Publications by authors named "Katja Deterding"

63 Publications

HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta.

Hepatol Commun 2021 Sep 24. Epub 2021 Sep 24.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility.
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http://dx.doi.org/10.1002/hep4.1821DOI Listing
September 2021

Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients.

Medicine (Baltimore) 2021 Jul;100(28):e26571

Department of Gastroenterology and Hepatology, University Hospital Essen, Germany.

Abstract: Co-infection of Hepatitis B (HBV) and Delta viruses (HDV) represent the most severe form of viral hepatitis. While treatment with pegylated Interferon alpha (PEG-IFNα) is well established, therapy with nucleoside or nucleotide analogues (NA) has been a matter of debate. We aimed to investigate the role of NA treatment in a well-defined single centre cohort.In a retrospective approach, we observed 53 HDV RNA positive and/or anti-HDV-positive patients recruited at a German referral centre between 2000 and 2019. Patients were followed for at least 3 months (mean time of follow up: 4.6 years; range: 0.2-14.1 years). Patients who had liver transplantation or hepatocellular carcinoma at the time of presentation were excluded. 43% (n = 23) were treated with NA, 43% (n = 23) received IFNα-based therapies and 13% (n = 7) were untreated.Liver cirrhosis was already present in 53% (28/53) of patients at first presentation. During follow-up, liver-related endpoints developed in 44% of all patients (n = 23). NA-treatment was associated with a significantly worse clinical outcome (P = .01; odds ratio [OR] = 4.92; CI = 1.51-16.01) compared to both, untreated (P = .38; OR = 0.46; CI = 0.80-2.61) and IFNα-based-treated patients (P = .04; OR = 0.29; CI = 0.89-0.94) in univariate logistic regression analysis. HBsAg levels declined by more than 50% during NA-based therapy in only 7 cases (7/23; mean time: 3.6 years; range: 0.8-8.5 years) and during IFNα-based therapy in 14 cases (14/23; mean time: 2.8 years, range 0.7-8.5 years). HDV RNA became undetectable during follow up in 30% of patients receiving NA alone (7/23; mean time: 5.0 years; range: 0.6-13.5 years), in 35% of patients receiving IFNα-based therapy (8/23; mean time: 2.9 years, range: 0.3-7.6 years).The effect of NA in patients with HBV/HDV co-infection is limited. Treatment with NA was associated with a higher likelihood of clinical disease progression. Interferon alpha therapy was beneficial in reducing liver complications and improves long-term outcome.
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http://dx.doi.org/10.1097/MD.0000000000026571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284709PMC
July 2021

[New therapeutic options for hepatitis D].

MMW Fortschr Med 2021 06;163(12):62-63

Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-0023-4DOI Listing
June 2021

Long-lasting Imprint in the Soluble Inflammatory Milieu despite Early Treatment of Acute Symptomatic Hepatitis C.

J Infect Dis 2021 Jan 31. Epub 2021 Jan 31.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Background: Treatment with direct acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C with DAAs may normalize most SIMs.

Methods: In this study, we made use of a unique cohort of acute symptomatic hepatitis C who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay (PEA) measuring 92 proteins.

Results: Profound SIM alterations were observed in acute HCV patients, with marked upregulation of IL-6 and CXCL10 while certain mediators were down-regulated (e.g. MCP-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (e.g. CDCP1, IL-18). Of note, SIMs that were down-regulated before DAA treatment remained suppressed while others that were initially unchanged, declined to lower values during treatment and follow-up (e.g.CD244).

Conclusions: Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu as compared to both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained. Thus, acute HCV-induced changes in the immune system may persist even after a short duration of viremia.
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http://dx.doi.org/10.1093/infdis/jiab048DOI Listing
January 2021

Inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients.

United European Gastroenterol J 2021 May 18;9(4):486-496. Epub 2021 Feb 18.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Introduction: The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon-free direct-acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance.

Objective: Here, we aimed at evaluating the effects of direct-acting antiviral therapy-induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct-acting antiviral-mediated hepatitis C clearance in cirrhosis patients was investigated.

Methods: Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct-acting antiviral treatment.

Results: Elevated pretherapy concentrations of specific soluble immune mediators including MCP-3, GDNF, CDCP1, IL-17C, IL-17A, signalling lymphocytic activation family 1, CCL11, FGF-5, LIF-R, interleukin 10 (IL-10), IL-10RA, IL-15RA, beta NGF, CCL28, CCL25 and NT-3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF-5 and IL-15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma-free patients experienced significant ameliorations.

Conclusions: These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct-acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct-acting antiviral therapies would be superior to the risk of developing carcinoma.
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http://dx.doi.org/10.1177/2050640620976991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259286PMC
May 2021

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

J Hepatol 2021 04 19;74(4):801-810. Epub 2020 Nov 19.

Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site, Frankfurt, Germany; Medizinische Klinik 2, St. Josefs-Hospital, Wiesbaden, Germany. Electronic address:

Background & Aims: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients.

Methods: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients.

Results: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12.

Conclusions: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients.

Lay Summary: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).
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http://dx.doi.org/10.1016/j.jhep.2020.11.017DOI Listing
April 2021

Sofosbuvir, velpatasvir, and voxilaprevir for patients with failure of previous direct-acting antiviral therapy for chronic hepatitis C: Results from the German Hepatitis C-Registry (DHC-R).

Z Gastroenterol 2020 Sep 18;58(9):841-846. Epub 2020 Sep 18.

University Hospital Frankfurt, Frankfurt am Main, Germany.

Despite the high effectiveness of direct-acting antivirals for the treatment of hepatitis C, a small proportion of patients do not respond to approved regimens. The combination regimen of SOF/VEL/VOX was recently approved for patients with failure to prior NS5A-based treatment. In this German real-world cohort including patients with cirrhosis (27.3 %) and previous decompensation events, 12 weeks of SOF/VEL/VOX resulted in high virologic response rates irrespective of disease severity and prior DAA regimen. Adverse events were mostly mild or moderate and comparable to those seen in the approval studies.
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http://dx.doi.org/10.1055/a-1217-7669DOI Listing
September 2020

Resistance-associated substitutions in patients with chronic hepatitis C virus genotype 4 infection.

J Viral Hepat 2020 10 26;27(10):974-986. Epub 2020 Jun 26.

Department of Internal 1, University Hospital, Goethe University, Frankfurt, Germany.

Data on the prevalence of resistance-associated substitutions (RASs) and their implications for treatment with direct-acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4-infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA-naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P < .0001). RASsL28V, L30R and M31L pre-existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein-protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance-tailored retreatment using first- and second-generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first-line treatment regimens.
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http://dx.doi.org/10.1111/jvh.13322DOI Listing
October 2020

Liver stiffness across different chronic liver disease under therapy with statin in a real life cohort.

Eur J Gastroenterol Hepatol 2021 02;32(2):223-229

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover.

Introduction: Statins have been associated with improved clinical outcomes in patients with viral hepatitis and after variceal bleeding. Still, the clinical benefit of statins is not well defined for different liver diseases. Moreover, associations between statin use and liver stiffness as well as event free survival have not been established.

Methods: Liver stiffness was evaluated in 6490 patients with liver disease (January 2012 till December 2016). Two hundred thirty-four of those received statin therapy, 468 controls without statins were selected by a 1:2 case by case matching using age, sex, underlying liver disease and BMI.

Results: Statins were given to 234 patients with chronic virus hepatitis (n = 104), nonalcoholic fatty liver disease (n = 52), autoimmune liver disease including autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis (n = 31) and hepatitis of unknown origin (n = 47). Follow-up data were available for 96 and 119 pairs (mean follow-up 2 years). Statin users showed reduced inflammatory activity. Elevated liver enzymes were reported in 57% of statin-treated compared with 70% of controls (mean alanine aminotransferase level 53 vs. 74 U/l; P < 0.001). Statin use was well tolerated in this cohort. Mean liver stiffness values were 10.7 kPa (SEM 0.7) and 15.5 kPa (SEM 0.7) accordingly (P < 0.0001). Decompensation was less likely to occur in the statin group, both groups do not defer in the incidence of liver tumor occurrence, transplantation or death (odds ratio = 1, P = nonsignificant).

Conclusions: Use of statins was well tolerated irrespective of liver disease. Statin users showed reduced hepatic inflammatory activity, less severe markers of liver stiffness and portal hypertension. There might be a beneficial effect of statin on the risk to experience hepatic decompensation.
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http://dx.doi.org/10.1097/MEG.0000000000001719DOI Listing
February 2021

Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta.

AIDS Rev 2019 ;21(3):126-134

Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen. Essen, Germany.

Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection.
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http://dx.doi.org/10.24875/AIDSRev.19000080DOI Listing
January 2020

Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses.

J Hepatol 2019 11 8;71(5):889-899. Epub 2019 Jul 8.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research, Hannover, Germany (DZIF), Partner-site Hannover-Braunschweig, Germany; Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany; Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. Electronic address:

Background & Aims: Hepatitis C virus (HCV)-specific CD8+ T cells are functionally impaired in chronic hepatitis C. Even though HCV can now be rapidly and sustainably cleared from chronically infected patients, the repercussions of HCV clearance on virus-specific CD8+ T cells remain elusive. Here, we aimed to investigate if HCV clearance by direct-acting antivirals (DAAs) could restore the functionality of exhausted HCV-specific CD8+ T cell responses.

Methods: HCV-specific CD8+ T cells in peripheral blood were obtained from 40 patients with chronic HCV infection, during and 6 months following IFN-free DAA therapy. These cells were analyzed for comprehensive phenotypes, proliferation, cytokine production, mitochondrial fitness and response to immune-checkpoint blockade.

Results: We show that, unlike activation markers that decreased, surface expression of multiple co-regulatory receptors on exhausted HCV-specific CD8+ T cells remained unaltered after clearance of HCV. Likewise, cytokine production by HCV-specific CD8+ T cells remained impaired following HCV clearance. The proliferative capacity of HCV multimer-specific CD8+ T cells was not restored in the majority of patients. Enhanced in vitro proliferative expansion of HCV-specific CD8+ T cells during HCV clearance was more likely in women, patients with low liver stiffness and low alanine aminotransferase levels in our cohort. Interestingly, HCV-specific CD8+ T cells that did not proliferate following HCV clearance could preferentially re-invigorate their proliferative capacity upon in vitro immune-checkpoint inhibition. Moreover, altered mitochondrial dysfunction exhibited by exhausted HCV-specific CD8+ T cells could not be normalized after HCV clearance.

Conclusion: Taken together, our data implies that exhausted HCV-specific CD8+ T cells remain functionally and metabolically impaired at multiple levels following HCV clearance in most patients with chronic hepatitis C. Our results might have implications in cases of re-infection with HCV and for HCV vaccine development.

Lay Summary: Direct-acting antiviral therapy results in cure of hepatitis C virus (HCV) in almost all treated patients. However, the impacts of HCV cure on immune responses remain controversial. Whether immune responses to HCV recover is important in cases of re-exposure, or for the resolution of extrahepatic manifestations. The main finding of our study was that HCV-specific T cells remain functionally impaired despite HCV clearance. This finding could explain the fact that HCV cure does not lead to protective immunity and that re-infections have frequently been observed.
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http://dx.doi.org/10.1016/j.jhep.2019.06.025DOI Listing
November 2019

HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection.

Liver Cancer 2019 Feb 18;8(1):41-65. Epub 2018 Jul 18.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis.

Design: PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology.

Results: Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epi-topes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs - with evidence of IL-12 being a major culprit.

Conclusion: Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.
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http://dx.doi.org/10.1159/000490360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388568PMC
February 2019

Role of soluble inflammatory mediators and different immune cell populations in early control of symptomatic acute hepatitis C virus infection.

J Viral Hepat 2019 04 1;26(4):466-475. Epub 2019 Feb 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

The natural course of acute Hepatitis C Virus (aHCV) infection is highly heterogeneous, and only few biomarkers have been identified to reliably predict the outcome of infection. We analysed a large panel of soluble inflammatory mediators, immune cell frequencies and phenotypes using peripheral blood samples from 26 patients with symptomatic aHCV infection from a controlled randomized clinical trial (ISRCTN88729946, www.isrctn.com). We found that patients with a spontaneous early HCV control demonstrated a distinct expression pattern of various soluble immune mediators including IFNα and IL-16. Immune cell phenotype and frequency differed between patients who cleared the viral infection early (n=13) and those who remained HCV RNA positive after 12 weeks of observation (n=13) with a reduced ratio of CD4 T cells to NK cells in the non-early clearer. Further, correlation analyses of 50 cytokines and chemokines revealed more positive correlations in between the distinct cytokines, especially for IFNα and IL-16, and between the cytokines and HCV RNA levels in spontaneous early clearer patients. Beyond that, in vitro stimulation of CD4 T cells with IL-16 reduced the susceptibility of these cells to killing by IFNα-activated NK cells. These data indicate that the immune cell composition and cytokine pattern varies considerably in patients with symptomatic aHCV infection. NK cell-mediated killing of CD4 T cells might affect early control of HCV infection.
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http://dx.doi.org/10.1111/jvh.13050DOI Listing
April 2019

Long-term changes in liver elasticity in hepatitis C virus-infected patients with sustained virologic response after treatment with direct-acting antivirals.

United European Gastroenterol J 2018 Oct 27;6(8):1188-1198. Epub 2018 Jun 27.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: The use of interferon-free direct-acting antiviral agents (DAAs) is associated with a rapid short-term decrease in liver stiffness in chronic hepatitis C-infected patients with sustained virologic response (SVR).

Objective: The objective of this article is to evaluate long-term changes in liver elasticity in hepatitis C patients with SVR using transient elastography (TE), FIB-4 and APRI.

Methods: A total of 143 patients were treated with DAAs and reached SVR. Patients received TE measurement (median (range)) at treatment start (baseline), follow-up week 24 (FU24) and follow-up week 96 (FU96). Laboratory data were examined at each date and FIB-4 and APRI were calculated.

Results: Liver elasticity showed a significant decrease from baseline to FU24 (13.1 (3.1-75) kPa to 9.3 (2.9-69.1) kPa;  < 0.0001) and declined further until FU96 (7.9 (2.4-59.3) kPa;  < 0.0001). Liver inflammation and liver function parameters normalised during long-term follow-up. Progression of liver stiffness between FU24 to FU96 despite viral clearance was observed in 24 patients (17%). Long-term liver stiffness progression was associated with aspartate aminotransferase levels and TE change from baseline to FU24.

Conclusion: During long-term follow-up, the majority of patients with SVR had further improved liver stiffness values. Still, a significant proportion of patients may show long-term liver stiffness progression and thus continued TE follow-up is recommended.
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http://dx.doi.org/10.1177/2050640618786067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169054PMC
October 2018

Different kinetics of liver stiffness using shear wave elastography in patients with chronic hepatitis C infection treated with interferon-free regimens.

Eur J Gastroenterol Hepatol 2019 01;31(1):67-74

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: Direct-acting antivirals (DAAs) lead to a high rate of sustained virologic response (SVR) in chronic hepatitis C infection. The aim was to evaluate liver stiffness kinetics, using acoustic radiation force impulse (ARFI) imaging elastography, during and after DAAs in patients who had reached SVR.

Patients And Methods: A total of 275 consecutive chronic hepatitis C virus-infected patients were included in this longitudinal prospective single-centre study. All patients received DAAs for 8 to 24 weeks, and liver stiffness measurements (LSMs) by ARFI at baseline, at week 4, week 12, week 24, and 24 weeks (SVR24) and 48 weeks (FU48) after the end of treatment were recorded. Transient elastography was performed at baseline and at SVR24.

Results: A decrease in LSM was detected at SVR24 by ARFI and transient elastography (P<0.001 and <0.001, respectively). A continuous gradual decrease in ARFI was observed in patients with cirrhosis versus a nonsignificant change in patients without cirrhosis until FU48 (P<0.001 vs. 0.877, respectively). At SVR24, higher baseline ARFI values (P=0.038) were associated with a decrease in LSM in patients with cirrhosis versus normal international normalization ratio (P=0.003), lower bilirubin (P=0.003), and higher albumin (P=0.007) in patients without cirrhosis. The incidence of liver stiffness decrease from baseline was higher in patients with cirrhosis than in those without cirrhosis (P<0.001), whereas the incidence of liver stiffness progression was more pronounced in advanced than in compensated cirrhosis (P<0.001).

Conclusion: After DAAs in patients with SVR, liver stiffness improves in patients with cirrhosis, whereas non-cirrhotic patients show no true change in liver stiffness. Liver stiffness worsens in patients with advanced liver disease.
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http://dx.doi.org/10.1097/MEG.0000000000001259DOI Listing
January 2019

Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity.

Nat Commun 2018 06 11;9(1):2275. Epub 2018 Jun 11.

Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186, Stockholm, Sweden.

Diversity is a central requirement for the immune system's capacity to adequately clear a variety of different infections. As such, natural killer (NK) cells represent a highly diverse population of innate lymphocytes important in the early response against viruses. Yet, the extent to which a chronic pathogen affects NK cell diversity is largely unknown. Here we study NK cell functional diversification in chronic hepatitis C virus (HCV) infection. High-dimensional flow cytometer assays combined with stochastic neighbor embedding analysis reveal that chronic HCV infection induces functional imprinting on human NK cells that is largely irreversible and persists long after successful interventional clearance of the virus. Furthermore, HCV infection increases inter-individual, but decreases intra-individual, NK cell diversity. Taken together, our results provide insights into how the history of infections affects human NK cell diversity.
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http://dx.doi.org/10.1038/s41467-018-04685-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995831PMC
June 2018

Human γδ T Cell Receptor Repertoires in Peripheral Blood Remain Stable Despite Clearance of Persistent Hepatitis C Virus Infection by Direct-Acting Antiviral Drug Therapy.

Front Immunol 2018 16;9:510. Epub 2018 Mar 16.

Institute of Immunology, Hannover Medical School, Hannover, Germany.

Human γδ T cells can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation. This study aimed to understand the clonal distribution of γδ T cells in peripheral blood of chronic HCV patients and following HCV clearance by interferon-free direct-acting antiviral drug therapies. To this end, γδ T cell receptor (TCR) repertoires were monitored by mRNA-based next-generation sequencing. While the percentage of Vγ9 T cells was higher in patients with elevated liver enzymes and a few expanded Vδ3 clones could be identified in peripheral blood of 23 HCV-infected non-cirrhotic patients, overall clonality and complexity of γδ TCR repertoires were largely comparable to those of matched healthy donors. Monitoring eight chronic HCV patients before, during and up to 1 year after therapy revealed that direct-acting antiviral (DAA) drug therapies induced only minor alterations of TRG and TRD repertoires of Vγ9 and Vγ9 cells. Together, we show that peripheral γδ TCR repertoires display a high stability (1) by chronic HCV infection in the absence of liver cirrhosis and (2) by HCV clearance in the course of DAA drug therapy.
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http://dx.doi.org/10.3389/fimmu.2018.00510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864898PMC
May 2019

Interferon-free cure of chronic Hepatitis C is associated with weight gain during long-term follow-up.

Z Gastroenterol 2017 Sep 12;55(9):848-856. Epub 2017 Sep 12.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

 The advent of direct-acting antivirals has revolutionized treatment of chronic hepatitis C with very high cure rates and excellent tolerability compared to interferon-based hepatitis C virus (HCV) treatment. However, long-term effects of interferon-free cure of HCV infection on the metabolic condition of patients have not been investigated so far.  We investigated weight development during and after antiviral treatment of hepatitis C. In a prospective single-center cohort study, interferon-free antiviral treatment was initiated in 284 patients. Each patient's weight was monitored 1 year before the start of treatment, at baseline (BL), end of treatment (EOT), follow-up week 24 (FU24), and follow-up week 48 (FU48).  Weight gain after HCV cure was observed in 20 %, 33 %, and 44 % of patients at EOT, FU24, and FU48, respectively. The mean overall weight change at FU48 compared to baseline was 1.45 kg (95 % CI 0.44; 2.46, p = 0.02, compared to the pretreatment period). Multivariate regression revealed age as the only factor predicting weight change at FU48 (B - 0.107, 95 % CI, - 0.202 to - 0.011, p = 0.03), while gender, cirrhosis, diabetes mellitus, ribavirin, and body mass index had no influence. In the subgroup of patients younger than 60 years, mean weight gain at FU48 compared to baseline was 2.8 kg (95 % CI, 1.23 - 4.4). In contrast, patients 60 years and older had a mean weight change of - 0.04 kg (95 % CI, - 1.12 to 1.03, p = 0.005).  Cure of HCV by interferon-free antiviral treatment was associated with weight gain in up to 44 % of patients during long-term follow-up. Weight gain occurred predominantly in patients younger than 60 years. The precise mechanism of weight gain remains to be elucidated.
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http://dx.doi.org/10.1055/s-0043-112656DOI Listing
September 2017

Stomach reduction or gastric bypass as risk factor for treatment failure after DAA therapy for hepatitis C?

J Hepatol 2018 04 22;68(4):851-853. Epub 2017 Nov 22.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research, partner-site Hannover-Braunschweig, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2017.10.035DOI Listing
April 2018

Real-world effect of ribavirin on quality of life in HCV-infected patients receiving interferon-free treatment.

Liver Int 2018 05 14;38(5):834-841. Epub 2017 Oct 14.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background & Aims: Ribavirin (RBV) is commonly used for the treatment of hepatitis C virus (HCV) infection. However, RBV is associated with a reduced quality of life (QOL). We aim to assess the impact of RBV on QOL in a real-world setting.

Methods: In a prospective study, QOL was measured by a SF-36 questionnaire in 174 patients. In all, 85 patients were treated with RBV and 89 patients without RBV. QOL was assessed at baseline, week 12 of treatment and 24 weeks after treatment.

Results: Patients treated with RBV were more likely to have HCV genotype 2 and 3 infection and cirrhosis (all P < .05). RBV-treated patients reported lower scores for several domains of QOL already at baseline. During HCV treatment, RBV-free treatment led to an increase in all measured dimensions of quality of life, whereas RBV treatment led to a decrease in the emotional and physical functioning. After treatment, all dimensions for QOL showed improvement across the study cohort, regardless whether RBV was part of the treatment regimen. However, 28.8%-45.2% of treated patients perceive a sustained reduction in their physical or mental capacity after treatment, not related to RBV usage or SVR, but related to older age (P = .03) and cirrhosis (P = .02).

Conclusions: During treatment, RBV leads to a reduced QOL, whereas RBV-free treatment leads to an increased QOL. After treatment, QOL strongly increases in both, RBV and RBV-free treated patients. Some patients perceive a sustained reduction in QOL, which seems unrelated to treatment.
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http://dx.doi.org/10.1111/liv.13601DOI Listing
May 2018

Successful retreatment of a patient with chronic hepatitis C genotype 2k/1b virus with ombitasvir/paritaprevir/ritonavir plus dasabuvir.

J Antimicrob Chemother 2017 05;72(5):1541-1543

Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research [a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI)], Hannover, Germany.

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http://dx.doi.org/10.1093/jac/dkw572DOI Listing
May 2017

Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study.

Lancet Infect Dis 2017 02 28;17(2):215-222. Epub 2016 Oct 28.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, German Liver Foundation, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address:

Background: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection.

Methods: In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918.

Findings: Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log IU/mL (1·71-7·20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament.

Interpretation: Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations.

Funding: Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).
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http://dx.doi.org/10.1016/S1473-3099(16)30408-XDOI Listing
February 2017

Viral and Host Responses After Stopping Long-term Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B.

J Infect Dis 2016 11 7;214(10):1492-1497. Epub 2016 Sep 7.

Department of Gastroenterology, Hepatology and Endocrinology.

This prospective study investigated viral and host markers after stopping long-term therapy with nucleos(t)ide analogues in noncirrhotic patients with hepatitis B e antigen-negative chronic hepatitis B. After stopping therapy, 13 of 15 patients experienced a virological relapse. Rebound of hepatitis B virus DNA and hepatitis B core-related antigen was associated with induction of plasma tumor necrosis factor, interleukin (IL) 10 , IL-12p70, CXCL10 and subsequent decline in hepatitis B surface antigen (HBsAg), with 20% HBsAg loss after long-term follow-up. The peak levels of hepatitis B virus DNA and hepatitis B core-related antigen after cessation of therapy were positively correlated with the level of HBsAg decline at week 48. Thus, stopping or interrupting NA treatment should be further investigated as a strategy to accelerate HBsAg loss.
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http://dx.doi.org/10.1093/infdis/jiw412DOI Listing
November 2016

Antiviral treatment and liver-related complications in hepatitis delta.

Hepatology 2017 02 30;65(2):414-425. Epub 2016 Nov 30.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG-IFNα) is effective in only 25%-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow-up, 5.2 years; range, 0.6-18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty-nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)-based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death developed in 55 patients (40%). Patients who received IFNα-based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07-0.9). Loss of HDV RNA during follow-up was more frequent in IFNα-treated patients and strongly linked with a lower likelihood to experience liver-related complications.

Conclusion: IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425).
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http://dx.doi.org/10.1002/hep.28876DOI Listing
February 2017

Direct-Acting Antiviral-Induced Hepatitis C Virus Clearance Does Not Completely Restore the Altered Cytokine and Chemokine Milieu in Patients With Chronic Hepatitis C.

J Infect Dis 2016 Dec 28;214(12):1965-1974. Epub 2016 Sep 28.

Department of Gastroenterology, Hepatology, and Endocrinology.

Background:  Persistent infection with hepatitis C virus (HCV) causes profound alterations of the cytokine and chemokine milieu in peripheral blood. However, it is unknown to what extend these alterations affect the progression of liver disease and whether HCV clearance normalizes soluble inflammatory mediators.

Methods:  We performed multianalyte profiling of 50 plasma proteins in 28 patients with persistent HCV infection and advanced stages of liver fibrosis or cirrhosis and 20 controls with fatty liver disease. The patients were treated for 24 weeks with sofosbuvir and ribavirin and underwent sampling longitudinally. Ten patients experienced viral relapse after treatment cessation.

Results:  The cytokine and chemokine expression pattern was markedly altered in patients with chronic HCV infection as compared to healthy controls and patients with nonalcoholic steatohepatitis. Distinct soluble factors were associated with the level of fibrosis/cirrhosis, viral replication, or treatment outcome. The baseline expression level of 10 cytokines distinguished patients with a sustained viral response from those who experienced viral relapse. While the majority of upregulated analytes declined during and after successful therapy, HCV clearance did not lead to a restoration of parameters that were suppressed.

Conclusions:  Chronic HCV infection appears to disrupt the milieu of soluble inflammatory mediators even after viral clearance. Thus, HCV cure does not lead to complete immunological restitution.
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http://dx.doi.org/10.1093/infdis/jiw457DOI Listing
December 2016

Safety and Effectiveness of Direct-Acting Antiviral Agents for Treatment of Patients With Chronic Hepatitis C Virus Infection and Cirrhosis.

Clin Gastroenterol Hepatol 2016 12 9;14(12):1821-1830.e6. Epub 2016 Jul 9.

Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada.

Background & Aims: Direct-acting antivirals (DAAs) have revolutionized treatment for patients with chronic hepatitis C virus (HCV) infection, leading to a high rates of sustained virologic response. This study assessed the real-world safety and effectiveness of DAA-based antiviral therapy for the treatment of cirrhotic patients with chronic HCV infection.

Methods: This international, multicenter cohort study included all consecutive patients with chronic HCV infection and cirrhosis who underwent antiviral therapy with second-generation DAAs. Data on all patients were analyzed to assess treatment response. Predictors of hepatic decompensation during antiviral therapy were assessed using Cox proportional hazards regression analyses.

Results: Until June 2015, 433 cirrhotic patients with chronic HCV infection started DAA-based treatment. Their mean age was 57.8 (±8.7) years, 277 (64.0%) patients were male, and 114 (26.3%) had a Child-Pugh (CP) score of B/C cirrhosis. The sustained virologic response rate at 12 weeks was similar among patients with a CP score of A (261 of 304 [85.9%]) and a CP score of B/C (83 of 101 [82.2%]; P = .37). A baseline albumin level less than 35 g/L (hazard ratio [HR], 3.11; 95% confidence interval [CI], 1.23-7.84; P = .005), baseline MELD score of 14 or higher (HR, 1.63; 95% CI, 1.03-2.61; P = .037), and HCV genotype 3 (HR, 2.05; 95% CI, 1.09-3.88; P = .033) were associated independently with hepatic decompensation during antiviral treatment among patients with a CP score of B/C.

Conclusions: This large cohort study showed that therapy is safe and effective in patients with compensated (CP score of A) cirrhosis. For patients with decompensated (CP score of B/C) cirrhosis, albumin level less than 35 g/L, MELD score of 14 or greater, and HCV genotype 3 are important risk factors for hepatic decompensation during DAA-based treatment. Therefore, these patients require close monitoring during antiviral therapy or treatment should be deferred until after transplantation.
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http://dx.doi.org/10.1016/j.cgh.2016.07.001DOI Listing
December 2016

Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy.

Eur J Immunol 2016 09 12;46(9):2204-10. Epub 2016 Jul 12.

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Immune exhaustion is a hallmark of chronic viral infections. However, pathogen eradication can result in reinvigorated immune responses. Indeed, this was recently suggested for antigen-specific CD8(+) T cells and NK cells in HCV-infected patients receiving an interferon-free treatment regimen. Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved innate-like effector T cells. Here, we show that MAIT cells are severely diminished in frequency in chronic HCV-infection, and in this regard the most affected immune cell type in peripheral blood of humans with this disease. Residual MAIT cells show an activated phenotype with high expression of granzyme B, HLA-DR, PD-1, and CD69 as well as altered transcription factor expression and suppressed responsiveness to MR1-dependent antigen stimulation. In contrast to other immune cells, MAIT cells are not reinvigorated after successful HCV-clearance using interferon-free therapy. The present results hence demonstrate persistent immune cell-dysfunction in humans despite successful elimination of a chronic pathogen.
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http://dx.doi.org/10.1002/eji.201646447DOI Listing
September 2016

Clinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens.

J Hepatol 2016 09 13;65(3):473-82. Epub 2016 Apr 13.

Department of Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany. Electronic address:

Background & Aims: The European Association for the Study of the Liver (EASL) guidelines recommend HCV RNA measurements at specific time points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyze whether on-treatment HCV RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays.

Methods: Samples were collected from 298 patients (HCV genotypes; GT1-5) at weeks (w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two university clinics and tested for HCV RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin (RBV) 12/24 w (n=99), pegylated-interferon-alfa (PegIFN)/SOF/RBV 12 w (n=51), SOF/simeprevir (SMV)±RBV 12 w (n=69) or SOF/daclatasvir±RBV 12/24 w (n=79).

Results: HCV RNA levels during the first 4weeks of SOF/RBV therapy were significantly lower in GT3 patients who achieved SVR compared with those who relapsed. All GT3 patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ⩾45IU/ml (p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR: 100% vs. 29%; p=0.0002). In contrast, HCV RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV RNA was frequently detected by ART at later stages of therapy. However, SVR rates remained high in these patients. At the end of SOF/SMV±RBV therapy HCV RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR.

Conclusions: HCV RNA levels assessed at week 2 of SOF/RBV therapy can predict relapse in GT3-patients. Detectable HCV RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension.

Lay Summary: We analyzed the predictive value of hepatitis C virus (HCV) RNA levels measured at different time points for treatment efficacy. We found that the level of HCV RNA measured at week 2 of antiviral therapy can be used to predict treatment success in patients with HCV genotype 3 infection treated with sofosbuvir and ribavirin but not in patients treated with other sofosbuvir-based regimens. Low level HCV RNA is frequently detected by the RealTime HCV assay during later stages of antiviral therapy. However, this is not associated with reoccurrence of HCV RNA after the end of treatment.
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http://dx.doi.org/10.1016/j.jhep.2016.04.006DOI Listing
September 2016

Flares during long-term entecavir therapy in chronic hepatitis B.

J Gastroenterol Hepatol 2016 Nov;31(11):1882-1887

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background And Aim: The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB).

Methods: CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as > 3× increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT > 3× ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA).

Results: Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg (n = 3) and hepatitis B surface antigen (n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance (n = 2) and non-compliance (n = 1).

Conclusion: The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares.
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http://dx.doi.org/10.1111/jgh.13377DOI Listing
November 2016
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