Spilios Manolakopoulos

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country‐specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.

Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic review

BACKGROUND & AIMS Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues. METHODS We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for> or = 24 months. RESULTS Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32-108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466). CONCLUSIONS Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC.

Outcome of hepatitis B e antigen–negative chronic hepatitis B on long‐term nucleos(t)ide analog therapy starting with lamivudine

We determined the clinical outcome of hepatitis e antigen (HBeAg)‐negative chronic hepatitis B patients treated with long‐term nucleos(t)ide analog therapy starting with lamivudine. We evaluated 201 such patients treated for 3.8 ± 1.4 years and 2 historical similar cohorts: 1 treated with interferon‐alfa (n = 209) and 1 untreated (n = 195). Virological or biochemical remission rate at 48 months under lamivudine was 34% or 36%, respectively, whereas adefovir was administered in 79 patients with virological–biochemical breakthroughs or no response. Of the lamivudine‐treated patients, 4 died, 1 underwent a transplantation, and another 8 developed major events, all having advanced fibrosis at baseline and all but 1 having experienced breakthroughs or no response. At 5 years, survival was 96%, and major event–free survival was 93%. The major event–free survival was significantly better in patients with than in those without virological remission under lamivudine. At the end of follow‐up, both survival and major event–free survival were independently associated with type of and response to treatment, being significantly better in patients under long‐term antiviral therapy or interferon sustained responders than in interferon non‐sustained responders or untreated cases (5‐year survival: 96% or 98% vs. 88% or 90%, respectively). In conclusion, in HBeAg‐negative chronic hepatitis B, long‐term nucleos(t)ide analog therapy starting with lamivudine significantly improves survival and reduces the risk of major complications, compared with interferon non‐sustained responders or untreated patients. In such patients with advanced fibrosis, close follow‐up for lamivudine resistance and prompt onset of additional antiviral therapy is required or the ab initio use of agent(s) with low resistance rates should be considered. (HEPATOLOGY 2005;42:121–129.)

Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study

Objective To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy. Design Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective–prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months. Setting A nationwide network of liver centres. Patients 818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity. Interventions All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy. Main outcome measures Development of HCC. Results During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p<0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients <50, 50–60 and >60 years old, respectively (p<0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission. Conclusions Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC.

Large balloon dilation vs. mechanical lithotripsy for the management of large bile duct stones: a prospective randomized study.

OBJECTIVES:The removal of large bile duct stones (>12 mm) after endoscopic sphincterotomy (EST) remains a challenging issue in therapeutic endoscopy. The aim of this prospective, randomized, controlled trial was to compare the effectiveness and complications of EST followed by large balloon dilation (LBD) with that of EST followed by mechanical lithotripsy (ML) for the management of large bile duct stones.METHODS:A total of 90 patients with large bile duct stones (12–20 mm) were randomized to EST followed by LBD (n=45) or EST followed by ML (n=45). Success rate was determined with a final cholangiogram, whereas type and rate of post-procedure complications were assessed prospectively.RESULTS:Complete bile duct stone removal was accomplished in 97.7% of patients subjected to EST–LBD as compared with 91.1% of those subjected to EST–ML (P=0.36). Post-procedure complications were observed in two (4.4%) patients subjected to EST–LBD and in nine (20%) patients subjected to EST–ML (P=0.049). Rates of pancreatitis were similar between the two groups (one case in each), as was post-endoscopic retrograde cholangio pancreatography (ERCP) hemorrhage (one case in each group). None of the patients subjected to EST–LBD developed cholangitis, while this was seen in six patients subjected to EST–ML (0.0 vs. 13.3%, P=0.026). One patient subjected to EST–ML developed perforation, which was successfully managed conservatively. None of our patients with complications died.CONCLUSIONS:EST followed by LBD is equally effective as EST followed by ML for the removal of large bile duct stones, although it is associated with fewer complications.

Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis

Background  Endotoxaemia is commonly seen in cirrhotic patients with ascites and this may be associated with increased portal pressure.

Sustained rise of portal pressure after sclerotherapy, but not band ligation, in acute variceal bleeding in cirrhosis

During variceal bleeding, several factors may increase portal pressure, which in turn may precipitate further bleeding. This study investigates the early effects of endoscopic injection sclerotherapy (EIS) and endoscopic band ligation (EBL) on hepatic venous pressure gradient (HVPG) during acute bleeding and the possible influence in outcome. In 50 cirrhotic patients with bleeding esophageal varices treated with EIS (n = 25) or EBL (n = 25), we performed repeated HVPG measurements before and immediately after endoscopic treatment (time 0) and every 24 hours for a 5‐day period. Endotherapy was continued until the varices were too small for further treatment. Both groups were comparable with regard to age, gender, Child‐Turcotte‐Pugh grade, and HVPG. In the EBL and EIS groups, a significant (P < .0001) increase was observed in mean portal pressure (20.7 mm Hg ± 4.4 SD and 21.5 mm Hg ± 4.5 SD, respectively) immediately after treatment (time 0) as compared with pretreatment (18.1 ± 4.5 and 18.1 ± 4.0). However, HVPG in the EBL group returned to baseline values within 48 hours after treatment, while in the EIS group it remained high during the 120‐hour study period (P < .0001). Bleeding stopped in all patients after endotherapy. During the 42‐day follow‐up period, the rebleeding rate over time was lower in the EBL group compared with the EIS group (P = .024). Patients with an initial HVPG greater than 16 mm Hg had, despite endoscopic treatment, a significantly higher likelihood of rebleeding (P = .05) and death (P = .024) and overall failure (P = .037). In conclusion, during acute variceal bleeding EIS, but not EBL, causes a sustained increase in HVPG, which is followed by a higher rebleeding rate. (HEPATOLOGY 2004;39:1623–1630.)

Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen–negative chronic hepatitis B virus infection?

The diagnosis of hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA ≥2,000 IU/mL. We evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg‐negative chronic HBV infection focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2,000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score ≥7 and/or stage ≥2 in Ishaks classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA ≥200,000, 20,000‐199,999, 2,000‐19,999, and <2,000 IU/mL, respectively (P < 0.001). Histological indication for treatment was more frequent in chronic hepatitis B patients with persistently elevated ALT (86% or 275/321), but it was also found in 74% (58/78) of those with transiently normal ALT (P = 0.025). All inactive carriers had HBV DNA <20,000 IU/mL. Histological indication for treatment was present in 17% (6/35) of inactive carriers always due to moderate (stage 2) fibrosis without active necroinflammation. Conclusion: HBeAg‐negative chronic HBV patients with persistently or transiently increased ALT and HBV DNA ≥20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA <20,000 and even <2,000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg‐negative patients with persistently normal ALT and HBV DNA >2,000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow‐up. (HEPATOLOGY 2008.)

Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: A systematic review

BACKGROUND & AIMS The adequacy of monitoring HBeAg-negative patients based on ALT activity is controversial and current guidelines favor liver biopsy in HBeAg-negative cases with normal ALT and HBV DNA >2000 IU/ml. We systematically reviewed all the available histological data on HBeAg-negative patients with persistently normal ALT (PNALT) to determine the prevalence of significant liver disease and its associating factors. METHODS Literature search to identify studies with adult HBeAg-negative patients who had PNALT as defined by the authors, a minimum follow-up of 1 year and histological data. Traditional cut-off values of normal ALT were used in all studies. The definitions of PNALT were considered as acceptable or good if there were ≥3 ALT determinations at unspecified intervals during 6-12 months or predefined intervals during ≥12-month periods, respectively. RESULTS Six studies including 335 patients met our inclusion criteria. Of these, four studies with 246 patients had good or acceptable definitions of PNALT. In the latter four studies, more than minimal (usually mild) necro-inflammatory activity was observed in 10% and more than mild fibrosis in 8% of all patients (moderate fibrosis: 7%, severe fibrosis: 1%, cirrhosis: 0%), and in 3% and 5% of patients with HBV DNA ≤20,000 IU/ml, respectively. CONCLUSIONS Histologically significant liver disease is rare in HBeAg-negative patients with PNALT based on stringent criteria and serum HBV DNA ≤20,000 IU/ml. Such cases can be considered as true inactive HBV carriers, who require neither liver biopsy nor immediate therapy but continued follow-up.

Endoscopic sclerotherapy versus variceal ligation in the long-term management of patients with cirrhosis after variceal bleeding: A prospective randomized study

BACKGROUND/AIMS Long-term endoscopic injection sclerotherapy of oesophageal varices prevents rebleeding in patients with cirrhosis surviving an acute variceal bleeding episode. However, this treatment is associated with a substantial complication rate. Endoscopic band ligation is a newly developed technique in an attempt to provide a safer alternative. The aim of this study was to compare the efficacy and safety of injection sclerotherapy versus variceal ligation in the management of patients with cirrhosis after variceal haemorrhage. METHODS Seventy-seven patients with cirrhosis who proved to have oesophageal variceal bleeding were studied. After initial control of haemorrhage by sclerotherapy, 40 of the patients were randomly assigned to sclerotherapy and 37 to ligation. Both procedures were performed under midazolam sedation at intervals of 7-14 days until all varices in the distal oesophagus were eradicated or were too small to receive further treatment. RESULTS The eradication of varices required a lower mean number of sessions with ligation (3.7 +/- 1.9) than with sclerotherapy (5.8 +/- 2.7, p = 0.002). The mean duration of follow-up was similar in both groups (15.6 months +/- 7.3 and 15 +/- 7.4, respectively). The proportion of patients remaining free from recurrent bleeding against time was significantly higher in the ligation group as compared to the sclerotherapy group (chi 2 = 3.86, p = 0.05). Only 13 patients (35%) developed complications in the ligation group as compared to 24 (60%, p = 0.05) in the sclerotherapy group. The mortality rate was similar in both groups (20% and 21%, respectively). CONCLUSIONS Variceal ligation is better than sclerotherapy in the long-term management of patients with cirrhosis after variceal haemorrhage which was initially controlled with sclerotherapy.