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International audience; Background & aims: Before antiviral therapy, kidney transplant recipients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) had poor outcomes. Since the 90s, nucleos(t)ide analogues have been widely used in HBV-infected patients, while interferon-based therapy was rarely used in HCV-infected patients. The aim of this study was to assess the impact of HBV and HCV on patient and graft survival, according to viral replication status.Methods: Data from January 1993 to December 2010 were extracted from the French national database CRISTAL. A total of 31,433 kidney transplant recipients were included, of whom 575, 1,060 and 29,798 had chronic hepatitis B, C, or were not infected, respectively.Results: Ten-year survival was lower in HCV-infected (71.3%) than in HBV-infected (81.2%, p = 0.0004) or non-infected kidney transplant recipients (82.7%, p

Current antiviral therapies, such as pegylated interferon-α and nucleos(t)ide analogues, effectively improve the quality of life of patients with chronic hepatitis B. However, they can only control the infection rather than curing infected hepatocytes. Complete HBV cure is hampered by the lack of therapies that can directly affect the viral minichromosome (in the form of covalently closed circular DNA [cccDNA]). Approaches currently under investigation in early clinical trials are aimed at achieving a functional cure, defined as the loss of HBsAg and undetectable HBV DNA levels in serum. However, achieving a complete HBV cure requires therapies that can directly target the cccDNA pool, either via degradation, lethal mutations or functional silencing. In this review, we discuss cutting-edge technologies that could lead to non-cytolytic direct cccDNA targeting and cure of infected hepatocytes.

Background & Aims: There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients.Methods: qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison. Results: qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p

Hepatitis B virus (HBV) infection is still one of the most important causes of liver disease, with 2 billion people infected worldwide and more than 600,000 deaths each year, caused in 94% of cases by chronic infection-related cirrhosis and hepatocellular carcinoma (HCC) [1–3]. The World Health Organization (WHO) estimates more than 360 million persons being chronic carriers worldwide (6% of the world population). The incidence of HBV infection has been declining over the last two decades thanks to the introduction of universal immunization programs and the implementation of blood-donor screening. Nevertheless, a significant number of adults and children are still infected each year, the latter often developing chronic infection and requiring an appropriate follow-up. In spite of a rather benign course of chronic disease during childhood and adolescence, HBV chronic carriers have a lifetime risk of developing HCC up to 25%, and an incidence of cirrhosis of 2–3% per year [4]. Safe and partially effective antiviral therapies are available, but few are licensed for use in children, and an accurate selection of subjects to treat and of the right timing for treatment is needed to optimize efficacy and reduce viral resistance. 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Alpay, Yeşim (Balikesir Author), "Background: Manynoninvasive methods, including aspartateaminotransaminase (AST)/alanineaminotransaminase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), Bonacini cirrhosis discriminant score (CDS), fibrosis-4 (FIB4) index, and age-platelet index (API), have been described to determine the stage of hepatic fibrosis. However, thesemethodsare developed for patients with chronic hepatitisC(CHC) andproduce conflicting results in the prediction of liver fibrosis in patients with chronic hepatitis B (CHB). Objectives: The aim of this study was to evaluate the relationship between 7 noninvasive models, including AAR, APRI, CDS, API, FIB-4, neutrophil-to-lymphocyte ratio (NLR), and red cell distribution width (RDW)-to-platelet ratio (RPR) in patients with CHB. Methods: The study population included all patients with CHB, undergoing liver biopsy to determine HBsAg and HBV DNA positivity in more than 6 months. Results: A total of 2520 treatment-naive CHB patients from 40 different centers were included in the study. In total, 62.6% of the patients were male, and the mean age was 40.60 +/- 12.34 years (minimum, 18 years; maximum, 77 years). The Ishak fibrosis score was >= 3 in 29.8% of the patients, indicating significant fibrosis. The mean API, APRI, CDS, NLR, FIB4, and RPR scores in the noninvasive models were significantly different between the groups with significant and low fibrosis (P < 0.05). All the noninvave models (API, APRI, AAR, CDS, NLR, RPR, and FIB4) were found to be significant in the discrimination of cirrhosis (P < 0.05). In the multiple logistic regression analysis, CDS, albumin, alkaline phosphatase (ALP), total bilirubin, neutrophil count, NLR, mean platelet volume (MPV), and FIB4 were independent indices for cirrhosis. Conclusions: In the present study, the role of noninvasive tests in the prediction of liver fibrosis stage and cirrhosis was evaluated in a large cohort of CHB patients. Overall, noninvasive models are gradually becoming more promising. Accordingly, the need for liver biopsy can be reduced with a combination of noninvasive methods in the future."

A new serological assay to detect antibodies against hepatitis C, based on a recombinant protein (BHC10) which incorporates structural and non-structural viral antigens, was tested in 67 healthy subjects and 409 patients with various forms of liver disease. Results were compared with the current assay based on the recombinant non-structural viral antigen c100 and with the recently introduced second-generation assay, Ortho2. None of the healthy subjects was positive by any of the assays. In patients with chronic non-A, non-B hepatitis the prevalence of anti-BHC10 was 96.8%, higher than anti-c100 (83.3%, p less than 0.001) and similar to Ortho2 (94.3%). False-positive results were less frequently found when BHC10 was used. These findings show that assays incorporating structural and non-structural antigens provide higher sensitivity to detect hepatitis C virus infection and they define an almost exclusive role of hepatitis C virus in the genesis of chronic non-A, non-B hepatitis.

In a multicentre trial, 82 patients known to be hepatitis B e antigen and hepatitis B virus DNA positive for at least 1 year, with elevated serum alanine aminotransferase levels and chronic liver lesions on biopsy, were randomized to receive either recombinant interferon alfa-2a at a dose of 4.5 million units thrice weekly for 4 months or no treatment. At the end of therapy, viral DNA clearance and aminotransferase normalization were significantly (p less than 0.05) more frequent in treated patients than in controls. After 16 months' follow up, the difference was still significant for hepatitis B e antigen clearance and transaminase normalization. Hepatitis B virus DNA reactivation was observed during follow up in 43% of treated patients and 50% of controls. Improvements in liver inflammation were observed in patients on interferon. High pre-treatment serum aminotransferase levels, female sex and a low score for fibrosis in the initial biopsy were predictive factors significantly (p less than 0.05) associated with termination of hepatitis B virus replication in treated cases. These results indicate that interferon is effective in inducing clearance of HBV from serum and improvement of biochemical and histological parameters of liver disease. However, a more prolonged regimen of therapy may be required to obtain stable suppression of hepatitis B virus replication.

Asia comprises more than 40 countries encompassing a wide geographic area with a very large population. Many of these countries have low-income economies together with high endemicity of chronic hepatitis B virus (HBV) infection, which is usually acquired perinatally or during early childhood. The well elucidated natural history of chronic HBV infection, together with the extensive research and the longest experience in the use of therapeutic agents in Asia have provided a great opportunity for Asian patients to benefit from recent advancements. However, treatment of chronic HBV infection is a complex task that requires individualized assessment, thus representing a great challenge for general physicians. The inherent problems of the drugs currently available, together with a lack of awareness of the disease among patients, government, and healthcare practitioners are obstacles to proper management of HBV. The most critical challenge and obstacle is the high cost of medical care and antiviral drugs. Lack of adequate reimbursement for treatment and diagnostic testing makes adherence to treatment guidelines impossible. Hence lamivudine is still widely used in Asia. To address these challenges, the ongoing awareness campaigns, active screening programs, educational activities are needed but must be enhanced. Cost-cutting measures and international support are essential to improve the difficult situation in this part of the world.

Chronic hepatitis B viral (HBV) infection remains a serious public health problem worldwide, as more than two billion people have been infected and 350 million are chronically infected [1,2]. Chronicity rates vary based on routes of exposure, with a chronicity rate of 5% in adult acquisition versus 90% in newborns [3]. 15–40% of chronically infected patients will develop adverse sequelae including cirrhosis, hepatic decompensation, and hepatocellular carcinoma [4–6]. Hepatocellular carcinoma (HCC), a potentially serious late complication of HBV infection, is now the fifth most common malignancy worldwide, especially in Asia and Africa [7,8]. The risk of developing HCC in patients with cirrhosis due to chronic HBV is about 1.5% per year [8,9]. Although HCC is more common in the setting of cirrhosis, with data showing that approximately 75% of HCC cases occur in patients with cirrhosis, cirrhosis may not necessarily precede HCC in HBV-infected people [10]. Zaman et al. in their study of 448 patients with HBV-associated HCC identified that in 70% of cases, HCC was diagnosed before cirrhosis was recognized [8,10]. As the prognosis of patients with late stage HCC is often grim, earlier detection of small tumors o3ers the potential for curative therapy. Hence, screening of high-risk populations has been recommended and various strategies have been advocated in an effort to identify and e3ectively treat early HCC and improve overall mortality. In addition to proper screening, identification of risk factors for the development of HCC plays an important role in prevention. As the global burden of HBV infection is enormous, it is virtually impossible to screen all infected patients for HCC. Therefore, the identification of risk factors, target populations, and predictive models are needed to help focus screening to the infected population that is most at risk for the development of HCC. In this issue of the Journal of Hepatology, Yuen et al. [11] attempt not only to identify the risk factors for HCC in patients with HBV, but also to develop a predictive risk score for patients at high risk for development of HCC. In this longitudinal study over a period of 10 years, 820 treatment naive patients with chronic HBV were followed at a liver clinic at Queen Mary’s Hospital in Hong Kong. These patients were followed every 3–6 months, and were monitored with HBV serology, liver biochemistry, and alpha-fetoprotein. Patents underwent radiologic imaging only if AFP levels were greater than 20 ng/mL. The primary endpoint was a diagnosis of HCC by either a positive histology or elevated AFP levels with imaging compatible with HCC. Of the 820 patients followed, 40 (4.9%) developed hepatocellular carcinoma. After analysis of the collected data, Yuen et al. [11] identified various virological and host risk factors for the development of HCC. In univariate analysis, male gender, older age, higher HBV DNA levels, presence of core promoter mutations, ALT >0.5 X ULN, and pre-existing cirrhosis were significant risk factors for the development of HCC. Of the other indices, such as comparing genotype B and C, precore and wild-type mutations, HBeAg/anti-HBe status on presentation, and HBeAg/anti-HBe seroconversion, no difference in the risk of HCC was found. Combining these data in a multivariable Cox Regression model, male gender (HR 2.98), increasing age (HR 1.07), higher HBV DNA levels (HR 1.28), core promoter mutations (HR 3.66), and presence of cirrhosis (HR 7.31) were independently associated with the development of HCC. With these independent associations, Yuen et al. [11] then created a predictive scoring system for the development of HCC by using a logistic regression equation including gender, age, HBV DNA, cirrhosis, and core promoter mutation. This scoring system, the “Guide with Age, Gender, HBV DNA, Core promoter mutations and Cirrhosis” (GAGHCC), attempts to predict the 5- and 10-year risk of development of HCC. The optimal cut-off of the HCC score for the prediction of 5- and 10-year development of HCC is 101, and once this threshold is reached, the risk increases exponentially. As core promoter mutations are not typically analyzed in clinical practice, Yuen et al. [11] then reformulated, tested, and had similar results in this predictive scoring system without the use of core promoter mutations. As HBV and HCC are major global problems, early identification of high-risk populations with the utilization of a validated scoring system allows for significant streamlining of screening modalities. However in this study, there were only 40 cases of HCC. Thus Yuen et al. [11] may have oversaturated their regression model with the analysis of six variables. Additionally, the authors validated the GAGHCC predictive score by performing the leave-one-out cross validation analysis. This method, although mathematically sound, is still not as effective as validation in another cohort of patients. Hence, further validation needs to be performed on other populations, including both high-risk and low-risk patients. It is reassuring that the risk factors identified by Yuen et al. [11] have been shown in other studies to be associated with HCC. Interestingly, HBeAg status and HBV genotype were not found to be significantly associated with HCC in their model. In contrast to these results, Yang et al. in a prospective population-based study following 11,893 men for the development of hepatocellular carcinoma reached different conclusions [12]. They identi-fied that the incident rate of HCC was approximately 3-fold higher in individuals who were positive for both HBsAg and HBeAg, as compared to men who were positive for HBsAg and negative for HBeAg [12]. Yuen et al. [11] also found no difference in the cumulative risk of HCC when comparing patients with genotype B or C. Previous studies suggested a difference in HCC risk based on genotypes. In a prospective cohort study of 1006 patients in Hong Kong, where 86 developed HCC, genotype C was independently associated with a higher risk of HCC than genotype B (HR:3.83; 95% CI, 2.15 to 6.81; P < .0001) [13]. In the current paper, Yuen et al. [11] made the argument that as basal core promoter (BCP) mutations are more common in genotype C, it is the BCP mutation that is the actual risk factor for HCC rather than genotype. However, in another study controlling for BCP status, Yang et al. showed that genotype C was an independent risk factor for HCC [14]. As genotyping and mutation analysis become more available, this issue will need to be clarified. Yuen et al. [11] derived this scoring system from a cohort of Chinese patients in a hospital liver clinic, which could contribute to a selection bias. As the incidence of HCC differs by race [3,15], it is unclear if this scoring system will be applicable to the non-Asian population. Clearly, future validation studies are needed in patients from different regions and other ethnicities. With validation, this “GAGHCC” scoring system may become a helpful screening tool. In the past two decades, we have made great strides in addressing chronic HBV infection as a global health problem. The success of HBV vaccination in various parts of the world has reduced the prevalence of infection, and ultimately, hepatocellular carcinoma [16]. However, much work is still needed in this field, as there is a huge demand for HCC surveillance. The ability for risk stratification of patients with HBV in predicting HCC not only addresses important public health issues, but also provides a rationale for resource allocation in health care. Yuen et al. [11] have attempted to consolidate the work of many in an effort to “push the envelope” even further. After identification of various independent risk factors for the development of HCC in the setting of chronic HBV, they introduce a novel predictive scoring system for the development of HCC. This scoring system combines each of the individual risk factors together to obtain an estimate of the overall risk for an individual patient. The future of the fight against chronic HBV and HCC appears to be a bright one, as the field of medicine continues to evolve. The move towards genomic medicine with the application of genome wide association studies will hopefully identify genetic factors that predispose HBV patients to the development HCC. The combination of genetic information in conjunction with a validated predictive scoring system based on various clinical parameters may promise a more personalized approach to medicine, ultimately leading to improved patient care.