Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe.

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week.

Evaluation of portal hypertension in the cirrhotic patient: hepatic vein pressure gradient and beyond.

Portal hypertension (PH) is a major complication of liver cirrhosis, as it predisposes to the development of serious clinical manifestations such as ascites, hepatic encephalopathy and variceal bleeding. Till now, the measurement of hepatic vein pressure gradient (HVPG) is the gold standard method to ascertain the presence and significance of PH, as many studies have shown its correlation with the appearance of varices and the possibility of variceal bleeding. However, the invasiveness of this procedure makes it difficult to be used in daily clinical practice. Several noninvasive methods with adequate capability of evaluating liver fibrosis, including elastographic techniques, are currently used as alternatives to HVPG in order to assess the presence and the severity of PH. The aim of this paper is to express an overview of the literature about the actual role of HVPG and all available noninvasive tests on the prediction of development of PH complications, to highlight their advantages and their potential limitations, and to provide the latest trends on clinical practice.

Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis B in the UK: systematic review and economic evaluation.

We compared the cost-effectiveness of various noninvasive tests (NITs) in patients with chronic hepatitis B and elevated transaminases and/or viral load who would normally undergo liver biopsy to inform treatment decisions. We searched various databases until April 2012. We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes quality-adjusted-life-years (QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four decision-making strategies: testing with NITs and treating patients with fibrosis stage ≥F2, testing with liver biopsy and treating patients with ≥F2, treat none (watchful waiting) and treat all irrespective of fibrosis. Treating all patients without prior fibrosis assessment had an incremental cost-effectiveness ratio (ICER) of £28,137 per additional QALY gained for HBeAg-negative patients. For HBeAg-positive patients, using Fibroscan was the most cost-effective option with an ICER of £23,345. The base case results remained robust in the majority of sensitivity analyses, but were sensitive to changes in the ≥ F2 prevalence and the benefit of treatment in patients with F0-F1. For HBeAg-negative patients, strategies excluding NITs were the most cost-effective: treating all patients regardless of fibrosis level if the high cost-effectiveness threshold of £30,000 is accepted; watchful waiting if not. For HBeAg-positive patients, using Fibroscan to identify and treat those with ≥F2 was the most cost-effective option.

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.

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.

High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review.

The combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues [NA(s)] is considered as the standard of care for prophylaxis against HBV recurrence after liver transplantation (LT), but the optimal protocol is controversial. We evaluated the efficacy of the newer NAs with high genetic barrier (hgbNA) [i.e. entecavir (ETV) or tenofovir (TDF)] with or without HBIG as prophylaxis against HBV recurrence after LT. In total, 519 HBV liver transplant recipients from 17 studies met the inclusion criteria and they were compared to those under lamivudine (LAM) and HBIG who had been selected in our previous review. Patients under HBIG and LAM developed HBV recurrence (115/1889 or 6.1%): (a) significantly more frequently compared to patients under HBIG and a hgbNA [1.0% (3/303), p < 0.001], and (b) numerically but not significantly more frequently compared to the patients who received a newer NA after discontinuation of HBIG [3.9% (4/102), p = 0.52]. The use of a hgbNA without any HBIG offered similar antiviral prophylaxis compared to HBIG and LAM combination, if the definition of HBV recurrence was based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11]. Our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence after LT.

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 hepcidin levels are related to the severity of liver histological lesions in chronic hepatitis C.

Hepcidin is synthesized in the liver and has a crucial role in iron homoeostasis. Its synthesis is up-regulated in chronic inflammation and iron excess. We examined the determinants of serum hepcidin and liver hepcidin mRNA levels and their association with histological lesions in patients with chronic hepatitis C (CHC) and healthy controls. We studied 96 patients with CHC and 30 controls. Serum hepcidin levels were measured by an in-house competitive ELISA. Hepcidin mRNA levels were determined by a one-step qRT-PCR in total RNA extracted from liver biopsy specimens of 27 patients with CHC and six disease controls. Histological lesions were evaluated according to Ishak's classification. Serum hepcidin was significantly lower in patients with CHC than healthy controls (14.6 ± 7.3 vs 34.6 ± 17.3 ng/mL, P < 0.001). In patients with CHC, serum hepcidin correlated positively with aspartate aminotransferase (r = 0.334, P = 0.001) and insulin resistance (r = 0.27, P = 0.016) and had a trend for correlation with alanine aminotransferase (r = 0.197, P = 0.057) and serum haemoglobin (r = 0.188, P = 0.067) but not with ferritin. A significant positive correlation was also found between serum hepcidin levels and both necroinflammation (r = 0.259, P = 0.011) and fibrosis (r = 0.214, P = 0.036). Serum hepcidin was among others an independent predictor of cirrhosis (odds ratio: 1.145, P = 0.039). Liver hepcidin mRNA levels did not differ between patients and controls and were relatively lower in patients with than without cirrhosis (19.3 ± 21.7 vs 38.3 ± 26.0, P = 0.067). Patients with CHC have reduced serum hepcidin levels, which correlate with worse necroinflammation and fibrosis. The previously mentioned observations suggest a viral effect on hepatic hepcidin production, but might also support its involvement in the inflammatory process.

Prevalence of glucose intolerance in patients with chronic hepatitis B or C: a prospective case-control study.

Despite several studies, the association of glucose intolerance with chronic hepatitis B (CHB) or C (CHC) virus infection remains controversial. We evaluated the prevalence of glucose intolerance by oral glucose tolerance test (OGTT) in patients with CHB or CHC in comparison with matched controls. In total, 189 consecutive outpatients with CHB or CHC and 189 subjects individually matched for age, sex and body mass index (BMI) were included. OGTT was performed in all cases, except in known diabetics, and glucose intolerance was defined as impaired glucose tolerance (IGT), OGTT-diabetes or known diabetes. Most patients with abnormal OGTT had normal fasting glucose (IGT: 69.8%, OGTT-diabetes: 54.5%). Compared with their own controls, CHB patients had a higher prevalence of IGT (13.6% vs 2.5%, P = 0.018) and family history of diabetes (34.6% vs 16.0%, P = 0.011), while CHC patents had higher prevalence of glucose intolerance (37.0% vs 15.7%, Rho = 0.001), mostly because of more frequent IGT (21.3% vs 6.5%, Rho = 0.003). After age and BMI adjustment, patients with CHC compared with those with CHB had significantly higher prevalence of glucose intolerance (37.0% vs 29.6%, P = 0.037). In conclusion, increased prevalence of glucose intolerance is documented by OGTT both in CHC and CHB patients compared with age, sex and BMI matched controls. Glucose intolerance is more frequent in CHC than CHB patients, regardless of known risk factors. An OGTT might be necessary at the baseline work-up of CHB or CHC patients, as a normal fasting glucose value does not exclude IGT or OGTT-diabetes.

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.

Longitudinal changes in serum HBV DNA levels and predictors of progression during the natural course of HBeAg-negative chronic hepatitis B virus infection.

We evaluated the longitudinal changes of viraemia and predictors of progression in a prospectively followed cohort of 150 untreated patients with HBeAg-negative chronic hepatitis B virus (HBV) infection. According to the first year of follow-up, 85 patients were classified into inactive carrier state and 65 into chronic hepatitis B (CHB). Serum HBV DNA levels were determined at baseline in all patients, at year-1 in carriers or last pretherapy visit in CHB patients and during alanine aminotransferase (ALT) elevations in carriers progressing to CHB. HBV DNA levels at any occasion were > or =80, > or =2000 or > or =20 000 IU/mL in 81%, 23% or 0% of carriers and 100%, 95% or 83% of CHB patients. The cumulative progression rate from carrier to CHB was 11%, 16%, 24% at 2-, 3-, 4 years and was independently associated with higher baseline ALT (always within traditional normal range) and baseline HBV DNA > or =2000 or > or =5000 IU/mL. In 12 carriers progressed to CHB, HBV DNA increased by >1 log(10) IU/mL. During 7.5 months of median follow-up, HBV DNA change > or =1 log(10) IU/mL was observed in 49% of CHB patients. In conclusion, serum HBV DNA levels are detectable in the majority of inactive HBV carriers exceeding 2000 IU/mL in only 23% and 20 000 IU/mL in none of them. Carriers have approximately 15% 3-year risk of progression to CHB, which is associated with higher baseline ALT and viraemia > or =2000-5000 IU/mL, and thus should be closely followed. Approximately 20% of HBeAg-negative CHB patients have HBV DNA <20 000 IU/mL with fluctuations >1 log(10) occurring in many of them.

A baseline tool for predicting response to peginterferon alfa-2a in HBeAg-positive patients with chronic hepatitis B.

BACKGROUND: Peginterferon induces off-treatment responses in approximately one-third of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. AIM: To develop an easy-to-use baseline prediction score to identify hepatitis B virus (HBV) genotype B-/C-infected HBeAg-positive Asian patients likely to respond to peginterferon alfa-2a. METHODS: Generalised additive models, multiple logistic regression (MLR) analysis and internal validation methods were applied to data from 647 HBeAg-positive patients from China, Hong Kong and Taiwan to develop a scoring system to predict response 24 weeks after completing a 48-week course of peginterferon alfa-2a. RESULTS: Five baseline factors (age, sex, alanine aminotransferase ratio, hepatitis B surface antigen (HBsAg) level and HBV DNA level) were retained in the final MLR for HBeAg seroconversion and used to develop a scoring system from 0 to 7. Among patients with scores of 0-1, 2-3, 4 or ≥5, HBeAg seroconversion was achieved in 6.4% (6/94), 23.0% (61/265), 36.4% (67/184) and 54.8% (57/104), respectively, and a combined response (HBeAg seroconversion plus HBV DNA <2000 IU/mL) in 5.3% (5/94), 12.8% (34/265), 25.0% (46/184) and 36.5% (38/104), respectively. Among patients with scores of 0-1, 2-3, 4 or ≥5, 57.0% (53/93), 12.3% (31/253), 3.4% (6/178) and 1.0% (1/100) had HBsAg ≥20 000 IU/mL at treatment Week 12; only 3/91 (3.3%) with HBsAg ≥20 000 IU/mL experienced a combined response at 24 weeks post-treatment (negative predictive value = 97% [88/91]). CONCLUSION: A pre-treatment scoring system using readily available baseline characteristics identifies HBeAg-positive Asian patients likely to experience sustained HBeAg seroconversion after treatment with peginterferon alfa-2a.

Prophylactic and therapeutic use of recombinant activated factor VII in patients with cirrhosis and coagulation impairment.

Patients with cirrhosis and impaired coagulation often pose major therapeutic problems during bleeding episodes or invasive procedures. Recombinant activated factor VII (rFVIIa), which has been licensed for the treatment of haemophilia patients with factor VIII or IX inhibitors, has been occasionally used in cirrhotic patients. We present five patients with cirrhosis and coagulopathy who received 1-4 recombinant activated factor VII infusions either prophylactically in order to safely undergo an invasive procedure or therapeutically in order to control a severe bleeding episode which did not respond to standard supportive care. In particular, recombinant activated factor VII infusions were given in two patients before a percutaneous liver biopsy, in one patient before teeth extraction and in two patients with haemoperitoneum after an invasive procedure. Infusions of recombinant activated factor VII achieved rapid correction of prothrombin time in all cases allowing the safe performance of invasive procedures or resulting in efficient control of the bleeding episode. In conclusion, recombinant activated factor VII seems to be a rather promising agent for the prevention or treatment of complications of haemostasis impairment in cirrhotic patients. However, its exact role in this setting needs to be evaluated within well-designed, controlled clinical trials.

Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C.

BACKGROUND/AIMS: Hepatic steatosis has not been adequately studied in chronic hepatitis B, while it is considered to be a cardinal feature in chronic hepatitis C and to be mainly metabolically induced in patients infected with genotype 1. We investigated the prevalence of and the parameters associated with steatosis in HBeAg-negative chronic hepatitis B. METHODS: We studied 213 patients with HBeAg-negative chronic hepatitis B and compared them with 163 patients with genotype-1 chronic hepatitis C. Steatosis was semi-quantitatively graded. RESULTS: Steatosis was significantly less frequent in chronic hepatitis B than chronic hepatitis C (60% versus 72%, P=0.016), but there was no difference in the prevalence of moderate/severe steatosis. In chronic hepatitis B, steatosis was associated only with higher body mass index (P=0.002), while moderate/severe steatosis was associated only with higher body mass index (P=0.043) and diabetes (P=0.031). Steatosis was relatively less frequent in chronic hepatitis B than chronic hepatitis C non-diabetic, normal-weight patients (45.6% versus 62.5%, P=0.063), but it did not differ in diabetic and/or overweight/obese patients with chronic hepatitis B or chronic hepatitis C. CONCLUSIONS: Hepatic steatosis in HBeAg-negative chronic hepatitis B (a) is less frequent than in genotype-1 chronic hepatitis C, (b) is mainly associated with presence of host metabolic factors, such as high body mass index and diabetes and (c) does not seem to be associated with the severity of liver histological lesions.

The Bcl-2/Bax system and apoptosis in ulcerative colitis.

BACKGROUND/AIMS: Ulcerative colitis (UC) constitutes a chronic inflammatory process of the colon of unknown etiology. Current data support a pivotal role of apoptosis in the evolution of pathogenesis of UC. We performed a prospective study in order to determine the role of Bcl-2, Bax and Bcl-x in the apoptotic pathway in UC. METHODOLOGY: We included 23 patients with UC and 11 controls. Histological severity of the disease was assessed according to the Sidney classification system. Patients in the UC group were divided in 2 groups according to histological severity of the disease. The TUNEL method was used for the in situ evaluation of apoptosis. Immunohistochemical staining was used for the detection of Bax, Bcl-2, Bcl-x. For the assessment of cellular proliferation we used the monoclonal antibody Ki67. Appropriate statistical methods were applied. RESULTS: Overall 77 specimens were assessed; 57 from UC patients and 20 from controls. Bcl-2, Bax and Bcl-x were upregulated in the group of patients with UC compared to controls. Nevertheless, Bax in epithelial cells and Bcl-x in lymphocytes were downregulated in patients with moderate/severe disease (p = 0.029 and 0.04 respectively). A weak correlation between epithelial apoptosis and Bcl-x expression in lymphocytes (r = 0.31, p = 0.02) was found. An even weaker correlation was also noticed between the epithelial component apoptosis and Bax in lymphocytes (r = 0.02, p = 0.07). CONCLUSIONS: Bcl-2/Bax system does not appear to be involved in the induction of apoptosis in UC. Activation of intraepithelial lymphocytes may be associated with epithelial apoptosis or simply represent epiphenomena related to the inflammatory process.

Hippocratic views in the treatment of rectal prolapse.

Known since antiquity, rectal prolapse was first studied systematically by Hippocrates (460-377 BC) who recognized the predisposing factors and proposed several therapeutic approaches such as defecation positions, manual retraction and specific herbal or mineral based anti-haemorrhagic and pain-killing poultices. Hippocratic medicine avoided invasive surgical procedures probably due to a lack of knowledge in human anatomy. However, Hippocrates' views astonishingly lasted in time, presenting similarities to current medical theories on rectal prolapse.

A partially overlapping treatment course with lamivudine and interferon in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHBe-) with interferon or lamivudine alone is inefficient and reports of combination treatment with both drugs, equivocal so far. AIM: To investigate the efficacy of a lamivudine-interferon combination therapy in 36 patients HBeAg-negative CHBe-. METHODS: Lamivudine was administered from 1 to 12 months and interferon-alpha2b from 7 to 18 months. A historical control group of 36 CHBe- patients, matched for age and sex and treated with the same dosage of interferon-alpha2b was used. All patients were followed up for > or =12-month post-treatment. RESULTS: The biochemical response rate at the end of treatment was 78% in lamivudine-interferon and 52.8% in interferon-control group (P = 0.026) and at 12-month post-treatment 38.9% and 22.2%, respectively (P = 0.125). Alanine aminotransferase normalization and serum HBV-DNA levels < or =30 000 cp/mL were observed in 50.0% of lamivudine-interferon-treated and 30.6% of interferon-treated patients at the end of treatment (P =0.093) and in 22.2% and 13.9% of patients, respectively, at 12-month post-treatment (P = 0.358). Moreover, alanine aminotransferase normalization and undetectable serum HBV-DNA (<400 cp/mL) was observed in 30.6% of lamivudine-interferon-treated and 8.3% of interferon-treated patients at the end of treatment (P = 0.017) and in 8.3% and 0% of patients, respectively, at 12-month post-treatment (P = 0.076). CONCLUSIONS: In CHBe-, 12 months after ending a lamivudine-interferon partially overlapping 18-month combination course, 22% of patients still maintain normal alanine aminotransferase and HBV-DNA levels < or =30 000 cp/mL. However, a 12-month interferon monotherapy course may achieve similar responses.

Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis?

BACKGROUND: Prognosis in cirrhotic patients has had a resurgence of interest because of liver transplantation and new therapies for complications of end-stage cirrhosis. The model for end-stage liver disease score is now used for allocation in liver transplantation waiting lists, replacing Child-Turcotte-Pugh score. However, there is debate as whether it is better in other settings of cirrhosis. AIM: To review studies comparing the accuracy of model for end-stage liver disease score vs. Child-Turcotte-Pugh score in non-transplant settings. RESULTS: Transjugular intrahepatic portosystemic shunt studies (with 1360 cirrhotics) only one of five, showed model for end-stage liver disease to be superior to Child-Turcotte-Pugh to predict 3-month mortality, but not for 12-month mortality. Prognosis of cirrhosis studies (with 2569 patients) none of four showed significant differences between the two scores for either short- or long-term prognosis whereas no differences for variceal bleeding studies (with 411 cirrhotics). Modified Child-Turcotte-Pugh score, by adding creatinine, performed similarly to model for end-stage liver disease score. Hepatic encephalopathy and hyponatraemia (as an index of ascites), both components of Child-Turcotte-Pugh score, add to the prognostic performance of model for end-stage liver disease score. CONCLUSIONS: Based on current literature, model for end-stage liver disease score does not perform better than Child-Turcotte-Pugh score in non-transplant settings. Modified Child-Turcotte-Pugh and model for end-stage liver disease scores need further evaluation.

Mycophenolate mofetil monotherapy in stable liver transplant patients with cyclosporine-induced renal impairment: a preliminary report.

BACKGROUND: Cyclosporine is the most common maintenance immunosuppressant in liver transplants patients, but it is often associated with nephrotoxicity. METHODS: We evaluated the safety and efficacy of monotherapy with mycophenolate mofetil (1 g twice daily) in five stable liver transplant patients with cyclosporine-induced renal impairment despite reduction of cyclosporine to subtherapeutic levels. Follow-up was 8.4+/-2.4 (range: 6-12) months. RESULTS: No major side effects have been observed to date. Serum creatinine levels were significantly reduced from a median of 201 micromol/L before to 142 micromol/L at 3 months after mycophenolate (P=0.04) and remained low at 6 months. New onset cellular rejection occurred in only one patient after 3 months on mycophenolate monotherapy, and it responded completely to an intravenous course of methylprednisolone. CONCLUSIONS: Monotherapy with mycophenolate mofetil in a dose of 1 g twice daily seems to significantly improve cyclosporine-induced renal impairment in stable liver transplant patients without major side effects or significant risk of rejection.

The role of different immunosuppression in the long-term histological outcome of HCV reinfection after liver transplantation for HCV cirrhosis.

BACKGROUND: The effect of the type of immunosuppression on the course of posttransplant hepatitis C virus (HCV) infection is unclear. The aim of this study was to evaluate the histological outcome of posttransplant HCV infection with respect to initial immunosuppressive therapy in a cohort of 59 of 65 HCV positive transplant patients who survived at least 12 months. METHODS: Initial immunosuppressive therapy was triple (cyclosporine or tacrolimus and azathioprine and prednisolone) in 41, double (cyclosporine and prednisolone) in 5, and single (cyclosporine or tacrolimus) in 13 patients. There was blinded histological evaluation, based on necroinflammatory activity (grading score:0-18) and fibrosis (staging score: 0-6). The median histological follow-up was 36 (12-72) months. RESULTS: In the last liver biopsy, high necroinflammatory activity indicating chronic hepatitis (grading score > or =4) was found in 42 (71%) and severe fibrosis or cirrhosis (staging score > or =4) in 18 (30.5%) patients. High necroinflammatory activity was associated significantly with absence of pretransplant alcohol abuse (P=0.01) and relatively with occurrence of posttransplant acute lobular hepatitis C (P=0.055). Development of severe fibrosis or cirrhosis was significantly associated only with the type of initial immunosuppressive therapy. In particular, severe fibrosis or cirrhosis developed significantly more frequently in patients treated with triple or double (17/46 or 37%) than with single initial immunosuppressive therapy (1/13 or 7.7%) (adjusted for biopsy time: P=0.045). CONCLUSIONS: Severe fibrosis or cirrhosis appears to develop in 30% of HCV transplant patients in a median of 3 years and to be associated with heavier initial immunosuppression.