Emilia Hadziyannis

Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.

BACKGROUND & AIMS Little is known about the biochemical and virological effects of stopping long-term nucleos(t)ide analogue therapy for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB). METHODS We performed a cohort observational study, following 33 HBeAg-negative patients with CHB, undetectable serum HBV DNA, and normal levels of aminotransferases after long-term (4 or 5 years) treatment with adefovir dipivoxil (ADV). All patients were followed for 5.5 years; follow-up visits included measurements of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and HBV DNA monthly for the first 6 months and every 3-6 months thereafter. Various factors were measured at baseline, the end of treatment (EOT), and following treatment to identify those associated with clearance of HBsAg. RESULTS During the first few months of the postdiscontinuation period, all patients experienced virological and 25 (76%) had biochemical relapse. During the follow-up period, 18 patients (55%) who had discontinued antiviral therapy achieved sustained response (HBV DNA level <2000 IU/L, persistently normal level of ALT). Among these, 13 (72%) cleared HBsAg. Fifteen patients (45%) with virological and/or biochemical relapse were re-treated with oral antiviral agents (11 during the first 18 months and 4 after the third year), without evidence of liver decompensation; only 1 lost HBsAg (6%). Higher pretreatment and EOT levels of ALT, no previous treatment with interferon, and lower level of HBsAg at the EOT were significantly associated with HBsAg clearance based on multivariate analysis. CONCLUSIONS In HBeAg-negative patients with CHB, it is safe and effective to discontinue ADV therapy after 4 or 5 years; 55% of patients have sustained responses, and 39% of patients lose HBsAg.

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.

Frequent conversion of tuberculosis screening tests during anti-tumour necrosis factor therapy in patients with rheumatic diseases

Objectives To determine the rate of tuberculosis (TB) screening test conversion during anti-tumour necrosis factor (TNF) therapy in rheumatic patients with negative baseline screening. Methods This was a prospective study of rheumatic patients with negative baseline TB screening (tuberculin skin test (TST): <5 mm, and negative T-SPOT.TB, QuantiFERON-TB Gold In Tube (QFT-GIT) and chest X-ray) treated with anti-TNF agents. All patients underwent re-screening for TB with all assays 1 year later. Factors associated with TB test conversion were analysed and compared between ‘converters’ and ‘non-converters’. Results Seventy patients (mean age 50.6±15.5 years) with rheumatic disease (33 with rheumatoid arthritis, 33 with spondyloarthropathies and 4 with other conditions) were enrolled. Patients were treated with different anti-TNFs (27 with adalimumab, 14 etanercept, 16 infliximab, 8 golimumab, 5 certolizumab pegol) for 1 year. Twenty patients (29%) displayed conversion of at least one screening assay 12 months after anti-TNF therapy: conversion of TST occurred in 9 (13%), T-SPOT.TB in 7 (10%) and QFT-GIT in 5 (7%). Only one patient had concomitant conversion of more than one screening test. Univariate and multivariate analysis revealed that only infliximab was associated with a decreased rate of TB screening assay conversion (OR 0.048, 95% CI 0.004 to 0.606, p=0.017). No patient (40% received isoniazid therapy) developed active TB during follow-up (27±12 months). Conclusions Approximately one third of patients with negative baseline TB screening develop conversion of at least one screening test during anti-TNF treatment. These findings should be considered when designing re-screening strategies and contemplating latent TB therapy.

The natural course of chronic hepatitis B virus infection and its management.

Chronic infection with the hepatitis B virus (HBV) runs a long natural course during which underlying changes in liver histology can progress to cirrhosis and hepatic decompensation, as well as to hepatocellular carcinoma. Therapeutic intervention is currently aiming at suppression of HBV replication by applying a number of pharmacological agents. For an optimum use of available therapies, good knowledge of the natural course of chronic infection, as well as of the role played by several viral, host, and environmental factors, is mandatory. The larger part of this chapter deals with how to treat the various subsets of patients with chronic hepatitis B (CHB), using mainly three first-line drugs: pegylated interferon-α2a, entecavir, and tenofovir, administered either in finite courses or indefinitely. The frequency of virological, serological, biochemical, and histological responses in the various subsets of patients, both during and after stopping treatment, is reviewed. It is stressed that the application of the highly potent antivirals entecavir and tenofovir, with acceptable safety records and with a high barrier to HBV resistance, represents major progress in the treatment of CHB. Despite the hitherto important developments in the treatment of viral hepatitis B, clinical cure of chronic HBV infection with HBsAg loss is achievable only in a few treated patients while eradication of HBV infection appears unrealistic. Development of new pharmacological agents acting at multiple targets of the replicative cycle of HBV may achieve higher efficacy and even cure of CHB.

Analysis of serum α-fetoprotein-L3% and des-γ carboxyprothrombin markers in cases with misleading hepatocellular carcinoma total α-fetoprotein levels

Serum fraction of α-fetoprotein L3 (AFP-L3%) and des-γ carboxyprothrombin (DCP) are proposed serum markers for the diagnosis of hepatocellular carcinoma (HCC). We evaluated their performance in two patient populations with total AFP levels non-diagnostic for HCC. From a cohort of 150 consecutive patients with HCC, 60 patients with total AFP <200 ng/ml were identified. Additionally, 50 patients with elevated AFP and no radiological evidence of HCC, for at least one year of follow-up, were included. AFP-L3% and DCP were measured by the Liquid Phase Binding Assay System (LiBASys). In cases where AFP-L3% was undetectable, a more sensitive method based on-chip electrokinetic reaction was applied. AFP-L3% was found to be positive in 22 (36.7%) of patients with HCC and 6 (12%) of non-HCC patients. DCP was found to be positive in 26 patients with HCC (43%) and in none of the non-HCC patients. Thirty-six out of sixty (60%) patients with HCC were positive for either AFP-L3% or DCP. With the on-chip technology, AFP-L3% was found to be positive in 10 patients with HCC and in 5 patients without HCC, who tested negative by LiBASys. The final sensitivity of combined AFP, AFP-L3% and DCP testing, in the entire cohort of patients with HCC, was 84%. The specificity of AFP-L3% and DCP in the studied population was 78.5 and 100%, respectively. The addition of AFP-L3% and DCP increased the sensitivity and specificity of total serum AFP for the diagnosis of HCC. The on chip AFP-L3% assay was more sensitive but less specific compared to LiBASys.

Hepatitis B surface antigen quantification in chronic hepatitis B and its clinical utility

Serum HBsAg levels have been quantified extensively in recent years with simple completely automated assays in the various phases of the natural course of chronic HBV infection, have been compared with cccDNA in the liver, with various markers of HBV replication and have been correlated with several viral, host and environmental variables. Low HBsAg levels in inactive carriers predict a spontaneous HbsAg loss. Quantification of HBsAg in serum at baseline and its decline under interferon-alfa based regimens, both in HBeAg-positive and HBeAg-negative CHB, provides important information on the prediction of sustained post-treatment outcomes and on subsequent HBsAg clearance. The value of HBsAg quantification in the monitoring of long term nucleos(t)ide analogue treatment of CHB and in the prediction of sustained response remains unclear. In this review, the most recent data regarding the overall clinical utility of HBsAg measurement in HBeAg-positive and -negative CHB and in their treatment, is critically presented.

Hepatitis C Virus (HCV)-Related Cryoglobulinemia: Cryoglobulin Type and Anti-HCV Profile

ABSTRACT Cryoglobulin characteristics in chronic hepatitis C (CHC) might be of importance for knowing more about the pathogenesis and treatment of the disease. We aimed to investigate the relationship between cryoglobulin types and their specificity against hepatitis C virus (HCV) antigenic epitopes in CHC patients. We analyzed samples from 43 patients with HCV-associated cryoglobulinemia, of whom 4 had concomitant lymphoma. Cryoglobulins were measured, purified, typed by immunofixation electrophoresis, and tested for IgG and IgM anti-HCV antibodies by immunoblot analysis and an enzyme-linked immunosorbent assay (ELISA). Clinical and other laboratory data were recorded. The median cryocrit level of the tested samples was 6%. Type I cryoglobulins were detected in 9.3% (4/43) of the cryoprecipitates, and type II cryoglobulins were detected in 48.8% (21/43) of the cryoprecipitates. IgM monoclonal protein, mainly IgM(κ), was found in 92% (23/25) of type I and II cryoprecipitates. Type III cryoglobulins were identified in 41.9% (18/43) of the patients and were associated with high blood serum IgG levels. In 81.3% (13/16) of type II and 92.3% (12/13) of type III cryoglobulins, there was IgG reactivity against the viral core region. Ninety-two percent and 32% of IgG anti-HCV core-positive cryoprecipitates had additional specificities against the NS3 and NS4 regions, respectively. Also, IgM anti-HCV antibodies were detected in 31% of the cryoprecipitates. In conclusion, all types of cryoglobulins were found in patients with HCV-associated cryoglobulinemia, with type II being the most frequently identified. Type III cryoglobulins were common and were associated with high serum IgG levels. HCV-related cryoglobulins demonstrated IgM, and particularly IgG, anti-HCV specificities, mainly against the core and NS3 epitopes.

Severe hepatitis C virus‐related cryoglobulinaemic sensory–motor polyneuropathy treated with pegylated interferon‐a2b and ribavirin: clinical, laboratory and neurophysiological study

Background/Aims: Severe involvement of central and/or peripheral nervous system is a rare complication of hepatitis C virus (HCV)‐related cryoglobulinaemia.

High serum lipopolysaccharide binding protein is associated with increased mortality in patients with decompensated cirrhosis

Lipopolysaccharide‐binding‐protein (LBP) is an acute‐phase‐protein produced by hepatocytes. Changes in LBP are associated with the dynamics of bacterial translocation and intestinal permeability in decompensated cirrhosis (DC). We assessed serum and ascitic‐fluid (AF) LBP and examined their association with mortality in patients with DC.

Hepatitis B s antigen kinetics during treatment with nucleos(t)ides analogues in patients with hepatitis B e antigen‐negative chronic hepatitis B

Serum hepatitis B s antigen (HBsAg) levels might be used as a predictor of virological breakthrough or of sustained off‐treatment virological response in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) patients. We evaluated the changes of HBsAg in those patients under nucleos(t)ide analogue(s) [NA(s)] therapy for ≥12 months.