A randomized, open-label, multicenter study evaluating the efficacy of peginterferon alfa-2a versus interferon alfa-2a, in combination with ribavirin, in naïve and relapsed chronic hepatitis C patients.

BACKGROUND/AIMS: A large multicenter trial to compare the efficacy of peginterferon alfa-2a with interferon alfa-2a, in combination with ribavirin, in chronic hepatitis C patients. Efficacy data for prior relapsers are reported because treatment recommendations for this patient population are not well defined. PATIENTS AND METHODS: This study was a multicenter, prospective, randomized clinical trial. The primary efficacy endpoint was sustained virologic response in naive patients (n = 348) and relapsers (n = 95). RESULTS: Sustained virologic response rates were similar in naïve patients and relapsers, both for non-pegylated and pegylated interferon (respectively 27 and 26% and 54 and 43%). Pegylated interferon given for 48 weeks did not improved the relapse rate: 15.9 and 27.3% for non-pegylated and 16.7 and 30.4% for pegylated interferon, naïve vs relapsers respectively. Stepwise logistic regression analysis revealed a significant association between slow response (detectable HCV RNA at week 12 and undetectable at week 24) and relapse in patients with an end-of-treatment response (55% versus 13% respectively; p = 0.02; odds ratio = 6.07). CONCLUSIONS: This trial confirms the value of using peginterferon alfa-2a in both naïve and relapsed patients and provides support for a more tailored approach to treatment for relapsers and particulary for patients with a slow viral response.

Fatal hypoxic hepatitis in a patient with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber's disease).

Hypoxic (ischemic) hepatitis generally requires the concurrence of an underlying condition which chronically exposes the liver to some degree of hypoxia (for example, congestive heart failure) combined with a triggering event (for example, arrhythmia) which further decreases the oxygen supply. We report a case of hypoxic hepatitis in which hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber's disease) constituted this underlying condition and gastrointestinal hemorrhage was the triggering event. To our knowledge, this is the first reported case of hypoxic hepatitis in hereditary hemorrhagic telangiectasia with the exception of therapeutic ligation or embolization of the hepatic artery so as to decrease shunting of liver blood. Hemodynamic mechanisms are proposed to explain this particular outcome.

Clinical trial: a randomized trial of pegylated-interferon-alpha-2a plus ribavirin with or without amantadine in treatment-naïve or relapsing chronic hepatitis C patients.

BACKGROUND: The combination therapy of pegylated-interferon-alpha2a plus ribavirin is considered as the standard of care for patients with chronic hepatitis C. A sustained viral response is obtained in 40-50% of naïve patients with genotype 1 and in around 80% of naïve patients with genotype 2 or 3. AIM: To assess whether amantadine, added to the conventional combination therapy, could improve the treatment efficacy. METHODS: In all, 630 patients (intent-to-treat population) with chronic hepatitis C were randomized into two groups: 316 patients (treatment group) received pegylated-interferon-alpha2a (180 microg once weekly) plus ribavirin (1000-1200 mg/daily) with amantadine (200 mg/daily); 314 patients (control group) received pegylated-interferon-alpha2a (180 microg once weekly) plus ribavirin (1000-1200 mg/daily) without amantadine. The duration of the treatment was 48 weeks for genotypes 1, 4, 5 and 6, and 24 weeks for genotypes 2 and 3. RESULTS: There was no statistically significant difference between treatments groups for any of the variables tested for. Subgroups of patients likely to take advantage of the addition of amantadine were not identified. CONCLUSIONS: This large study definitely excludes the role of amantadine in addition of conventional combination therapy in the treatment of chronic hepatitis C patients.

Portal vein thrombosis as the first sign of a primary myeloproliferative disorder: diagnostic interest of the V617F JAK-2 mutation. A report of 2 cases.

Portal vein thrombosis is, in some cases, related to a myeloproliferative disorder but the diagnosis of the latent forms may be difficult in case of normal blood counts. We report two cases of patient with portal vein thrombosis of unknown origin in whom the presence of the V617F mutation of the Janus Kinase 2 gene lead to the diagnosis of primary myeloproliferative disorder, confirmed on bone marrow examination. The search of the V617F mutation of the Janus Kinase 2 gene has to be performed in all cases of portal vein thrombosis of unknown origin.

Weekly pegylated interferon alpha-2b vs daily interferon a-2b versus standard regimen of interferon a-2b in the treatment of patients with chronic hepatitis C virus infection.

BACKGROUND AND STUDY AIMS: The combination of Pegylated (PEG)interferon alpha-2b and ribavirin is considered to be the standard treatment for naïve chronic hepatitis C patients. Study aims are to evaluate the differences between standard interferon and PEG-interferon by conducting a multi-centre, controlled randomized trial comparing 3 groups. Group A : daily interferon alfa-2b at a dose of 4 MIU + ribavirin, Group B : PEG-interferon alfa-2b at a dose of 100 mcg/week + ribavirin; Group C: interferon alfa-2b at a dose of 3 MIU TIW + ribavirin PATIENTS AND METHODS: Multicentrer, open label study including naïve chronic Hepatitis C Virus patients randomised in three groups with a ratio of 2:2:1. Group A: daily interferon alpha-2b (4 MIU s.c. for patients > 65 kg or 0.06 MIU/kg < 65 kg) and ribavirin, group B: PEG-interferon alpha-2b (100 microg s.c. weekly for patients > 65 kg or 1.5 microg/kg weekly for patients < 65 kg) and ribavirin and group C (reference arm) : interferon alpha-2b (3MIU s.c. TWI) and ribavirin. The duration of the treatment was 48 weeks for all 3 groups, with a 6 month follow-up period. 336 patients were enrolled in the study and included in the intention-to-treat analysis; 78 never started treatment (35 in group A, 28 in group B and 15 in group C): 101 in group A, 98 in group B and 59 in group C. RESULTS: Demographic data, PCR results and reasons for early withdrawal have been statistically analysed. At baseline, the 3 groups did not show any statistical difference regarding age, gender, race, genotypes and METAVIR score. At week 24 on treatment, HCV ribonucleic acid RNA was undetectable in 87% in group A, in 79% in group B and in 69% in group C. At the end of treatment, 73% 74% and 58% respectively, had a negative PCR result. At week 24 of follow-up, these results were 71%, 64% and 48%, respectively. When comparing the efficacy of the daily interferon (+ ribavirin) and the PEG-interferon (+ ribavirin) regimen, no statistical difference was found (p = 0.32). In group A, 38% of drop-outs were due to adverse events compared to 37% in group B and 58% in group C. No statistical differences were observed regarding safety. CONCLUSION: Daily weight based interferon alpha-2b dosing and PEG interferon alpha-2b weighed based dosing once weekly both in combination with Ribavirin offer the same efficacy and safety rates.

Feasibility, safety and cost-effectiveness of transjugular liver biopsy following major surgery in patients with haemophilia.

Prior to the introduction of virally inactivated clotting factor concentrates, the majority of patients with haemophilia became infected with the hepatitis C virus. Although transjugular liver biopsy can be safely performed in these patients, the procedure is associated with a significant financial burden mainly related to replacement therapy with clotting factor. The purpose of this study was to evaluate the feasibility and safety of transjugular liver biopsy in patients with haemophilia substituted with clotting factor concentrates for major surgical procedures. Over the last 5 years, transjugular liver biopsy was performed in nine patients with haemophilia within 1-10 days after orthopaedic (7), thoracic (1) or abdominal surgery (1). All patients had abnormal liver function tests and persistent hepatitis C viraemia. At the time of the biopsy, patients received recombinant factor VIII delivered by dose-adjusted continuous infusion through a central catheter inserted preoperatively in the left internal jugular (n = 8) or in an ante-cubital vein (n = 1). Before the biopsy, basal FVIII levels were raised to 80-100% by a bolus infusion and maintained above 80% for 24 h. The biopsy was informative in all cases. Only one patient developed an episode of supraventricular dysrhythmia. No bleeding or infectious complications were observed. When compared with elective liver biopsy performed outside the postsurgical period, the cost-savings per biopsy were 19 875 +/- 2660 euro. This study shows that intensive replacement therapy required by surgical procedures provides a safe and cost-effective opportunity for transjugular liver biopsy in patients with haemophilia and active hepatitis C.

Black pigments in the liver related to gold and titanium deposits. A report of four cases.

Black pigments are rarely described in the liver. We report four patients with chronic cholestasis and black pigments described on liver histological examination. Energy-dispersive X-ray analysis identified these black pigments as gold particles in the first three patients and titanium particles in the fourth. The origin of the gold deposits was unknown in this first patient and related to gold salts therapy in the two others. Titanium deposits was associated with hepatic granulomas and related to total knee replacement.

The management of patients with mild hepatitis C.

Infection with the hepatitis C virus (HCV) represents an important public health problem and is a leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Chronic hepatitis C is a heterogeneous disease. Many patients have mild disease at presentation but not all of them will develop advanced liver disease. However, the identification of these patients with mild hepatitis C who will show progressive disease is difficult and is based on histological criteria and the assessment of co-factors (age, alcohol intake, steatosis). In addition, serum transaminases that are persistently normal on several occasions during 18 months may point to a more benign course. Patients with mild hepatitis C should not be excluded "a priori" from the possibility of being treated, as treatment with pegylated interferon and ribavirin is safe and effective in this group. Overall, the decision to initiate therapy should be individualized and based on the severity of the disease by liver biopsy, the potential of serious side effects, the probability of response and the motivation of the patient.

The HepCar registry: report on a one-year registration program of hepatocellular carcinoma (HCC) in Belgium. What is daily practice in HCC?

INTRODUCTION: Due to a rise in HCV induced liver cirrhosis, hepatocellular carcinoma becomes more prevalent in Western European countries. The HepCar registry is an initiative in which patients with hepatocellular carcinoma, their treatment and follow up are registered. MATERIALS AND METHODS: Belgian physicians were asked to report all new cases of hepatocellular carcinoma which were seen between January 2003 and December 2003. Reporting was done on a voluntary basis. Data reported were: demographic figures, the nature of the underlying liver disease, presentation characteristics of the tumour, laboratory findings and choice of therapy. Every six months, a reminder was sent to determine survival. RESULTS: 131 patients (94 male/37 female) were reported. Mean age was 63 years +/- 13. Underlying liver disease was HCV (n = 54, 41%), HBV (n = 22, 17%), alcoholic liver disease (n = 39, 30%) and miscellaneous (n =16, 12%). Diagnosis of hepatocellular carcinoma was made by surveillance in 47 (36%) patients. After logistic regression, survival was 5 times better for patients inside the Milan criteria (one lesion less than 5 cm in diameter or less than 3 nodules each less than 3 cm in the absence of vascular invasion and metastasis). DISCUSSION: Tumours inside the Milan criteria have a better survival. The majority of the patients have an underlying cirrhosis as background for the development of a HCC.

Daily induction combination treatment with alpha 2b interferon and ribavirin or standard combination treatment in naive chronic hepatitis C patients. A multicentre randomized controlled trial.

The standard treatment for patients with chronic hepatitis C is a 6-12-month combination therapy with interferon alpha and ribavirin. Induction treatment could result in a faster early decline of the hepatitis C virus (HCV) load and a better response rate. Naive chronically infected HCV patients (n = 454) were randomized into two arms to receive either induction treatment with interferon alpha 2b 5 million units (MU) subcutaneously (s.c.) daily during a period of 8 weeks (arm A); or treatment with interferon alpha 2b 5 MU s.c. three times a week (TIW) for a period of 8 weeks (arm B). After week 8, interferon treatment in both arms was 3 MU s.c. TIW for a total period of 12 months. In both arms, ribavirin (1000-1200 mg orally per day) was added at week 4. Induction treatment resulted in a higher virological response at week 8 of treatment (66%vs 47%; P < 0.01). However, response at the end of treatment and at 6 months follow-up was not different (53%vs 50%, 41%vs 33%). The occurrence of adverse events and the drop-out rate were similar in both arms. Although an early virological response is observed more frequently in the induction treatment, end of treatment response and sustained responses did not differ.

Symptomatic ileocolic fistula as a complication of endoscopic laser therapy. A case report.

Since 1973, laser photo therapy is used in the treatment of gastrointestinal neoplasms as well as in various forms of intestinal hemorrhage. Complications including hemorrhage, stenosis and perforation are well documented but ileocolic fistulas after laser therapy for a villous adenoma have been rarely reported. We report the case of a patient with diarrhea related to an ileocecal fistula. This fistula appeared 1 year after laser therapy for a villous tumor of the cecum.

Treatment of hepatitis C: impact on the virus, quality of life and the natural history.

Results of treatment for chronic hepatitis C have improved substantially during the last decade. Combination treatment with interferon alpha 3 MU tiw and ribavirin 1000-1200 mg daily during 24 to 48 weeks leads to sustained virologic response (SVR) in approximately 40% of patients, two to three times more than interferon alpha monotherapy. It was considered standard therapy at the EASL Consensus Conference of February 1999. Recently, results have been published on treatment with pegylated interferons alone and in combination with ribavirin. Pegylated interferon treatment leads to almost doubling of SVR rate as compared with standard interferon monotherapy. Combination of pegylated interferon alpha with ribavirin is most promising, leading to a SVR rate of 54 to 56%. It is to be expected that this treatment will become the new standard. Selected patients with geno-type 2 or 3 have now a SVR rate of almost 80%. Response to treatment also leads to significant improvement of quality of life and survival, probably by reducing the risk of developing hepatocellular carcinoma. Recent data suggest that early interferon alpha treatment of patients with acute hepatitis C largely prevents the development of chronicity.

Biliary complications of large Echinococcus granulosus cysts: report of 2 cases and review of the literature.

Hydatid cysts are often incidentally found and remain clinically silent. However complications can occur. We present 2 patients who developed biliary complications due to a large hydatid cyst. In the first patient compression on the intrahepatic bile ducts and cystic duct by the cyst, caused cholangitis and cholecystitis. Moreover the cyst had ruptured into the right intrahepatic bile ducts. A sphincterotomy was performed with extraction of hydatid sand. A pericystectomy was necessary because of infectious deterioration of the patient. Albendazole was continued for 8 weeks after surgery. The second case presented with jaundice and weight-loss since 1 month. A large hydatid cyst caused compression on the bile duct bifurcation with proximal bile duct dilatation. A cystectomy was performed 2 weeks after albendazole therapy initiation, which was continued for 8 weeks after surgery. Follow-up of both surgical interventions was unremarkable. Although Echinococcus granulosus in not prevalent in Belgium, we must be aware of this pathology in patients coming from high endemic regions.

High prevalence of hepatitis C virus infection in Belgian intravenous drug users and potential role of the "cotton-filter" in transmission: the GEMT Study.

AIMS: To estimate viral seroprevalences for HCV, HBV and HIV among belgian intravenous (IVDU) and non intravenous (non-IVDU) drug users; to assess risk factors for HCV infection in IVDU; to assess feasibility of chronic hepatitis C follow-up in this population. DESIGN: Cross-sectional study. Demographic and behavioural characteristics were obtained by a standardized questionnaire. Serum samples were tested for HCV, HBV and HIV. SUBJECTS AND SETTING: 329 patients (244 IVDU and 85 non-IVDU) attending ten general practitioners in 1995. RESULTS: HCV seroprevalence was 78.3%; it was 35.7% for HBV and 0.9% for HIV in IVDU, vs 2.4%, 8.3% and 0%, respectively, in non-IVDU. In logistic regression analysis, independent risk factors for HCV infection were: 1/sharing of syringes and/or of "cottons" used as filters (adjusted prevalence odds ratio [POR] = 31.7; 95% confidence interval [CI] = 9.8-102.5), 2/duration of injecting upper than one month (adjusted POR = 8.6; CI = 3.0-24.7) and 3/age (adjusted POR = 1.2 by year of difference; CI = 1.0-1.3). A biochemical follow-up was obtained in 70% of HCV seropositive users; 79.5% of them had chronic hepatitis C (mean value of ALT = 3.5 times upper normal value, range 1.1-23.0). Among these, 24.7% went through liver biopsy during the three years follow-up period of the study. CONCLUSIONS: HCV seroprevalence is very high among belgian IVDU. Prevention strategies have to focus on neophytes injectors. They must be urgently revisited for what concern needles/syringes exchange programs: "cottons" must be included. Follow-up and treatment of chronic hepatitis C seem to be poorly effective among drug users.

HLA association of amoxicillin-clavulanate--induced hepatitis.

BACKGROUND & AIMS: Drug-induced immunoallergic hepatitis typically affects a minority of patients exposed to a particular drug. Its rarity is believed to be due to metabolic or immunologic idiosyncrasy. The presence of an immunologic idiosyncrasy might imply an HLA association. Previous studies reporting an HLA association of drug-induced hepatitis included only small numbers of patients and used serological HLA typing. METHODS: We studied 35 patients with biopsy-documented amoxicillin-clavulanate-induced hepatitis. HLA-A and -B were typed using alloantisera and compared with those of 300 controls (volunteer bone marrow donors). HLA-DRB and -DWB were typed by polymerase chain reaction-line probe assay, with 60 volunteer bone marrow donors serving as controls. RESULTS: The study group was characterized by a higher frequency of DRB1*1501-DRB5*0101-DQB1*0602 haplotype (57.1% vs. 11.7% in controls, P < 0.000005; after correction for the large number of comparisons, P < 0.0002). Patients with DRB1*1501-DRB5*0101-DQB1*0602 haplotype were more likely than patients without it to have a cholestatic (70% vs. 60%) or mixed (30% vs. 13%) than a hepatocellular pattern of hepatitis (0% vs. 27%) (P < 0.05). CONCLUSIONS: Amoxicillin-clavulanate-induced hepatitis is associated with the DRB1*1501-DRB5*0101-DQB1*0602 haplotype. The data support the view that an immunologic idiosyncrasy, mediated through HLA class II antigens, plays a role in the pathogenesis of drug-induced immunoallergic hepatitis. HLA association has a limited impact on the expression of hepatitis.