Successful switch to tenofovir after suboptimal response to entecavir in an immunocompromised patient with chronic hepatitis B and without genotypic hepatitis B virus resistance

We report a case of an immunocompromised patient affected by chronic hepatitis B virus (HBV) with high basal HBV viremia (>8 log(10) IU/ml) who failed an entecavir regimen, despite the absence of primary or secondary drug resistance mutations. The patient achieved sustained virological success (serum HBV DNA <12 IU/ml) when tenofovir was added to the treatment. This case highlights the difficulty in choosing an optimal therapy in such specific conditions and supports the concept of tailoring therapy (including combination regimens) on the basis of the particular conditions of each individual patient

Novel HBsAg markers tightly correlate with occult HBV infection and strongly affect HBsAg detection.

Occult HBV infection (OBI) is a threat for the safety of blood-supply, and has been associated with the onset of HBV-related hepatocellular carcinoma and lymphomagenesis. Nevertheless, genetic markers in HBsAg (particularly in D-genotype, the most common in Europe) significantly associated with OBI in vivo are missing. Thus, the goal of this study is to define: (i) prevalence and clinical profile of OBI among blood-donors; (ii) HBsAg-mutations associated with OBI; (iii) their impact on HBsAg-detection. OBI was searched among 422,278 blood-donors screened by Nucleic-Acid-Testing. Following Taormina-OBI-definition, 26 (0.006%) OBI-patients were identified. Despite viremia <50IU/ml, HBsAg-sequences were obtained for 25/26 patients (24/25 genotype-D). OBI-associated mutations were identified by comparing OBI-HBsAg with that of 82 chronically-infected (genotype-D) patients as control. Twenty HBsAg-mutations significantly correlated for the first time with OBI. By structural analysis, they localized in the major HBV B-cell-epitope, and in HBsAg-capsid interaction region. 14/24 OBI-patients (58.8%) carried in median 3 such mutations (IQR:2.0-6.0) against 0 in chronically-infected patients. By co-variation analysis, correlations were observed for R122P+S167L (phi=0.68, P=0.01), T116N+S143L (phi=0.53, P=0.03), and Y100S+S143L (phi=0.67, p<0.001). Mutants (obtained by site-directed mutagenesis) carrying T116N, T116N+S143L, R122P, R122P+Q101R, or R122P+S167L strongly decreased HBsAg-reactivity (54.9±22.6S/CO, 31.2±12.0S/CO, 6.1±2.4S/CO, 3.0±1.0S/CO and 3.9±1.3S/CO, respectively) compared to wild-type (306.8±64.1S/CO). Even more, Y100S and Y100S+S143L supernatants show no detectable-HBsAg (experiments in quadruplicate). In conclusions, unique HBsAg-mutations in genotype-D, different than those described in genotypes B/C (rarely found in western countries), tightly correlate with OBI, and strongly affect HBsAg-detection. By altering HBV-antigenicity and/or viral-particle maturation, they may affect full-reliability of universal diagnostic-assays for HBsAg-detection

Anti-HBV treatment induces novel reverse transcriptase mutations with reflective effect on HBV S antigen

The identification of novel reverse-transcriptase (RT) drug-resistance mutations is critical in predicting the probability of success to anti-HBV treatment. Furthermore, due to HBV-RT/HBsAg gene-overlap, they can have an impact on HBsAg-detection and quantification

Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro

An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation

Clinical and prognostic analysis of hepatitis B virus infection in diffuse large B-cell lymphoma

<p>Abstract</p> <p>Background</p> <p>Hepatitis B virus (HBV) infection in diffuse large B-cell lymphoma (DLBCL) patients is a common complication in China. However, the clinical relevance of HBV infection with respect to DLBCL disease stages and patient survival remains unclear. The main objective of the current study was to analyze the clinical features and to evaluate the prognostic factors of HBV infection in DLBCL patients.</p> <p>Methods</p> <p>In this retrospective study, DLBCL patients were divided into two groups as HBsAg-positive (n = 81) and HBsAg-negative (n = 181) patients. The HBsAg-positive patients were further divided into two subgroups based on their hepatic function during chemotherapy. Various statistical analyses were used to determine the significance of the relevant clinical parameters.</p> <p>Results</p> <p>Compared with the HBsAg-negative group, the HBsAg-positive DLBCL group displayed a younger median onset age (46 year vs 51), more advanced stage at grade III/IV (58% vs 42%, p = 0.016), and more frequent hepatic dysfunction before (21% vs 5.5%, p < 0.001) and during (49.4% vs 16.6%, p < 0.001) chemotherapy. Female DLBCL patients exhibited a higher frequency of HBsAg positivity (p = 0.006). However, in both groups the median overall survival (OS) duration (55.8 vs 66.8 months) and response rates (91% vs 90.4%) were similar. In the HBsAg-positive DLBCL group, the poor prognostic factors were advanced stage (p < 0.001) and hepatic dysfunction during chemotherapy (p = 0.02). The OS of HBsAg-positive patients with hepatic dysfunction during chemotherapy was significantly shorter than those without liver dysfunction (p = 0.016), and the OS rates at 3 years were 48% and 72%, respectively. The use of rituximab did not increase the rates of liver dysfunction in HBsAg-positive DLBCL patients.</p> <p>Conclusion</p> <p>Compared with HBsAg-negative patients, the HBsAg-positive DLBCL patients had earlier onset and more advanced stage. The disease stage and hepatic dysfunction during chemotherapy and were two significant prognostic factors in the HBsAg-positive DLBCL patients. This study suggests that prophylactic treatment of HBV may be of great importance in the cases of HBsAg-positive patients.</p

HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors

Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed whether specific HCV-genotypes are differently prone to develop resistance to linear and macrocyclic protease-inhibitors (PIs)

HBV reactivation with fatal fulminating hepatitis during rituximab treatment in a subject negative for HBsAg and positive for HBsAb and HBcAb

A 51-year-old man who was hepatitis B surface antigen (HBsAg)-negative and positive for anti-hepatitisB surface antigen (anti-HBs) and anti-hepatitis B core antigen (anti-HBc), during rituximab therapy for chronic Lymphocytic leukemia, developed reactivation of hepatitisB virus (HBV) infection with hepatitis that proceededtowards hepatic failure and death in spite of lamivudine therapy. HBsAg remained persistently negative, notwithstanding a high HBV-DNA titer. Our observation, following other cases of fatal reactivation of HBV infection in patients receiving rituximab, suggests that, in all patients with previous markers of HBV infection, lamivudine prophylaxis should be considered during rituximab therapy. © Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2005

Epidemiological burden estimates for pathologies with a non constant risk: an application to HCV in Italy according to age, Metavir score, and genotype

Abstract: Between western European countries, the hepatitis C virus (HCV) endemic is highest in Italy. The main objective of this paper is to estimate the endemic diffusion of hepatitis C at the national level and by geographical area, with an extrapolation at the regional level and by uniform cohorts of subjects (by sex and year of birth). The secondary objective is a stratification by gravity of the estimated statistical figures to provide an overview of possible targets of the new anti-HCV treatments. PubMed and the Cochrane Library were searched for relevant Italian populations studies regarding HCV prevalence. Random and fixed effect models were used for pooling data. To develop the epidemiological model, a meta-analysis of studies of Italian populations and the explicit consideration of the changes in the etiology of the disease in different cohorts (by year of birth) of population and the impact of effective treatments that have been introduced since the 1990s. A Markovian transition model, which is based on the distribution of HCV+ and HCV Ribonucleic Acid (RNA)+ subjects, provides a plausible assessment of the Italian situation. The Meta-analysis of Observational Studies in Epidemiology recommendations/statements were followed. In 2014, 1569,215 HCV+ subjects (95% credible interval [CrI]: 1202,630–2021,261) were estimated in Italy, with a 2.58% prevalence (95% CrI: 1.98%–3.33%). A total of 828,884 HCV RNA+ subjects (95% CrI: 615,892–1081,123), which is equal to a 1.36% prevalence (95% CrI: 1.01%–1.78%), is higher in southern Italy and the islands (1.9%) than in central–northern Italy (1.1%). The predominance of adult and elderly subjects, with an old or very old infection, inevitably entails a significant number of HCV RNA+ subjects in the advanced stages of the illness. According to our estimates, approximately 400,000 subjects have cirrhosis, decompensated cirrhosis, and hepatocarcinoma, with a median age of 70 years. The model aims to support policymakers to define action plans by providing an estimate of both the emerged infected population and nonemerged infected population by age, gender, gravity, genotype, and geographical area. In the future, the model may contribute to simulation of the costs and outcome of different action strategies that can be adopted by health authorities