Ifi Institute for Interdisciplinary Medicine

Hamburg, Germany

Ifi Institute for Interdisciplinary Medicine

Hamburg, Germany
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PubMed | Hospital General Universitari Vall dHebron, University of Leipzig, Medical University of Bialystok, Ford Motor Company and 8 more.
Type: Journal Article | Journal: Journal of hepatology | Year: 2016

While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients.Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up.In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy.APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy.

Petersen J.,IFI Institute for Interdisciplinary Medicine | Ratziu V.,University Pierre and Marie Curie | Buti M.,CIBER ISCIII | Janssen H.L.A.,Rotterdam University | And 10 more authors.
Journal of Hepatology | Year: 2012

Background & Aims: Long-term viral suppression is a major goal to prevent disease progression in patients with HBV. Aim of this study was to investigate the efficacy and safety of entecavir plus tenofovir combination in 57 CHB partial responders or multidrug resistant patients. Methods: Investigator-initiated open-label cohort study. Quantitative HBV-DNA measurement and resistance testing (line-probe-assays and direct-sequencing) at baseline and every 3 months. Results: Fifty seven patients (37 HBeAg+), median age 45 years, previously treated with a median of three lines of antiviral therapy (range 1-6), 24/57 with advanced liver disease, were included. Median ALT at baseline was 1.0 ULN (range 0.3-22) and HBV-DNA 1.5 × 10 4 IU/ml (range 500-1 × 10 11 IU/ml). Median treatment duration of combination therapy was 21 months. HBV-DNA level dropped 3 logs (median, range 0-8 log; p <0.0001), 51/57 patients became HBV-DNA undetectable, median after 6 months (95% CI, 4.6-7). The probability for HBV DNA suppression was not reduced in patients with adefovir or entecavir resistance or in patients with advanced liver disease. Viral suppression led to decline in ALT (median 0.7 ULN; range 0.2-2.4; p = 0.001). Five patients lost HBeAg (after 15, 18, 20, 21, and 27 months, respectively), one patient showed HBs-seroconversion. Patients with advanced disease did not show clinical decompensation, two patients with cirrhosis and undetectable HBV DNA developed HCCs. No death, newly induced renal impairment or lactic acidosis were reported. Conclusions: Rescue therapy with entecavir and tenofovir in CHB patients harboring viral resistance patterns or showing only partial antiviral responses to preceding therapies was efficient, safe, and well tolerated in patients with and without advanced liver disease (249). © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Lutgehetmann M.,University of Hamburg | Mancke L.V.,University of Hamburg | Volz T.,University of Hamburg | Helbig M.,University of Hamburg | And 7 more authors.
Hepatology | Year: 2012

No specific drugs are currently available against hepatitis delta virus (HDV), a defective virus leading to the most severe form of chronic viral hepatitis in man. The lack of convenient HDV infection models has hampered the development of effective therapeutics. In this study, naïve and hepatitis B virus (HBV) chronically infected humanized uPA/SCID mice were employed to establish a small animal model of HBV/HDV coinfection and superinfection. For preclinical antiviral drug evaluation, the GMP version of the myristoylated preS-peptide (Myrcludex-B), a lipopeptide derived from the pre-S1 domain of the HBV envelope, was applied to prevent de novo HBV/HDV coinfection in vivo. Virological parameters were determined at serological and intrahepatic level both by real-time polymerase chain reaction (PCR) and by immunohistochemistry. Establishment of HDV infection was highly efficient in both HBV-infected and naïve chimeric mice with HDV titers rising up to 1 × 10E9 copies/mL. Notably, HDV superinfection led to a median 0.6log reduction of HBV viremia, which although not statistically significant suggests that HDV may hinder HBV replication. In the setting of HBV/HDV simultaneous infection, a majority of human hepatocytes stained HDAg-positive long before HBV spreading was completed, confirming that HDV can replicate intrahepatically also in the absence of HBV infection. Furthermore, the increase of HBV viremia and intrahepatic cccDNA loads was significantly slower than in HBV mono-infected mice. Treatment with the HBV entry inhibitor Myrcludex-B, efficiently hindered the establishment of HDV infection in vivo. Conclusion: We established an efficient model of HBV/HDV infection to exploit mechanisms of viral interference in human hepatocytes and to test the efficacy of an HDV-entry inhibitor in vivo. (HEPATOLOGY 2011) © 2011 American Association for the Study of Liver Diseases.

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.

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.

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.

Giersch K.,University of Hamburg | Allweiss L.,University of Hamburg | Volz T.,University of Hamburg | Helbig M.,University of Hamburg | And 8 more authors.
Journal of Hepatology | Year: 2015

Background & Aims: The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice. Methods: Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence. Results: Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-ß, hIFN-ß and hIFN-λ) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling. Conclusions: Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDVassociated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Lutgehetmann M.,University of Hamburg | Bornscheuer T.,University of Hamburg | Volz T.,University of Hamburg | Allweiss L.,University of Hamburg | And 6 more authors.
Gastroenterology | Year: 2011

Background & Aims: Interferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection for reasons that are not clear. We investigated whether HBV infection reduced IFN-αmediated induction of antiviral defense mechanisms in human hepatocytes. Methods: Human hepatocytes were injected into severe combined immune-deficient mice (SCID/beige) that expressed transgenic urokinase plasminogen activator under control of the albumin promoter. Some mice were infected with HBV; infected and uninfected mice were given injections of human IFN-α. Changes in viral DNA and expression of human interferon-stimulated genes (ISGs) were measured by real-time polymerase chain reaction, using human-specific primers, and by immunohistochemistry. Results: Median HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 hours after each injection of IFN-α, but increased within 24 hours. IFN-α activated expression of human ISGs and nuclear translocation of signal transducers and activators of transcription1 (STAT1) in human hepatocytes that repopulated the livers of uninfected mice. Although baseline levels of human ISGs were slightly increased in HBV-infected mice, compared with uninfected mice, IFN-α failed to increase expression of the ISGs OAS-1, MxA, MyD88, and TAP-1 (which regulates antigen presentation) in HBV-infected mice. IFN-α did not induce nuclear translocation of STAT1 in HBV-infected human hepatocytes. Administration of the nucleoside analogue entecavir (for 20 days) suppressed HBV replication but did not restore responsiveness to IFN-α. Conclusions: HBV prevents induction of IFN-α signaling by inhibiting nuclear translocation of STAT1; this can interfere with transcription of ISGs in human hepatocytes. These effects of HBV might contribute to the limited effectiveness of endogenous and therapeutic IFN-α in patients and promote viral persistence. © 2011 AGA Institute.

PubMed | IFI Institute for Interdisciplinary Medicine, University of Lyon, Leberzentrum Checkpoint, University of Medicine and 8 more.
Type: Journal Article | Journal: Hepatology international | Year: 2016

In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen.In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1mg) plus TDF (300mg) and treated for 96weeks.At baseline, 62% of patients were HBeAg(+) and mean HBV DNA was 4.4log10IU/mL. Patients had received 1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53%), lamivudine (LVD 22%), TDF (12%), adefovir (ADV 4%), or telbivudine (2%), or combinations of these agents (7%); 58% had evidence of single- or multidrug resistance mutations (LVD 52%, ETV 26%; ADV 7%). Response rates for HBV DNA <50IU/mL were 76% (70/92) at week 48 (primary endpoint), and 85% (78/92) at week 96, including 80% (16/20) in prior LVD failures, 100% (4/4) in ADV failures, 82% (9/11) in TDF failures, and 88% (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed.In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96weeks in the majority (85%), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.

PubMed | Hannover Medical School, Hepatologische Schwerpunktpraxis Herne, IFI Institute for Interdisciplinary Medicine, University of Leipzig and 8 more.
Type: | Journal: Alimentary pharmacology & therapeutics | Year: 2017

Treatment of chronic hepatitis C genotype 3 (GT3) is more challenging compared with other genotypes. Since 2014, several new treatment regimens have been approved but sometimes based on limited data.To validate the use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection under real-word conditions.The German Hepatitis C-Registry is a large national non-interventional real-world study for patients with chronic hepatitis C. A total of 1322 GT3 patients were enrolled (211 untreated and 1111 treated patients).Between February 2014 and September 2015, five different treatment strategies have been used (PegIFN+RBV, PegIFN+RBV+SOF, SOF+RBV, DCV+SOFRBV, LDV/SOFRBV). Treatment uptake and use of treatment concepts changed markedly and rapidly during the study influenced by new approvals, guideline recommendations, and label updates. PegIFN-based therapies constantly declined while DCV-based therapies increased with one interruption after the approval of LDV/SOF, which was frequently used until new guidelines recommended not using this combination for GT3. Per-protocol SVR ranged from 80.9% in the PegIFN+RBV group to 96.1% in PegIFN+RBV+SOF treated patients. Treatment-experienced patients with cirrhosis showed a suboptimal SVR of 68% for SOF+RBV but a high SVR of 90-95% for DCV+SOFRBV. The safety analysis showed more adverse events and a stronger decline of haemoglobin for RBV containing regimens.Real-world data can validate the effectiveness and safety for treatment regimens that had previously been approved with limited data, in particular for specific subgroups of patients. The present study demonstrates how rapid new scientific data, new treatment guidelines, new drug approvals and label changes are implemented into routine clinical practice today.

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