Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference.

In the WHO-EURO region, around 28 million people are currently living with chronic viral hepatitis, and 120,000 people die every year because of it. Lack of awareness and understanding combined with the social stigma and discrimination exacerbate barriers related to access to prevention, diagnosis and treatment services for those most in need. In addition, the persisting economic crisis has impacted on public health spending, thus posing challenges on the sustainable investment in promotion, primary and secondary prevention, diagnosis and treatment of viral hepatitis across European countries. The Hepatitis B and C Public Policy Association in cooperation with the Hellenic Center for Disease Prevention and Control together with 10 partner organizations discussed at the Athens High Level Meeting held in June 2014 recent policy developments, persisting and emerging challenges related to the prevention and management of viral hepatitis and the need for a de minimis framework of urgent priorities for action, reflected in a Call to Action (Appendix S1). The discussion confirmed that persisting barriers do not allow the full realisation of the public health potential of diagnosing and preventing hepatitis B and C, treating hepatitis B and curing hepatitis C. Such barriers are related to (a) lack of evidence-based knowledge of hepatitis B and C, (b) limited access to prevention, diagnosis and treatment services with poor patient pathways, (c) declining resources and (d) the presence of social stigma and discrimination. The discussion also confirmed the emerging importance of fiscal constraints on the ability of policymakers to adequately address viral hepatitis challenges, particularly through increasing coverage of newer therapies. In Europe, it is critical that public policy bodies urgently agree on a conceptual framework for addressing the existing and emerging barriers to managing viral hepatitis. Such a framework would ensure all health systems share a common understanding of definitions and indicators and look to integrate their responses to manage policy spillovers in the most cost-effective manner, while forging wide partnerships to sustainably and successfully address viral hepatitis.

Serum HBsAg kinetics and usefulness of interferon-inducible protein 10 serum in HBeAg-negative chronic hepatitis B patients treated with tenofovir disoproxil fumarate.

The kinetics of serum HBsAg and interferon-inducible protein 10 (IP10) levels in patients with chronic hepatitis B infection treated with tenofovir are unclear. We evaluated the changes of HBsAg levels and the predictability of IP10 for HBsAg decline in 160 HBeAg-negative patients receiving tenofovir for ≥12 months. Serum samples taken before and at 6, 12, 24, 36 and 48 months after tenofovir were tested for HBsAg levels. In 104 patients, serum samples before tenofovir were tested for IP10 levels. Compared to before tenofovir, HBsAg levels decreased by a median of 0.08, 0.11, 0.24, 0.33 and 0.38 log10 IU/mL at 6, 12, 24, 36 and 48 months, respectively (P < 0.001). HBsAg kinetics did not differ between nucleos(t)ide analogue(s) naive and experienced patients. The 12-, 24-, 36- and 48-month cumulative rates of ≥0.5 log10 HBsAg decline were 8%, 16%, 24% and 41% and of HBsAg ≤100 IU/mL were 9%, 12%, 14% and 18%, respectively. The only factor associated with HBsAg ≤100 IU/mL was lower HBsAg levels before tenofovir (P < 0.001), while HBsAg decline ≥0.5 log10 was associated with higher IP10 levels (P = 0.002) and particularly with IP10 > 350 pg/mL (P < 0.001). In conclusion, tenofovir decreases serum HBsAg levels in both nucleos(t)ide analogue(s) naive and experienced patients with HBeAg-negative chronic hepatitis B infection. After 4 years of therapy, HBsAg ≤100 IU/mL can be achieved in approximately 20% of patients, particularly in those with low baseline HBsAg levels. HBsAg decline is slow (≥0.5 log10 in 40% of patients after 4 years) and is associated only with higher baseline serum IP10 levels.

Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Genotype 4 HCV infection is difficult to cure with pegylated interferon and ribavirin. Results from a Greek Nationwide Cohort Study.

BACKGROUND AND AIM: Patients with genotype 4 (G4) chronic hepatitis C (CHC) are considered a difficult to treat population, although current data on G4 treatment responsiveness and duration are controversial. Greece represents a country with an intermediate prevalence of G4 infections, offering an opportunity to compare treatment outcomes by genotype and to identify potential prognostic factors for sustained virologic response (SVR). METHODS: All CHC patients from the HepNet.Greece, an ongoing nationwide cohort study on viral hepatitis, with known hepatitis C virus (HCV) genotype who received treatment with Peg-IFNa and ribavirin were analyzed. RESULTS: From 4443 patients, 951 (61.7% males, 78.4% Greeks, median age 40.6 years, 10% cirrhosis) fulfilled the inclusion criteria. G4 was found in 125 (13.1%) patients. Genotype distribution was not significantly different between Greeks and immigrants. Patients with G4 had similar odds of SVR compared to G1 but significantly lower compared to G2/G3. Age, treatment discontinuation, presence of cirrhosis and previous history of HCV-treatment were associated with lower probabilities of SVR. Ethnicity did not affect SVR for all genotypes while response to treatment was similar between Greek and Egyptian patients groups (35.7% vs 40.9%, p=0.660%) with G4 infection. The relation between SVR and genotype did not substantially change after adjustment for age, gender, cirrhosis, treatment interruption and history of HCV-treatment. CONCLUSIONS: The findings of this large cohort of CHC patients with a well balanced genotype distribution further supports the idea of considering G4 as a difficult to treat genotype. Further investigation is needed to identify genotype specific prognostic factors.

The role of tenofovir in preventing and treating hepatitis B virus (HBV) reactivation in immunosuppressed patients. A real life experience from a tertiary center.

INTRODUCTION/AIM: Patients who present HBV reactivation during immunosuppressive treatment are prone to develop life threatening decompensation of the liver function, therefore prophylaxis and treatment are strongly recommended. So far there are no data regarding the role of tenofovir in this context. Therefore, the aim of our study was to describe our "real life" experience with the use of tenofovir (TDF) in patients who underwent immunosuppressive treatment. RESULTS: 38 patients with immunosuppression received antiviral treatment with tenofovir (25 patients as prophylaxis and 13 patients as treatment of HBV reactivation). In all 25 patients in whom prophylactic treatment with tenofovir was administered no HBV flare occurred during immunosuppression and the levels of serum HBV-DNA became or remained undetectable during the follow up period (mean follow up 17.2 months, range 6-54). One patient experienced HBsAg seroconversion. In the 13 patients who exhibited HBV reactivation TDF treatment resulted in complete biochemical and virological response within 6 months except two patients with high pretreatment HBV-DNA levels who became HBV-DNA negative at 9 months. No exacerbation of liver disease or liver related death has been observed. One patient who presented with decompensated cirrhosis during HBV reactivation returned into a compensated state after treatment. No side effects of tenofovir have been documented. CONCLUSION: Tenofovir seems to be highly effective and safe in the prophylaxis and rescue treatment of HBV reactivation in patients who receive immunosuppression therapy.

The usefulness of transient elastography in the assessment of patients with HBeAg-negative chronic hepatitis B virus infection.

Histological severity is often mandatory for the management of HBeAg-negative chronic HBV patients. We evaluated the performance of transient elastography (TE) in this setting. We included 357 untreated HBeAg-negative patients with ≥ 1 reliable liver stiffness measurement (LSM-kPa) by TE: 182 inactive carriers with HBV-DNA < 2000 (n = 139) or 2000-19 999 IU/mL (n = 43) and 175 patients with chronic hepatitis B (CHB). In carriers, HBV-DNA > 2000 and/or LSM > 6.5 were considered as biopsy indications. LSMs did not differ between carriers with low and high viremia, but were lower in carriers than in patients with CHB (5.8 ± 1.7 vs 9.0 ± 5.6, P < 0.001) offering moderate differentiation between these two groups (AUROC: 0.705). LSMs did not change significantly in carriers after 16 (12-24) months. In carriers with a liver biopsy, Ishak's staging scores were similar between cased with low and high viremia but higher in cases with LSM > 6.5 than ≤ 6.5 kPa. Moderate fibrosis (stages: 2-3) was detected in 0/10 carriers with only HBV-DNA > 2000 IU/mL, 2/10 (20%) carriers with only LSM > 6.5 and 5/10 (50%) carriers with both HBV-DNA > 2000 and LSM > 6.5 (P = 0.009). In patients with CHB, LSMs correlated significantly with grading and staging scores and offered excellent accuracy for ≥ moderate, ≥ severe fibrosis or cirrhosis (AUROC ≥ 0.919-0.950). TE can be helpful for the noninvasive assessment of HBeAg-negative chronic HBV patients. In conclusion, LSMs offer excellent accuracy for fibrosis severity in HBeAg-negative patients with CHB and can identify carriers with high risk of moderate fibrosis, which may be present in up to 35% of carriers with LSM > 6.5 kPa and 50% of carriers with LSM > 6.5 kPa and HBV-DNA > 2000 IU/mL.

Cirrhosis but not neutropenia is associated with the development of infection in patients with chronic hepatitis C undergoing treatment with pegylated interferon-alpha and ribavirin.

Peginterferon-alpha (PegIFNa) frequently causes neutropenia, mainly due to bone marrow suppression. The aim of this study was to explore factors that are associated with infections during antiviral treatment. We analysed data from 275 chronic hepatitis C (CHC) patients with compensated liver disease who underwent 318 courses of PegIFNa and ribavirin. Neutropenia was defined as neutrophils <1000 cells/µL. Mean leucocytes count significantly decreased from baseline to treatment nadir (7081 ± 2182 vs 3293 ± 1331 cells/µL, P < 0.001), while neutropenia was observed in 32% during treatment. Thirty-one infections were observed. The incidence rate for infection was assessed at 1.46 infections per 100 person-months of therapy. The hazard rate for infection did not correlate with the neutrophils' nadir or the decrease in white blood cells. In multivariate Cox's regression analysis, cirrhosis was the only factor that was significantly associated with the occurrence of infection. Our data show that the development of bacterial infections during treatment with PegIFNa and ribavirin in patients with compensated CHC is not associated with reduction or the nadir of white cells or neutrophil counts. Baseline cirrhosis is the only factor related with infection during treatment. The common practice of dose adjustment or discontinuation of interferon should be revised; careful assessment of liver damage before therapy and close monitoring during therapy are essential in all patients receiving interferon-based regimes, to minimize the detrimental consequences of infections.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Significant epidemiological changes in chronic hepatitis C infection: results of the nationwide HEPNET-GREECE cohort study.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection is an important health problem worldwide. The aim of the study is to describe the baseline characteristics and possible epidemiological changes of the patients with chronic HCV infection included in a nationwide Greek study. PATIENTS AND METHODS: two thousand eight hundred seventeen (2817) patients, followed-up at 20 hepatology centres throughout Greece between the years 1997 and 2006 were enrolled in the study. RESULTS: Intravenous drug use (IDU) and history of blood transfusion prior to 1992 was reported in 30.7% and 22.6% of our patients, respectively. In 1865 (66.2%) patients with known genotypes, the distribution for genotype 1, 2, 3 and 4 was 45.1%, 7%, 34% and 13.9% respectively. Genotype 1 was more common in older people, in women (55.9% p<0.001) and patients with transfusion-related hepatitis (61.6% p<0.001). Genotype 3 was more common in younger patients, in men (43% p<0.001) and in IDUs (63.3% p<0.001). A significant reduction of transfusion-related hepatitis C incidence (p<0.001) in conjunction with the proportion of genotype 1 (p<0.001) was observed during the last three decades while an increase in IDU infected patients and genotype 3 was detected. CONCLUSIONS: Our study showed a significant change in HCV genotype distribution and source of HCV infection during the last three decades and under that scope, urgent actions are needed in order to control the spread of HCV infection.

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.

Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.

OBJECTIVES: The aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection. METHODS: 14 patients with chronic HBV infection, 19 HBV-vaccinated patients and 19 patients with resolved HBV infection were included in the study. All HBV-infected patients received combination therapy with oral antivirals and anti-TNF agents. During treatment the levels of hepatitis B surface antibodies (anti-HBs) in HBV-vaccinated patients and of serum HBV DNA in patients with chronic or resolved HBV infection were monitored. RESULTS: No viral reactivation was observed in patients with resolved HBV infection while anti-HBs titres decreased during anti-TNF treatment in vaccinated patients, similarly to patients treated with methotrexate alone. None of the HBV-infected patients developed liver decompensation or a significant increase in alanine aminotransferase levels. One patient (7%) treated with lamivudine and etanercept showed viral reactivation due to the emergence of a lamivudine-resistant mutant strain. CONCLUSIONS: Anti-TNF agents represent a safe option for patients with chronic HBV infection when combined with antiviral therapy, as well as in patients previously exposed to HBV receiving no HBV prophylaxis. Resistant HBV strains may arise in patients with chronic hepatitis B, necessitating the initial use of anti-HBV agents with a low risk of resistance.

Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study.

BACKGROUND: Chronic hepatitis C (CHC) induces insulin resistance (IR) and subsequently diabetes. AIM: To examine viral, metabolic and histological predictors of IR in 275 CHC patients to test the hypothesis that IR differs among HCV genotypes and that viral replication directly affects IR. METHODS: We studied 275 nondiabetic treatment-naïve CHC patients. Histological lesions were evaluated according to Ishak. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: HOMA > 3.0 was found in 37% of patients, independently associated with higher BMI and GGT. In genotype non-3 patients, HOMA > 3.0 was associated with higher BMI and GGT values, while no significant association was noted in genotype 3 patients. In non-obese patients with minimal fibrosis, HOMA > 3.0 was found in 20% of cases without significant differences among genotypes. No association between HOMA > 3.0 and HCV-RNA levels was found. Severe fibrosis (stage 5-6) related to older age (OR:1.048), HOMA-IR (OR:1.177), necroinflammation (OR: 2.990) and higher ALT (OR: 1.009) and GGT (OR:1.006). CONCLUSIONS: IR develops at early stages of CHC without significant differences among genotypes. It is more frequent in obese patients with steatosis and contributes to fibrosis progression. However, IR does not seem to be associated with viraemia and therefore its exact pathogenetic mechanism in CHC remains elusive.

Quantitative detection of the M204V hepatitis B virus minor variants by amplification refractory mutation system real-time PCR combined with molecular beacon technology.

Mutations in the highly conserved tyrosine-methionine-aspartate-aspartate (YMDD) motif are frequently associated with resistance to antivirals and represent a major concern in the treatment of hepatitis B virus (HBV) infection. Conventional methods fail to detect minority populations of drug-resistant viral quasispecies if they represent less than 25% of the total sample virus population. The amplification refractory mutation system real-time PCR (ARMS RT-PCR) was combined with molecular beacon technology using the LightCycler system. The samples from HBV patients selected for assay evaluation included (i) 57 samples from treatment-naïve patients for biological discriminatory ability (cutoff) estimation, (ii) 12 samples from patients with treatment failure that were M204V positive by sequencing, and (iii) 13 samples from patients with treatment failure that were negative for mutation at codon 204 by sequencing. The discriminatory ability of the assay was 0.25% when tested with laboratory-synthesized DNA target sequences. The median mutant-to-wild-type ratio for samples from naive patients tested positive for the wild type and for mutant variants was 0.01% (5th and 95th percentiles = 0.0001 and 0.04%, respectively). A value of 0.04% was selected as the biological cutoff of the assay of clinical samples. In all samples M204V positive by sequencing (12/12), the mutant variant was detected as the predominant population (range, 82.76 to 99.43%). Interestingly, in 5 (38%) of 13 samples negative by sequencing, the M204V variant was detected at a ratio above the biological cutoff (0.05 to 28%). The assay represents an efficient technique for the early detection and quantification of M204V variants before mutant strains emerge to dominate the population.

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. AIM: To investigate the effect of intestinal decontamination on liver haemodynamics in alcohol-related cirrhotic patients with ascites. METHODS: We included 30 patients. At day 0, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed. Patients received rifaximin (1200 mg/day) for 28 days. At day 29, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed again. RESULTS: Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45(0-3.1) vs. 0.7(0-2.7), P < 0.0001] and splanchnic circulation [1.8(0-3.4) vs. 0.8(0-2.1), P < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (P = 0.001) was not noted at day 29 (P = 0.137). HVPG measurement was possible in 28 patients. Median (range) HVPG values were 18 mmHg (12.7-26.3) on day 0 vs. 14.7 mmHg (7-20) on day 29 (P < 0.0001). HVPG decreased after rifaximin in 23, remained stable in two and increased in three patients. CONCLUSION: Hepatic venous pressure gradient values decreased significantly after intestinal decontamination with rifaximin in patients with alcohol-related decompensated cirrhosis and this might have been achieved through significant reduction of plasma endotoxin levels.

Long-term therapy with adefovir dipivoxil in hepatitis B e antigen-negative patients developing resistance to lamivudine.

BACKGROUND: The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation. AIM: To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants. METHODS: Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy. RESULTS: The median follow-up after adefovir's onset was 31 (18-40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <10(4) copies/mL (P > 0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively (P > 0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy (P = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months. CONCLUSION: In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.

Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection.

BACKGROUND AND AIMS: In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early liver injury. An investigation was carried out into whether the serum levels of caspase-generated fragments of cytokeratin-18 (CK-18) are associated with the severity of liver lesions in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection. Patients/ METHODS: CK-18 fragment serum levels were determined in 115 treatment-naive, consecutive HBV patients and 30 healthy controls. Hepatic-expression of CK-18 fragments was evaluated by immunocytochemistry in chronic hepatitis B patients. RESULTS: CK-18 fragment levels (U/l) were significantly lower in healthy controls (mean (SD), 154 (31)) than in 53 inactive carriers (172 (24), p = 0.003) and in 62 chronic hepatitis B patients (474 (488), p<0.001). The receiver operating characteristic curve showed excellent diagnostic accuracy (c-statistic: 0.87) for differentiating inactive carriers from chronic hepatitis B patients. A CK-18 fragment cut-off level of 240 U/l gave a sensitivity of 60%, and a specificity and positive predictive value of 100% for chronic hepatitis B diagnosis. CK-18 fragment levels were also lower in inactive carriers than in 16 chronic hepatitis B patients with transiently normal alanine aminotransferase (ALT; 327 (256), p = 0.001), offering good accuracy for such a differentiation (c-statistic: 0.78). In chronic hepatitis B patients, serum CK-18 fragments correlated positively with ALT/aspartate aminotransferase (AST), viraemia, grading score and their immunohistochemical hepatic expression, and negatively with platelet counts, but not with fibrosis or steatosis severity. CONCLUSIONS: Serum apoptotic caspase activity is strongly associated with the presence of liver injury in patients with HBeAg-negative chronic HBV infection. CK-18 fragment levels seem to be a very useful marker for differentiation between the inactive HBV carrier state and HBeAg-negative chronic hepatitis B, but not for estimation of the severity of liver histological lesions among HBeAg-negative chronic hepatitis B patients.

Clinical trial: The effect of somatostatin vs. octreotide in preventing post-endoscopic increase in hepatic venous pressure gradient in cirrhotics with bleeding varices.

BACKGROUND: Hepatic venous pressure gradient (HVPG) increases significantly after endoscopic therapy in patients with bleeding oesophageal varices, which may precipitate further haemorrhage. Whether vasoactive drugs can suppress these changes remains unknown. AIM: To investigate the efficacy of somatostatin when compared with octreotide in preventing the post-endoscopic increase in HVPG during acute bleeding and whether the changes affect outcome. METHODS: Thirty-three cirrhotics with bleeding varices were randomized to receive somatostatin (n = 17) or octreotide (n = 16) under double-blind conditions, soon after their admission. HVPG measurements were performed before and immediately after endoscopic treatment. RESULTS: In the somatostatin group, postendotherapy HVPG values did not change significantly when compared with pre-treatment values (18.9 vs. 17.2, P = 0.092). Conversely, in the octreotide group, HVPG increased significantly after endoscopy (18.2 vs. 20.8, P = 0.003). The probability of 6-week survival without treatment failure was significantly higher in the somatostatin group (P = 0.024). Post-endoscopic HVPG value was independently associated with 6-week failure. CONCLUSIONS: Somatostatin, but not octreotide, effectively prevents the post-endoscopic increase in HVPG, which may be associated with low probability of treatment failure.

Lamivudine monotherapy in HBeAg-negative chronic hepatitis B: prediction of response-breakthrough and long-term clinical outcome.

BACKGROUND: Factors that predict response and breakthrough phenomenon to lamivudine monotherapy in patients with HBeAg-negative chronic hepatitis B have not been well defined. AIM: To determine pre-treatment and on treatment variables that predict initial response and breakthrough in patients with HBeAg-negative chronic hepatitis B receiving long-term lamivudine. METHODS: Seventy-nine patients, with chronic HBeAg-negative hepatitis B, who received lamivudine for a median of 31 months were included in the study. RESULTS: Initial virologic and biochemical response was observed in 73 (92%) and 70 (89%) patients, respectively, while 34 (47%) and 15 (21%) patients developed virological and biochemical breakthrough, respectively. High levels of necroinflammation in liver biopsy were associated with a higher probability of initial virological and biochemical response. Patients with pre-treatment serum hepatitis B virus DNA concentrations of more than 10(6) copies/mL were three times more likely to develop virologic breakthrough. Two patients died, one with baseline cirrhosis because of liver failure during biochemical breakthrough while the second death was liver and treatment unrelated. CONCLUSIONS: In HBeAg-negative chronic hepatitis B, initial response to lamivudine therapy is associated with necroinflammation, while baseline serum hepatitis B virus DNA exceeding 10(6) copies/mL is a strong predictor for breakthrough because of drug-resistant mutations. Severe complications are uncommon and are associated with biochemical breakthrough and pre-existing cirrhosis.

Primary prophylaxis of variceal bleeding in cirrhotics unable to take beta-blockers: a randomized trial of ligation.

AIM: To compare endoscopic banding ligation vs. no treatment in cirrhotics with intolerance or contraindications to beta-blockers for prevention of first bleeding in portal hypertension. METHODS: A sample size of 214 was planned with all sizes of varices. However, the trial was stopped due to increased bleeding in 52 patients in the ligation group. The baseline severity liver disease and endoscopic features were similar. Ligation group: 25 (M/F = 21/4, mean age: 60 +/- 9.37 years); 27 not-treated group: 27 (M/F = 17/10, mean age: 63 +/- 10.27). RESULTS: The mean follow-up period was 19.5 +/- 13.3 months: five bled in the ligation group (20%), three from varices (two after banding at 11 and 17 days; one during the procedure), and two from gastropathy; two bled in the not-treated group (7%- two both varices) (P = 0.24). There were seven deaths in the ligation group and 11 in the not-treated group (P = 0.39). CONCLUSION: Sixty per cent of the bleeding in the banding group was probably iatrogenic, requiring the study to be stopped. Endoscopic banding ligation was no better than no treatment. This study suggests that ligation may be harmful when used as primary prophylaxis, similar to prophylactic sclerotherapy in the past.