 2006.The conference was dominated by presentationson therapy of viral hepatitis. Several new antiviral agents have been developed and the main message this year was that an early antiviral response – both in hepatitis B and C - is predictive of a beneficial long-term outcome.There were some interesting contributions in the field of acute variceal bleeding, primary liver cancer and non-alcoholic fatty liver disease. The therapeutic arsenal of the hepatologist is now expanded with drugs that correct thrombocytopenia and hyponatraemia.

1. Viral Hepatitis

Hepatitis B

Recent evidence from large cohort studies (presented by Chen and Iljoeje at EASL 2005) suggests that patients with chronic hepatitis B and HBV-DNA levels below 4 log copies/ml have a markedly reduced risk of developing cirrhosis or hepatocellular carcinoma. It may therefore be an attractive strategy to keep HBV-DNA as low as possible. At this year’s
EASL meeting, Zeuzem (abstract 51) presented in a retrospective analysis of the phase III GLOBE trial, interesting data concerning the early viral suppression in patients treated with nucleoside analogues.The GLOBE trial demonstrated that telbivudine, a novel nucleoside analogue, was more effective than lamivudine in patients with chronic hepatitis B. Patients
who achieved a low HBV-DNA (< 300 copies/ml) early on (at 24 weeks of treatment with adefovir or telbivudine) had a high probability of HBV-DNA clearance at 1 year and remaining free of resistance to nucleoside analogues.
Many experts advocate the careful follow-up of HBV-DNA levels with a sensitive assay during therapy with nucleoside analogues, in order to detect the occurrence of resistance early on and take appropriate action (association with other antiviral agent).

Lamivudine monotherapy commonly leads to emergence of lamivudine resistance, causing virologic and biochemical rebound and negative clinical effects. Adefovir dipivoxil prevents liver disease progression in patients with lamivudine resistance. The efficacy and safety of long-term adefovir treatment are unknown for patients outside clinical trials.The multicenter prospective/retrospective analysis of patients in Italian Expanded Access Program (EAP) evaluated efficacy,safety, and resistance in lamivudine-resistant patients (n=738) receiving adefovir (Lampertico et al.; abstract 116). Most patients with lamivudine-resistant chronic HBV infection achieved undetectable HBV DNA and ALT normalization with adefovir ± lamivudine.Adefovir plus lamivudine combination therapy was associated with lower risk of virologic rebound than adefovir monotherapy. This study suggests that it may be appropriate to treat patients with lamivudine resistance
with the combination of adefovir and lamivudine.

Despite the fact that there are several new nucleoside and nucleotide analogues in the treatment of chronic hepatitis B,pegylated interferon remains an attractive first-line strategy. In a previous trial of patients with HBeAg-positive chronic HBV infection (Lau et al., N Engl J Med. 2005;352: 2682) peginterferon alfa-2a (40KD) (Pegasys®) monotherapy was found superior to lamivudine monotherapy at 6 months post-treatment, with a significantly higher rate of seroconversion and HBV-DNA response. At EASL 2006 Lau (abstract 50) evaluated the durability of the responses to peginterferon alfa-2a monotherapy in patients from same study 1 year post-treatment. Virologic and serologic responses to 48 weeks of peginterferon alfa-2a in patients with HBeAg-positive chronic HBV infection, were largely maintained at 1 year posttreatment.Some patients achieved new serologic responses in months 6-12 post-treatment.

Hepatitis C: optimising therapy with pegylated interferon and ribavirin

Attempts are underway to shorten treatment duration or ribavirin dose in patients with hepatitis C. Several small studies suggested that shorter duration of treatment may be sufficient to induce sustained viral response (SVR). The ACCELERATE trial compared 16 or 24 weeks of therapy with peginterferon alfa-2a (Pegasys®) plus ribavirin (Copegus®) in 1.496 patients with HCV genotype 2 or 3, the largest study ever conducted in these genotypes. Shiffman (abstract 734) presented the final results of this trial, which demonstrated that 16 weeks of treatment was inferior to the current standard of care (24 weeks of treatment). A significantly higher SVR rate was observed with 24 weeks compared with 16 weeks of treatment, irrespective of HCV genotype infection, rapid viral response or baseline serum HCV RNA level.

Ferenci (abstract 82) discussed the interim results of a randomised controlled trial, aimed at investigating reduction of ribavirin dose in HCV genotype 2/3 patients. Patients (n=282) were randomized to peginterferon alfa-2a (40KD) (Pegasys®) 180μg/week plus ribavirin (Copegus®) 400 or 800 mg/day for 24 weeks. Ribavirin 400 mg/day was as effective as 800 mg/day when used in combination with peginterferon alfa-2a, in inducing sustained virologic response (SVR).However, many experts feel that further follow-up data and confirmatory studies are required before changing the current standard of care.

Ferenci (abstract 8) also presented a study in genotype 1/4 patients, treated with peginterferon alfa-2a (40KD) (Pegasys®) plus Ribavirin (Copegus®), which showed that that the highest sustained viral response rates (SVR) were achieved in those patients with the lowest HCV-RNA level after 4 weeks’ treatment (“rapid viral response”; RVR). Seventy-seven percent of genotype 1 and 4 patients with an RVR achieved a SVR following 24 weeks’ treatment. The greater the viral suppression at week 4, the lower the chance of relapse.

Ribavirin combined with peginterferon alfa-2b (Pegintron®) is associated with anaemia in approximately 25% of patients.Viramidine is a ribavirin prodrug activated in liver and is less likely to cause anaemia than ribavirin. The VISER1-study is a double-blind, controlled, phase III multicenter trial, randomizing 970 HCV treatment naive patients to Pegintron®) 1.5 μg/kg/week sc plus ribavirin or viramidine for 24/48 weeks (depending on genotype) (Benhamou et al.; abstract 751).The frequency of treatment-related anaemia was significantly lower for viramidine compared with ribavirin. Unfortunately, viramidine was inferior in terms of SVR when compared with ribavirin in intent-to-treat analysis. A higher exposure to viramidine was associated with a higher SVR rate, but also increased the rate of anaemia.

2. ACUTE VARICEAL BLEEDING

A group from Linz (Austria) has developed an intriguing new therapy to stop an acute variceal bleeding, which may render the classical balloon tamponade obsolete. The device is a covered, self-expanding metal stent that was placed in the oesophagus of 17 patients, who failed pharmacological and/or endoscopic therapy for an acute variceal bleeding. The bleeding could be stopped in all patients.The stent was left in place for 2 to 14 days, which allowed a definitive therapy for the variceal bleeding.The stent could be removed endoscopically without any problem. Interestingly, the stent can be implanted at home (without need for endoscopy) (Hubmann et al., abstract 24).

3. HEPATOCELLULAR CARCINOMA

Gish (abstract 28) presented the results of a phase 3 randomised controlled study, comparing the survival of 446 patients from USA, South Africa and Europe with advanced HCC treated with either the investigational agent nolatrexed (NOL; a thymidylate synthese inhibitor) or classical doxorubicin (DOX). Interestingly, there was a (modest) survival benefit in favour of DOX (median survival 31 wks versus 20.7 wks for NOL, p = 0.005), but the activity was minimal (response rate 4.1%). Despite this moderate activity, it is still considered ethical to conduct placebo-controlled studies for advanced HCC.

At EASL 2006 we reported the results of a Belgian multi-center study, investigating the role of long acting release octreotide (Sandostatin LAR) in patients with advanced HCC (Verslype et al.; abstract 281). Patients (n=109) were randomly assigned to the combination of octreotide and tamoxifen or tamoxifen alone. There was no difference in terms of median survival, alpha-foetoprotein decrease, tumor regression or improvement of quality of life between the two groups.Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, alpha-foetoprotein below <400 ng/ml and Okuda stage I.

The importance of HBV-vaccination in the prevention of hepatocellular carcinoma was illustrated by a study from Taiwan (Chien et al., abstract 247). The investigators linked the HBV vaccination status of 3.855.485 newborns (infants vaccinated between July 1984 and March 2000) listed in computerized national database with data on newly diagnosed HCC from national cancer registry database. Interestingly, the incidence of HCC decreased with each subsequent dose of HBV vaccine.Compared with those who received 1-2 doses of vaccine, incidence of HCC was 58% lower for boys who received 4 doses of vaccine, and 56% lower for girls who received 4 doses of vaccine.

4. DRUGS FOR THROMBOCYTOPENIA AND HYPONATRAEMIA

Cirrhosis and hyponatraemia: vasopressin V2 receptor antagonist

The group from Barcelona reported on satavaptan, a selective vasopressin V2 receptor antagonist, on serum sodium concentration and ascites in patients with cirrhosis and hyponatraemia. One hundered and ten patients were treated for 14 days with eiher 5 mg, 12.5 mg or 25 mg satavaptan, once daily. Sodium increased significantly with the dose of 5 mg,
body weight decreased and there was no adverse effect on renal function or blood pressure. The most significant side effect was thirst.The compound will be evaluated soon in large trials throughout Europe (Gines et al, abstract 732).

Eltrombopag for treatment of thrombocytopenia

Thrombocytopenia represents a significant problem in hepatitis C patients, either induced by the disease itself and/or interferon therapy. Eltrombopag is an orally administered platelet growth factor, that stimulates megakaryocyte proliferation and differentiation through activation of the thrombopoietin receptor. Safety and efficacy of eltrombopag in HCV patients was evaluated in a phase II, randomized, placebo-controlled,multicenter trial (McHutchinson; abstract 745). The presented interim analysis suggests that eltrombopag was effective and well tolerated in HCV-infected thrombocytopenic patients. There were improvements in platelet levels at all dose levels, but the best response was seen at the highest dose of elthrombopag (75 mg/day), with a more than four-fold increase in baseline platelet counts.

5. NON-ALCOHOLIC FATTY LIVER DISEASE

Causes of death

Non-alcoholic steatohepatitis is considered a main cause of liver disease, which will become more important in the near future. Swedish investigators studied the survival and causes of death in 212 patients with elevated liver enzymes associated with non-alcoholic fatty liver disease (NAFLD), in comparison with 44.745 controls.The mean follow-up was 15.3 + 1.4 years. Patients with NAFLD had a lower survival and died mainly form cardiovascular disease. Interestingly, NAFLD precedes the occurrence of type II diabetes (Ekstedt et al., abstract 91). In conclusion, patients with NAFLD especially need a doctor who takes care of cardiovascular preventive measures.

Treatment with an insulin sensitzing agent rosigglitazone

Vlad Ratziu (France, abstract 738) presented the results of a the FLIRT trial.This is a one year randomized, placebo controlled double blind trial of rosiglitazone (8 mg daily) in 63 patients with non-alcoholic steatohepatitis. They noted histological improvement in the rosiglitazone group (less steatosis). As expected with this compound, there was a slight weight increase in the treatment group.