Stephanos J. Hadziyannis

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

BACKGROUND & AIMSnLittle 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).nnnMETHODSnWe 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.nnnRESULTSnDuring 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.nnnCONCLUSIONSnIn 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.

Impact of HBV, HCV and GBV-C/HGV on hepatocellular carcinomas in Europe: results of a European concerted action

Abstract Background/Aims: To investigate the impact of hepatitis B (HBV) and C (HCV) infections on hepatocellular carcinoma (HCC) in Europe. Methods: Five hundred and three patients with HCC, from six liver centers, were included. All 503 sera and 80 liver samples were tested for HBV DNA and HCV RNA by polymerase chain reaction. GBV-C/HGV RNA was also tested in 57 sera. Results: HBsAg and anti-HCV were detected in 19% and 40.1% of the patients, respectively. Serum and liver HBV DNA were detected in 82% and 91% of the HBsAg positive subjects. HBV DNA was also detected in the serum and liver of 33% and 47% of HBsAg negative patients. In this group, serum HBV DNA was more prevalent in anti-HBs and/or anti-HBc patients (47.9%), compared to those without any HBV marker (25.1%). HCV RNA was detected in 89% and 7% of anti-HCV positive and negative cases, respectively, HCV 1b being the most prevalent genotype (80%). Coinfection with HBV and HCV was shown in 20.4% of patients, while only 29% had neither HBV nor HCV. GBV-C/HGV RNA was detected in only 457 sera. Conclusions: This study offers the first large analysis of HCC in Europe, based on both serology and molecular tests. It demonstrates the major impact of HBV and HCV, but not of GBV-C/HGV, in liver carcinogenesis in Northern as well as Southern Europe. It also stresses the need to use viral genome detection in epidemiological studies when serological tests are negative.

Interrupted replication of hepatitis B virus in liver tissue of HBsAg carriers with hepatocellular carcinoma

To search for events underlying reduction of peripheral viremia and integration of hepatitis B virus (HBV) DNA into the liver cell genome in long-term virus carriers with hepatocellular carcinoma, paired samples of liver and tumor tissue were analyzed by molecular hybridization and immunological methods. Most tumor tissues contained integrated viral DNA; in none was extrachromosomal HBV DNA detected. Integrated HBV DNS was also found in peritumor liver tissue in the majority of patients. However, liver of patients either with or without peripheral viremia also contained free HBV DNA and replicative intermediates. In three nonviremic patients with replicative HBV DNA in liver, viral core antigen expression was markedly reduced or absent, whereas viral envelope protein (surface antigen) expression was normal. In one case, replicative intermediates in liver were sensitive to DNase I digestion, indicating that viral DNA was not encapsidated in normal viral core particles. These results suggest that decreased or defective core antigen production can lead to reduced viremia associated with blocked virus assembly/secretion and accumulation of unencapsidated HBV DNA replicative intermediates in the liver cell. Accumulation of such HBV DNA molecular forms in the liver may lead to an increased propensity for HBV DNA to integrate into the host genome, which has been found with high frequency in hepatic neoplasms from patients infected with hepatitis B virus.

Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin.

Objective. Patient- and virus-related factors influence the response of patients with chronic hepatitis C to interferon-based therapy. The purpose of this study was to model the probability of achieving a sustained virological response in individual patients, taking into consideration various predictive factors. Material and methods. We combined data from two randomized, multinational trials in which patients received peginterferon alfa-2a (40KD) plus ribavirin. The logistic regression model for patients infected with hepatitis C virus genotype 1 included age, viral load, histology, alanine aminotransferase quotient, body mass index, treatment duration, ribavirin dose and adherence. Results. In the genotype 1 model, varying baseline factors had a striking effect on the probability of sustained virological response. A dramatic difference in the probability of sustained virological response was seen in a series of hypothetical patients in whom five factors were varied to represent best and worst case scenarios. The best case scenario (age 20 years; no cirrhosis/bridging fibrosis; alanine aminotransferase quotient =7; body mass index 20 kg/m2; viral load 40,000 IU/mL) was associated with a 97% probability of sustained virological response, compared with 7% in the worst case scenario (age 60 years; cirrhosis/bridging fibrosis; alanine aminotransferase quotient =1; body mass index 30 kg/m2; viral load 9,000,000 IU/mL). Both adherence to treatment and achieving an early virological response increased the probability of sustained virological response. Conclusions. In treatment-naïve patients with chronic hepatitis C, host factors play a major role in determining treatment outcome and the logistic regression model is useful for predicting the probability of sustained virological response in individual patients.

Immunopathogenesis of hepatitis B e antigen negative chronic hepatitis B infection

Hepatitis B e antigen (HBeAg) negative chronic hepatitis B represents currently the predominant form of chronic hepatitis due to the hepatitis B virus (HBV) in several parts of the world. In this review, recent data regarding the process of HBeAg negative HBV strain selection during the course of chronic HBV infection are presented and the potential virus and/or host-mediated mechanisms that lead to chronic liver necroinflammation, i.e. chronic hepatitis are outlined.

Use of α-interferon in the treatment of chronic delta hepatitis

Abstract Chronic delta hepatitis is a severe disease with a rapidly progressive course for which currently no effective treatment exists. Treatment with α-interferon (α-IFN) can inhibit HDV replication and improve serum chemistries in a number of patients. Meta-analysis of five randomized controlled trials using at least 5 MU/m 2 of α-IFN t.i.w. for a minimum of 3 months showed that α-IFN had a statistically significant effect in normalizing ALT values during therapy at a p level of χ 2 = 24.13) but had no significant effect on ALT activity after its discontinuation. From hitherto available results, it appears that the best treatment schedule is a 5 MU standard dose of α-IFN given daily (QD) or 9 MU t.i.w. for at least 1 year, which is associated with a remission of the disease in 50–70% of patients. A trial conducted in Greece showed that the mean duration of disease remission under α-IFN therapy was 3.8 months per year compared to 1.7 months per year of non-treatment (relative risk=2.8). Unlike hepatitis B, no factors predictive of the response to α-IFN therapy have been identified except, perhaps, for the duration of the disease. No adjuvants have been found to enhance the efficacy of α-IFN treatment and no therapeutic alternatives are available at present. Advances in understanding HDV replication and the pathogenetic mechanisms in chronic delta hepatitis may bring about significant improvement in its therapy in the future.

Hepatitis C virus infection in Greece and its role in chronic liver disease and hepatocellular carcinoma

The aim of this study was to evaluate the prevalence of hepatitis C virus infection (HCV) in Greece, to estimate its frequency in chronic liver disease and to explore the role of HCV infection in the aetiology of hepatocellular carcinoma. A series of 1034 patients with chronic liver disease of various aetioloigies and 299 patients with hepatocellular carcinoma allocated to two case-control studies was tested for anti-HCV. Twelve recent reports on HCV infection in Greece were reviewed and analyzed. The results of the present study indicate the existence of a large pool of HCV infection in Greece and an impressive spread of the virus in high-risk groups. Chronic HCV infection was found to account for 83.6% of patients with chronic non-A, non-B hepatitis parenterally transmitted, 56.5% of cases of sporadic community-acquired disease and for almost 1/4 of all patients with chronic liver disease. The relative risks for development of hepatocellular carcinoma of patients with chronic HCV infection was 6.3 in the first and 13.7 in the second case-control study, increasing to 20.0 and 18.7, respectively, when hepatitis B surface antigen (HBsAg) was positive. Serum HBV-DNA was positive and/or anti-HBc IgM levels were high in 12 of 15 (80%) patients with hepatocellular carcinoma positive only for HBsAg, and in 7 of 15 (47%) positive both for HBsAg and antibodies to HCV. The present data support the view that hepatitis B and C virus have an interacting role in the origin of hepatocellular carcinoma.

Fulminant hepatitis after flutamide treatment

Two cases of severe acute hepatitis in patients taking flutamide for metastatic prostatic carcinoma are reported. Jaundice and marked increase in aminotransferases occurred after 6-8 weeks of treatment. Continuation of flutamide administration was associated with the development of hepatic encephalopathy and a marked prolongation of prothrombin time. One of the patients died of acute liver failure and the other survived after prolonged hospitalization. Rechallenge was not performed because of the severity of the clinical picture. Liver histology showed extensive hepatic necrosis. These two cases strongly suggest that flutamide, in addition to its cholestatic side effects, can induce acute hepatitis potentially with a fulminant and lethal course. Journal of Hepatology.

Serum β2 microglobulin in malignant lymphoproliferative disorders

Serum beta‐2‐microglobulin (S‐β2M) was measured at diagnosis in 44 patients with lymphocytic leukemias and 47 with malignant lymphomas. Among patients with chronic lymphocytic leukemia (CLL) S‐β2M was raised (>3 mg/1) in 74% and in 23.5% of those with acute lymphoblastic leukemia (ALL). The frequencies for non‐Hodgkins lymphoma (NHL) and Hodgkins disease (HD) were 59.2% and 40%, respectively. In CLL patients high serum values correlated with large tumor mass, as estimated by Rais clinical criteria (P < 0.001), by total peripheral lymphocytes (r = 0.41, P < 0.05) and by the percentage of bone marrow infiltration of the lymphocytes (P < 0.01). A significant relation was also found in CLL patients between S‐β2M level and survival (P < 0.05). In ALL no association was found between S‐β2M level with peripheral lymphoblast concentration, French‐American‐British (FAB) subclassification, splenomegaly, and survival. In NHL patients a significant association was found between S‐β2M levels and stage of disease (P < 0.01) and an obscure relation (P < 0.01) and an obscure relation (P < 0.1) with the presence of lymph nodes greater than 3 cm in diameter, splenomegaly, and hepatomegaly. No significant association was found between S‐β2M level and histologic subtypes, presence of B symptoms, bone marrow involvement, and survival. In HD patients a significant association was found between the level of S‐β2M and stage of disease (P < 0.05) and presence of splenomegaly (P < 0.05). No association was found between S‐β2M level and histologic subtypes, lymph nodes greater than 3 cm in diameter, bone marrow involvement, and B symptoms. A significant relation was found between S‐β2M level and survival in HD patients with widespread disease (P < .025).

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.