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Dandri M.,University of Hamburg | Lutgehetmann M.,University of Hamburg | Petersen J.,Ifi Institute for Interdisciplinary Medicine
Seminars in Immunopathology | Year: 2013

Liver disease associated to persistent infection with the hepatitis B virus (HBV) continues to be a major health problem of global impact. In spite of the existence of an effective vaccine, approximately 360 million people are chronically infected worldwide, who are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Although current therapeutic regimens can efficiently suppress viral replication, the unique replication strategies employed by HBV permit the virus to persist within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment with polymerase inhibitors. The narrow host range of HBV has hindered progresses in understanding specific steps of HBV replication and the development of more effective therapeutic strategies aiming at achieving sustained viral control and, eventually, virus eradication. This review will focus on summarizing recent advances obtained with well-established and more innovative experimental models, giving emphasis on the strength of the different systems as tools for elucidating distinct aspects of HBV persistence and for the development of new therapeutic approaches. © 2012 Springer-Verlag. Source

Hoffmann C.,Study Center | Hoffmann C.,University of Kiel | Hentrich M.,Oncology and Palliative Care | Gillor D.,University of Cologne | And 14 more authors.
HIV Medicine | Year: 2015

Objectives: The incidence of HIV-related non-Hodgkin lymphoma (NHL) but not that of Hodgkin lymphoma (HL) has been declining. The aim of the study was to compare HIV-infected patients with NHL and HL with respect to antiretroviral therapy (ART) exposure at the time of lymphoma diagnosis. Methods: HIV-infected patients with NHL and HL included in a prospective multicentre cohort study since January 2005 were compared with respect to ART exposure and viral load at the time of lymphoma diagnosis. Results: As of 31 December 2012, data for 329 patients with NHL and 86 patients with HL from 31 participating centres were available. Patients with HL were more likely to be on ART (73.5% vs. 39.1%, respectively; P<0.001) and more frequently had a viral load below the detection limit (57.3% vs. 27.9%, respectively; P<0.001) than patients with NHL. The proportion of patients with HL was 8.0% in ART-naïve patients, 34.8% in patients with current HIV RNA <50 HIV-1 RNA copies/mL, and 50.0% in patients with both HIV RNA <50 copies/mL for >12 months and a CD4 cell count of >200 cells/μL. Of note, 45.8% of all patients with NHL were not currently on ART and had a CD4 count of <350 cells/μL. Conclusions: This prospective cohort study shows that HL was as common as NHL in patients with sustained viral suppression and limited immune deficiency. In contrast to NHL, the majority of patients with HL were on effective ART, suggesting that ART provides insufficient protection from developing HL. The high proportion of untreated patients with NHL suggests missed opportunities for earlier initiation of ART. © 2014 British HIV Association. Source

Giersch K.,University of Hamburg | Helbig M.,University of Hamburg | Volz T.,University of Hamburg | Allweiss L.,University of Hamburg | And 10 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Clinical studies have shown that hepatitis delta virus (HDV) infection can persist for years and intrahepatic latency of the large delta antigen (HDAg) has been detected following liver transplantation. However, large HDAg arising via RNA-editing is associated with increasing amounts of non-infectious HDV quasi-species. This study investigated whether HDV could persist intrahepatically in the absence of HBV in vivo and whether infectious HDV could subsequently be released following HBV super-infection. Methods Humanized mice were infected with HDV particles lacking HBV. To test for rescue of latent HDV infection 3 and 6 weeks HDV mono-infected mice were super-infected with HBV. Viral loads and cell toxicity were determined by qRT-PCR and immunohistochemistry. Results The presence of HDAg-positive human hepatocytes determined after 2, 3, and 6 weeks of HDV inoculation demonstrated establishment and maintenance of intrahepatic HDV mono-infection. Although intrahepatic amounts of large HDAg and edited HDV RNA forms increased over time in HDV mono-infected livers, HBV super-infection led to prompt viremia development (up to 108 HDV RNA and 107 HBV-DNA copies/ml) even after 6 weeks of latent mono-infection. Concurrently, the number of HDAg-positive human hepatocytes increased, demonstrating intrahepatic HDV spreading. The infectivity of the rescued HDV virions was verified by serial passage in naive chimeric mice. Conclusions HDV mono-infection can persist intrahepatically for at least 6 weeks before being rescued by HBV. Conversion of a latent HDV infection to a productive HBV/HDV co-infection may contribute to HDV persistence even in patients with low HBV replication and in the setting of liver transplantation. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

Volz T.,University of Hamburg | Lutgehetmann M.,University of Hamburg | Allweiss L.,University of Hamburg | Warlich M.,University of Hamburg | And 5 more authors.
Antiviral Therapy | Year: 2012

Background: Suppression of viral replication with nucleoside/nucleotide inhibitors has been shown to greatly improve the outcome of chronic HBV infection. b-l-nucleoside analogues, especially β-L-deoxycytidine derivatives represent one of the most efficient groups of antiretroviral compounds. We recently described that hydroxylation of the amino group of these β-L-deoxycytidine derivatives preserved their strong HBV inhibitory activity in vitro, but strongly reduced their cytotoxicity. From this new group of compounds we selected β-L-2′,3′-didehydro-2′,3′- dideoxy-N 4-hydroxy-5-fluorocytidine (L-Hyd4FC) for a first in vivo investigation. The aim of this study was to determine the antiviral activity of L-Hyd4FC in HBV-infected human liver chimeric urokinase plasminogen activator (uPA)/SCID mice. Methods: Stably infected animals (median 6×10 7 HBV DNA/ml) were injected daily with either l-Hyd4FC (50 mg/kg) or saline as controls. Mice treated with lamivudine served to compare the in vivo antiviral potency of L-Hyd4FC. Virological changes were determined by quantitative PCR. Results: Treatment with L-Hyd4FC for 4 weeks induced a 2-log reduction of viraemia, while a median 1.5-log decline was achieved with lamivudine. Intrahepatically, L-Hyd4FC induced a median eightfold decline of viral activity (relaxed circular DNA/covalently closed circular DNA), and threefold reduction of pregenomic RNA/GAPDH levels. No significant decline of subgenomic HBV transcripts, as well as of circulating hepatitis B e antigen and hepatitis B surface antigen was detected. Maintenance of human serum albumin concentrations throughout the study, negative TUNEL staining and occurrence of viral rebound after drug withdrawal indicated that L-Hyd4FC was not toxic in human hepatocytes. Conclusions: Administration of L-Hyd4FC in uPA/SCID mice harbouring HBV-infected human hepatocytes demonstrated the high antiviral potency of this drug in vivo. Such characteristics make L-Hyd4FC a good candidate for further investigations a as potential HBV therapeutic agent. ©2012 International Medical Press. Source

Petersen J.,Ifi Institute for Interdisciplinary Medicine | Buti M.,Hospital General Universitario Vall dHebron
Expert Review of Gastroenterology and Hepatology | Year: 2012

Treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogs is often required over a prolonged period to achieve durable virologic suppression. One barrier to the success of long-term therapy is the emergence of drug-resistant mutants. Current guidelines therefore recommend the most potent drugs with optimal resistance profiles, that is, entecavir and tenofovir are used as first-line monotherapies in CHB. Characteristics of the hepatitis B virus, the disease, the patient and the drug can influence the response to antiviral treatment and risk of relapse. This review discusses factors to consider maximizing the chances of successful long-term treatment of CHB, and provides an overview of the long-term efficacy and safety data that have become available over the 4-5 years since entecavir and tenofovir were first approved for the treatment of CHB. Recent findings on whether and under what circumstances long-term therapy of CHB might be stopped are also discussed. © 2012 Expert Reviews Ltd. Source

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