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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., Competing Interests: Johannes Vermehren: sponsored lectures (national oriInternational): AbbVie, Gilead, Intercept, Merck. Markus Cornberg: sponsored lectures (national or international): AbbVie, Gilead, Merck/MSD, Siemens Healthcare, Falk Foundation e. V.; other: advisory committee or review panel: Merck/MSD, AbbVie, Spring. Albrecht Stoehr: grants: Abbvie, Bristol-Myers-Squibb, Gilead, Janssen, MSD, ViiV; sponsored lectures (national or international): AbbVie, Bristol-Myers-Squibb, Gilead, Janssen, MSD, ViiV; other: advisory boards: AbbVie, Bristol-Myers-Squibb, Gilead, Janssen, MSD, ViiV. Hartwig Klinker: grants: Abbvie, BMS, Gilead, Janssen, MSD; sponsored lectures (national or international): AbbVie, BMS, Gilead, Janssen, MSD; other: advisory boards: AbbVie, BMS, Gilead, Hexal, Janssen, MSD. Karl-Georg Simon: sponsored lectures (national or international): AbbVie, FALK, Gilead, MSD; other: advisory committee or review panel: AbbVie, MSD. Gerlinde Teuber: sponsored lectures (national or international): AbbVie, Gilead Sciences, Intercept, MSD; other: advisory committee or review panel: AbbVie, Gilead. Katja Deterding: sponsored lectures (national or international): AbbVie, Gilead, Merck/MSD; other: advisory committee: Gilead, AbbVie. Julian Schulze zur Wiesch: sponsored lectures: Gilead, MSD, AbbVie. Maria-Christina Jung: nothing to disclose. Yvonne Serfert: nothing to disclose. Michael P. Manns: grants: AbbVie, BMS, Janssen, Gilead, Merck (MSD); sponsored lectures (national or international): AbbVie, BMS, Janssen, Gilead, Merck (MSD); consultant: AbbVie, BMS, Janssen, Gilead, Merck (MSD). Stefan Zeuzem: consultancies and lecture honoria: AbbVie, Gilead, Intercept, Janssen, Merck/MSD. Heiner Wedemeyer: reports personal fees from Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk, AbbVie, Novartis, GSK, Roche Diagnostics, Eiger, ITF, and MyrGmbH; grants/research support from MSD, Novartis, Gilead, Roche, Abbott, and Roche Diagnostics. Christoph Sarrazin: grants: Abbott, Gilead, Janssen, Qiagen, Roche, Siemens; sponsored lectures (national or international): Abbott, AbbVie, Achillion, BMS, Gilead, Janssen, Merck/MSD, Qiagen, Roche, Siemens; other: advisory boards: Abbott, AbbVie, BMS, Gilead, Janssen, Merck/MSD, Roche., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background:  Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described., Patients and Methods:  Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available., Results:  Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %)., Conclusions:  Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective., Competing Interests: Annika Schmitt: consulting: AbbVieRainer Günther: has nothing to discloseStefan Mauss: sponsored lectures (national or international): Gilead, AbbVie, MSD; advisory committee or review panel: Gilead, AbbVie, MSDKlaus H.W. Boeker: speaking and teaching: AbbVie, Gilead, MSDPeter Buggisch: advisory committee or review panel: AbbVie, Gilead, MSD, Intercept; speaking and teaching: AbbVie, Gilead, Falk, Merz, MSD, NorgineHeribert Hillenbrand: has nothing to discloseChristine John: has nothing to discloseHartwig Klinker: advisory committee or review panel: AbbVie, BMS, Gilead, Hexal, Janssen, MSD, Shionogi; grant/research support: AbbVie, Arrowhead, BMS, Janssen, Gilead, MSD, Novartis; speaking and teaching: AbbVie, BMS, Gilead, Janssen, MSDAnita Pathil: consultant: AbbVie; sponsored lectures (National or International): AbbVie, BMS, Gilead, JanssenKarl-Georg Simon: advisory committee or review panel: AbbVie, Gilead, MSD; speaking and teaching: AbbVie, FALK, Gilead, MSDYvonne Serfert: has nothing to discloseClaus Niederau: grants: AbbVie, Falk, Genzyme, Gilead, MSD, Novartis, Shire; consultant: AbbVie, Alexion, Genzyme, Gilead, Janssen, MSD, Shire; sponsored lectures: (National or International): AbbVie, Alexion, Biogen, BMS, Falk, Genzyme, Gilead, Janssen, MSD, Novartis, ShireJohannes Vermehren: sponsored lectures (national or international): AbbVie, Gilead, Intercept, Merck.Heiner Wedemeyer: personal fees from Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk, AbbVie, Novartis, GSK, Roche Diagnostics, Eiger, ITF, and MyrGmbH; grants/research support from MSD, Novartis, Gilead, Roche, Abbott, and Roche Diagnostics.Christoph Sarrazin: speaker and consultation for AbbVie, Gilead, MSD/Merck, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background:  The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations., Methods:  This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or other IFN-free regimens: daclatasvir + sofosbuvir (DCV + SOF), ledipasvir/sofosbuvir (SOF/LDV), paritaprevir/r + ombitasvir ± dasabuvir (PrOD), with or without ribavirine (R)., Results:  A total of 5496 subjects were followed during the period. During this period, clinical recommendations and treatment patterns evolved rapidly in response to new evidence from clinical trials and clinical routine and regulatory approval of additional regimens. High SVR12 rates were seen in this cohort, even in hard-to-treat patient subgroups. In the multivariate analysis, gender, age, advanced cirrhosis, and intensified treatment for cirrhotics were associated with treatment outcome., Conclusion:  Despite limited knowledge of the optimal utilization of the newly approved DAA combinations and treatment durations as well as their comparative efficacy and safety profiles, high SVR rates were achieved regardless of the DAA combination. These outcomes were facilitated by the rapid adaptation of clinical recommendations. Future situations with high unmet medical need may follow a similar approach., Competing Interests: CS has received speaker and consultancy fees from Abbvie, Abbott, BMS, Gilead, Janssen, Merck and Siemens.PB has received speaker and consultancy fees from AbbVie, Falk, Gilead, Merz Pharma and MSD.SM has received speaker and consultancy fees from AbbVie, Gilead, Janssen and MSD.TM has received speaker and consultancy fees from AbbVie, Falk, Intercept, Gilead, MSD, Novartis and Roche.TZ has received speaker and consultancy fees from AbbVie, Astellas, BMS, Boehringer Ingelheim, Gilead Sciences, Janssen, MSD, Novartis, and Roche.HK has received speaker and consultancy fees from AbbVie, BMS, Gilead, Hexal, Janssen and MSD.AP has received speaker and consultancy fees from Janssen, Gilead, AbbVie und BMS.MS is an employee of Janssen.CN is an employee of Janssen.ILD is an employee of Janssen.KGS has received speaker and consultancy fees from AbbVie, BMS, Janssen, Falk, Gilead, Norgine, Merz, MSD., (© Georg Thieme Verlag KG Stuttgart · New York.)

Treatment decisions are based on extent of fibrosis in patients with chronic hepatitis C (HCV) infection. Noninvasive diagnostic tools may help to avoid liver biopsy. We investigated the diagnostic accuracy of noncommercial serum scores in comparison with transient elastography (TE). Data analysis was undertaken based on 2458 patients enrolled in the German Hepatitis C Registry, in a prospective, observational study. Aspartate aminotransferase-to-platelet ratio index (APRI), FORNS index and FIB-4 score were calculated and the diagnostic accuracy was compared to TE. As estimated by TE, 955 (38.9%) patients had absence of significant fibrosis (SF), 736 (29.9%) patients had SF, and 767 (31.2%) patients were shown to have cirrhosis. Patients with absence of SF had a sustained virological response (SVR) rate of 97.9%, whereas SVR was attained in 96.2% and 92.2% in those with SF and cirrhosis, respectively (P < 0.0001). The area under the receiver operator characteristic curve (AUROC), sensitivity and specificity in discriminating of SF were 0.789, 0.596 and 0.939 by APRI; 0.838, 0.852 and 0.748 by FORNS index; and 0.828, 0.658 and 0.946 by FIB-4 score. AUROCs for the prediction of cirrhosis, sensitivity and specificity were 0.881, 0.851 and 0.854 by APRI; 0.846, 0.948 and 0.628 by FORNS index; and 0.907, 0.907 and 0.848 by FIB-4 score. In conclusion, in the present multicentre real-world cohort, SF and cirrhosis were predicted with high accuracy with noncommercial serum markers using TE as reference. Further prospective long-term follow-up is necessary to compare biomarkers with TE concerning liver-related outcome and overall mortality., (© 2018 John Wiley & Sons Ltd.)

Background:  More than 250 000 patients suffer from chronic hepatitis C in Germany. Several potent, direct-acting antiviral drugs have been approved since 2014. The aim of the German Hepatitis C-Registry (DHC-R) is to describe the epidemiology and patient care of hepatitis C and to investigate the efficacy and safety of new treatment options in real-world settings., Methods:  The DHC-R is a prospective multicenter non-interventional registry study that includes 327 centers throughout Germany. All approved treatment options have been documented. The current analysis differentiated 4 phases: 2/2014 - 12/2014, 1/2015 - 12/2015, 1/2016 - 7/2017 and 8/2017 - 7/2018., Findings:  Between February 2014 and July 2018, 12 170 patients were included in the registry (61.3 % male), and antiviral treatment was initiated in 11 268. The mean age declined from 52.3 years (phase 1) to 49.3 years (phase 4), while the proportion of patients with previous or ongoing drug abuse increased (26.3 % to 43.1 %). In 2014, 35.1 % of treated patients had liver cirrhosis, which declined to 16.5 % in phase 4. The HCV genotype distribution showed marked fluctuations, with most recent increases in HCV genotype 3 (30 % in phase 4). Per-protocol sustained virological response rates increased from 92.8 % in 2014 to 94.4 % in 2017/18 with excellent tolerability., Summary:  The DHC-R mirrors patient care of chronic hepatitis in the real-world setting in Germany and provides insights into epidemiology developments. It also confirms the high efficacy and safety of novel treatment options., Competing Interests: Dr. Dietrich Hüppe hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: MSD Sharp&Dohme GmbH, Janssen Cilag GmbH, Roche Pharma AG, Bristol-Myers Squibb GmbH&Co. KGaA, Falk Pharma, Boehringer Ingelheim Pharma GmbH & Co. KG, Novartis Pharma Germany GmbH, Norgine GmbH, AbbVie GmbH & Co. KG, Gilead Sciences GmbH, Ferring Arzneimittel GmbH, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: With the aging of the hepatitis C virus (HCV)-infected patient cohort and the availability of highly effective and tolerable treatment regimens, an increasing number of elderly patients are now eligible for HCV therapy. This study investigated clinical and epidemiologic characteristics of elderly HCV-infected patients as well as the effectiveness and safety of available therapies., Methods: Patients were enrolled into the German Hepatitis C Registry (DHC-R), a prospective, multicenter, real-world cohort study. Patients were treated at the discretion of the physician, and data were collected by a web-based system., Results: Of 7133 patients who initiated treatment, 686 (9.6%) were > 70 years of age. In patients > 70 years, intent-to-treat (ITT) SVR12 was 92.6% (514/555) compared to 90.7% (4521/4985) in patients ≤ 70 years of age. Overall, adverse events (AEs) were reported in 374 (54.5%) and 3435 patients (53.3%) > 70 or ≤ 70 years of age; 7.6% (52) and 3.6% (235) in the respective age groups had a serious AE. Twenty-two (3.2%) and 62 (1.0%) of the patients > 70 or ≤ 70 years discontinued treatment due to AEs. Death was reported in 34 patients, of whom eight were > 70 years of age. Frequent comorbidities in patients > 70 years of age were cardiac disease, renal disease and diabetes. Psychiatric disorders, substance abuse and viral co-infection were more frequent in younger patients., Conclusion: Direct-acting antiviral therapies were well tolerated in patients older than 70 years. SVR12 rates in the elderly patient group were similar to those observed in younger patients. Differences in the prevalence of comorbidities between age groups warrant individualized attention with respect to drug-drug interactions and therapy adherence. The study was registered in the German Clinical Trials Register, DRKS-ID: DRKS00009717.

There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. Three hundred forty-two chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co-infected patients [11.1%]). SVR12 rates in the "intention-to-treat" analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir ± ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir ± ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir ± ribavirin for 12 weeks 71.4% (10/14), and sofosbuvir/ledipasvir ± ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow-up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir ± ribavirin for 12 weeks and sofosbuvir/ledipasvir ± ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment-experienced or HIV/HCV co-infected patients., (© 2017 Wiley Periodicals, Inc.)

Background: HCV has complex interactions with human lipid metabolism leading to down regulation of cholesterol levels. Interferon (IFN) therapy has been shown to decrease cholesterol even further. With the availability of second-generation direct-acting antiviral agents (DAA) the effect of suppressing and eliminating HCV on lipid metabolism warrants reevaluation., Methods: Prospective German multicentre cohort on HCV- and HIV-HCV-infected patients treated with direct-antiviral agents (GECCO). Lipids were assessed at baseline, during and after therapy. Wilcoxon test corrected for multiple testing was used., Results: For the analysis, 520 patients with chronic hepatitis C were available. Patients with chronic hepatitis C were treated as follows: sofosbuvir (SOF)/pegylated IFN (PEG-IFN)/ribavirin (RBV; HCV=34, HIV-HCV=36), SOF/RBV (HCV=47, HIV-HCV=16), SOF/simeprevir (HCV=9, HCV-HIV=2), SOF/daclatasvir +/- RBV (HCV=27, HIV-HCV=47), SOF/ledipasvir +/- RBV (HCV=147, HCV-HIV=100) and ombitasvir/paritaprevir/ritonavir +/- dasabuvir +/- RBV (2D, HCV=2, HCV-HIV=6; 3D, HCV=39, HCV-HIV=8). On treatment there was a statistically significant increase in total cholesterol for any IFN-free DAA regimen, which was maintained after end of therapy. Changes of total cholesterol were driven by changes in low-density lipoprotein cholesterol, whereas high-density lipoprotein cholesterol remained unchanged. In contrast, total cholesterol decreased on SOF/PEG-IFN/RBV and increased after end of therapy above baseline levels. Triglycerides increased during treatment with SOF/PEG-IFN/RBV, but not on DAA-only regimens., Conclusions: Suppressing and eliminating HCV with IFN-free DAA regimens increased cholesterol levels, but had no effect on triglycerides. In contrast IFN-based therapy decreased cholesterol and increased triglycerides during treatment and led to increases in cholesterol after achieving sustained virological response.

Background: Shortening the duration of treatment with HCV direct-acting antivirals (DAAs) leads to substantial cost reductions. According to the label, sofosbuvir and ledipasvir can be prescribed for 8 weeks (SL8) in noncirrhotic women or men with HCV genotype 1 and low viral loads. However, real-world data about the efficacy and safety of SL8 are largely missing., Methods: Interim results from an ongoing prospective, multicenter cohort of 9 treatment centers in Germany (GECCO). All patients started on treatment with HCV DAAs since January 2014 were included. This report describes safety and efficacy outcomes in 210 patients with HCV monoinfection and 35 with human immunodeficiency virus (HIV)-HCV coinfection given SL8 in a real-world setting., Results: Of 1353 patients included into the GECCO cohort until December 2015, a total of 1287 had complete data sets for this analysis; 337 (26.2%) fulfilled the criteria for SL8 according to the package insert, but only 193 (57.2%) were eventually treated for 8 weeks. Another 52 patients did not fulfill the criteria but were treated for 8 weeks. SL8 was generally well tolerated. The overall sustained virologic response rate 12 weeks after the end of treatment was 93.5% (186 of 199). The on-treatment response rate was 99.4% (159 of 160) in HCV-monoinfected and 96.4% (27 of 28) in HIV-HCV-coinfected patients. Ten patients were lost to follow-up., Conclusions: SL8 seems highly effective and safe in well-selected HCV-monoinfected and HIV-HCV-coinfected patients in a real-world setting., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The likelihood of a sustained virological response (SVR) is the most important factor for physicians and patients in the decision to initiate and continue therapy for chronic hepatitis C (CHC) infection. This study identified predictive factors for SVR with peginterferon plus ribavirin (RBV) in patients with CHC treated under 'real-life' conditions. The study cohort consisted of patients from a large, retrospective German multicentre, observational study who had been treated with peginterferon alfa-2a plus RBV or peginterferon alfa-2b plus RBV between the years 2000 and 2007. To ensure comparability regarding peginterferon therapies, patients were analysed in pairs matched by several baseline variables. Univariate and multivariate logistic regression analyses were used to determine the effect of nonmatched baseline variables and treatment modality on SVR. Among 2378 patients (1189 matched pairs), SVR rates were 57.9% overall, 46.5% in HCV genotype 1/4-infected patients and 77.3% in genotype 2/3-infected patients. In multivariate logistic regression analysis, positive predictors of SVR were HCV genotype 2 infection, HCV genotype 3 infection, low baseline viral load and treatment with peginterferon alfa-2a. Negative predictors of SVR were higher age (≥40 years), elevated baseline gamma-glutamyl transpeptidase (GGT) and low baseline platelet count (<150,000/μL). Among patients treated with peginterferon plus RBV in routine clinical practice, genotype, baseline viral load, age, GGT level and platelet levels all predict the likelihood of treatment success. In patients matched by baseline characteristics, treatment with peginterferon alfa-2a may be a positive predictor of SVR when compared to peginterferon alfa-2b., (© 2010 Blackwell Publishing Ltd.)