sofosbuvir in chronic hepatitis C

Accepted Manuscript Real-world effectiveness of 8 weeks treatment with ledipasvir/sofosbuvir in chronic hepatitis C Peter Buggisch, Johannes Vermehren, Stefan Mauss, Rainer Günther, Eckart Schott, Anita Pathil, Klaus Boeker, Tim Zimmermann, Gerlinde Teuber, HeikePfeiffer Vornkahl, Karl-Georg Simon, Claus Niederau, Heiner Wedemeyer, Stefan Zeuzem PII: DOI: Reference:

S0168-8278(17)32431-5 https://doi.org/10.1016/j.jhep.2017.11.009 JHEPAT 6750

To appear in:

Journal of Hepatology

Received Date: Revised Date: Accepted Date:

5 January 2017 2 November 2017 3 November 2017

Please cite this article as: Buggisch, P., Vermehren, J., Mauss, S., Günther, R., Schott, E., Pathil, A., Boeker, K., Zimmermann, T., Teuber, G., Vornkahl, H-P., Simon, K-G., Niederau, C., Wedemeyer, H., Zeuzem, S., Real-world effectiveness of 8 weeks treatment with ledipasvir/sofosbuvir in chronic hepatitis C, Journal of Hepatology (2017), doi: https://doi.org/10.1016/j.jhep.2017.11.009

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Real-world effectiveness of 8 weeks treatment with ledipasvir/sofosbuvir in chronic hepatitis C Peter Buggisch1* , Johannes Vermehren2, Stefan Mauss3, Rainer Günther4, Eckart Schott5, Anita Pathil6, Klaus Boeker7, Tim Zimmermann8, Gerlinde Teuber9, Heike-Pfeiffer Vornkahl10, Karl-Georg Simon11, Claus Niederau12, Heiner Wedemeyer13, Stefan Zeuzem2* 1

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ifi-institute for interdisciplinary medicine, Hamburg; University Hospital Frankfurt, Frankfurt am Main;

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Center for HIV and Hepatogastroenterology, Duesseldorf; Universitätsklinikum Schleswig-Holstein

(UKSH), Campus Kiel, Kiel; 5Charité Campus Virchow-Klinikum (CVK), Berlin; 6University Hospital 7

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Heidelberg, Heidelberg; Hepatologische Praxis, Hannover; University Hospital Mainz, Mainz; 9

Hepatologische Praxis, Frankfurt;

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e.factum GmbH, Butzbach; Hepatologische Praxis, Leverkusen;

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St. Josef-Hospital, Katholisches Klinikum Oberhausen, Oberhausen;

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Hannover Medical School,

Hannover *Address for correspondence Peter Buggisch, MD, Dr. ifi-institute for interdisciplinary medicine Lohmühlenstr. 5 20099 Hamburg, Germany Email: [email protected] Phone: +49 (0)40 2840760-0 Fax: +49 (0)40 2840760-222 Stefan Zeuzem, MD, Prof. University Hospital Frankfurt Department of Medicine 1 Theodor-Stern-Kai 7 60596 Frankfurt am Main, Germany Email: [email protected] Phone: +49 (0)69 6301-4544 Fax: +49 (0)69 6301-87676

Keywords: HCV genotype 1, real world, 8 weeks treatment, Ledipasvir/Sofosbuvir, German Hepatitis C-Registry Electronic word count main text: 4,491/6,000 Electronic word abstract: 256/275 Number of figures and tables: 4 tables, 1figure, 2 supplementary tables Conflict of interest statements Peter Buggisch reports personal fees from AbbVie, BMS, Falk, Gilead, Janssen, Merz Pharma, and MSD outside the submitted work. Johannes Vermehren reports personal fees from Abbott, AbbVie, BMS, Gilead, MSD, Medtronic, and Roche outside the submitted work. Stefan Mauss reports personal fees from AbbVie, Bristol-Meyers-Squibb, Gilead Sciences, Janssen-Cilag, MSD Sharp&Dohme/Merck, and ViiV, outside the submitted work. Rainer Günther reports personal fees from AbbVie, BMS, MSD, and Gilead outside the submitted work. Eckart Schott reports personal

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fees from Gilead, Roche, Bayer, BMS, AbbVie, Janssen, MSD, Novartis, Falk, and Janssen outside the submitted work. Anita Pathil reports personal fees from AbbVie, BMS, and Gilead outside the submitted work. Tim Zimmermann reports personal fees from AbbVie and BMS outside the submitted work. Gerlinde Teuber reports personal fees from MSD, Gilead, AbbVie, Falk, BMS, and Janssen outside the submitted work. Klaus H.W. Boeker reports personal fees from Gilead Sciences, MSD Sharp & Dohme/Merck, AbbVie, and other from Janssen, outside the submitted work. Heike Pfeiffer-Vornkahl is employee of e.factum GmbH (CRO) working for AbbVie, Bristol Myers-Squibb, Gilead, Janssen, Leberstiftungs-GmbH Deutschland, MSD, and Roche. Karl-Georg Simon reports personal fees from AbbVie, BMS, Janssen, MSD, Falk, Gilead, Norgine, and Merz outside the submitted work. Claus Niederau reports grants and personal fees from MSD, Roche, BMS, Novartis, Boehringer-Ingelheim, Janssen, AbbVie, and Gilead outside the submitted work. 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 outside the submitted work. Stefan Zeuzem reports personal fees from Abbvie, Bristol-Myers Squibb Co., Gilead, Merck & Co., and Janssen outside the submitted work. Financial support The German Hepatitis C-Registry (DHC-R) is a project of the German Liver Foundation (Deutsche Leberstiftung) managed by Leberstiftungs-GmbH Deutschland in cooperation with the Association of German gastroenterologists in private practice (bng, Bund Niedergelassener Gastroenterologen) with financial support from the German Center for Infection Research (DZIF) as well as from the companies AbbVie Deutschland GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Gilead Sciences GmbH, Janssen-Cilag GmbH, MSD Sharp & Dohme GmbH, and Roche Pharma AG. The authors are independent from the funding companies in data analysis, data interpretation, report writing, and publication. Author contributions Peter Buggisch: data collection, data analysis, data interpretation, writing the article, tables; Johannes Vermehren: data analysis, data interpretation; Stefan Mauss: patient recruitment, data collection, data interpretation; Rainer Günther: patient recruitment, data collection; Eckart Schott: patient recruitment, data collection; Anita Pathil: patient recruitment, data collection; Klaus H.W. Boeker: patient recruitment, data collection; Tim Zimmermann: patient recruitment, data collection; Gerlinde Teuber: patient recruitment, data collection; Heike Pfeiffer-Vornkahl: data analysis, statistics; Karl-Georg Simon: patient recruitment, data collection, data interpretation; Claus Niederau: data interpretation; Heiner Wedemeyer: data analysis, data interpretation; Stefan Zeuzem: data analysis, data interpretation, writing the article Clinical Trial number DRKS00009717 (German Clinical Trials Register, DRKS)

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Abstract Background and aims: Ledipasvir/Sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the summary of product characteristics (SmPC), 8 weeks treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of 8 week regimen of LDV/SOF under real-world conditions available. Aim of the present study was to characterise patients receiving 8 weeks LDV/SOF compared with 12 weeks treatment duration and to describe outcome of therapy in routine clinical practice. Methods: The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Results: Overall, 84.6% (2,034/2,404) of the Intention-to-Treat (ITT) population and 98.2% (2,029/2,066) of the Per Protocol (PP) population achieved SVR12. In the 8 week group, 85.1% (824/968) of ITT and 98.3% (821/835) of PP patients achieved SVR12, while in the 12 week group, 85.5% (1210/1415) of ITT, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). Conclusions: Under real world conditions a high proportion of eligible patients received 8 week LDV/SOF treatment. Relapse occurred in particular in patients who did not meet the selection criteria according to the SmPC. Lay summary: In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8 week) resulted in equivalent cure

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rates to 12 weeks treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Introduction The availability of all-oral direct acting antivirals (DAAs) has led to rapid advances in the treatment of chronic hepatitis C virus (HCV) infection over recent years. Clinical trials have shown sustained virological response (SVR) rates above 90% with well-tolerated combinations of DAAs, including in patients with traditionally more difficult to treat disease, such as those with cirrhosis and HIV co-infection. Ledipasvir-sofosbuvir (LDV/SOF) is a fixed-dose combination of DAAs which inhibit HCV nonstructural (NS) 5A and 5B proteins. The large-scale ION series of phase III clinical trials demonstrated SVR rates between 93– 100% in treatment-naïve and treatment-experienced patients, with and without cirrhosis, with once-daily administration of LDV/SOF ± ribavirin (RBV) for 8 to 24 weeks (Afdhal 2014a and 2014 b; Kowdley 2014). Based on the findings of these and other studies, LDV/SOF with or without RBV is indicated in Europe for the treatment of adult patients with HCV genotype 1, 3, 4, 5 and 6 infection, with a treatment duration of 8, 12 or 24 weeks depending on HCV genotype and patient factors including previous treatment history and the presence of cirrhosis. In the ION-3 study, treatment with LDV/SOF for 8 weeks was shown to be noninferior to 12 weeks in previously untreated genotype 1 patients without cirrhosis, with no benefit of the addition of RBV (Kowdley 2014). Accordingly, the European Summary of Product Characteristics (SmPC) recommends that 8 weeks treatment with LDV/SOF can be considered in these patients. Relapse rates in ION-3 were low overall, although slightly higher in the 8 week treatment group compared with the 12 week group (5% vs. 1%, respectively) (Kowdley 2014). Subsequently, a post hoc analysis of data from ION-3 determined a cut-off value for baseline HCV RNA levels of < 6 million IU/mL, which may identify patients less likely to relapse with 8 weeks of therapy. While this cut off is also listed as an indicator for 8 weeks of treatment in US prescribing information for LDV/SOF, the

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European SmPC does not include this as a recommendation, although European treatment guidelines suggest that this should be considered (EASL 2015). A shorter treatment duration results in several countries in lower treatment cost potentially resulting in health care savings which may allow treatment of more patients for the same overall cost (O’Brien 2016). In addition, shorter courses of treatment may also increase patient compliance. However there are currently limited data on the use and effectiveness of 8 week regimens of LDV/SOF in routine practice. Although data from highly controlled clinical trials are essential to demonstrate the safety and efficacy required to support registration, it is important that results are confirmed in real-world therapy settings, where patient populations are more diverse and management more challenging. The aim of the current study was therefore to characterise the population of patients receiving 8 weeks compared with 12 weeks of treatment with LDV/SOF and to describe outcomes in routine clinical practice.

Patients and methods Patient population The German Hepatitis C-Registry (Deutsches Hepatitis C-Register, DHC-R) is a multicenter, non-interventional registry study. The study protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines approved by the Institutional Review Board (Ethics Committee of Ärztekammer Westfalen-Lippe; reference number 2014395-f-S). The DHC-Registry was registered at the Federal Institute for Drugs and Medical Devices (BfArM; number 2493) and the German Clinical Trials Register (DRKS; ID DRKS00009717). All participants had to provide written informed consent before being enrolled in the registry. Inclusion criteria were chronic hepatitis C virus (HCV) infection with detectable HCV-RNA and ≥18 years of age. Exclusion criteria were pregnancy (patient or female partner of male patient), women in nursing period or women of childbearing age

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without reliable contraception and contraindications for use of antiviral treatment. The choice of antiviral therapy was at the discretion of the physician. Main parameters of interest included demographic data, history of hepatitis C, viral genotype and viral load, laboratory parameters, fibrosis assessment (transient elastography and/or histology if available), concomitant diseases, data of treatment and dosage of HCV medication and other concomitant medication, virological outcomes with end of treatment response and SVR, and all (severe) adverse events during treatment and follow-up. Patient data were recorded via a web browser based Electronic Data Capture (EDC) system without software installation on site (BEO, e.factum GmbH) hosted at a Clinical Research Organization (CRO). Data quality was reviewed by study monitors via plausibility checks to assure completeness and accuracy. Furthermore, queries were issued in order to verify or resolve unlikely and/or extreme values. On-site monitoring was conducted in randomly selected sites and when queries had to be solved. Patient enrolment started on November 24, 2014. As the registry is prospective, all data can only be documented up to three months retrospectively. In order to prevent bias due to noninclusion of patients treated with DAAs which received marketing authorization in Europe before November 24, 2014 (SOF, LDV, Daclatasvir and Simeprevir), a prolonged retrospective documentation period was allowed to record antiviral therapies, which started on or after February 1, 2014. The present analysis is based on 2,404 GT1 patients documented in the DHC-R between February 1, 2014 and June 30, 2016. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. Therapy durations of 50 to 61 days or 70 to 98 days after treatment initiation were defined as “8 weeks” and “12 weeks”, respectively. The safety population (intention-to-treat-1, ITT1) consisted of all defined patients who completed treatment with LDV/SOF for 8 or 12 weeks (Fig. 1). As the planned treatment duration (8 weeks vs. 12 weeks) was not recorded in the registry it was not possible to 6

allocate early terminators to either the 8 week group or the 12 week group for the ITT-1 analysis. The 21 patients with other treatment durations are indicated in Figure 1. The effectiveness population (ITT2) included all patients who initiated and completed treatment with LDV/SOF and who have reached the timepoint SVR 12 (FU1). The per protocol (PP) analysis group included only those patients who had completed treatment, who did not discontinue treatment due to low compliance, and for whom follow-up data were available.

Assessments and endpoints Demographic and other baseline variables were determined prior to treatment initiation and included age, sex, race/ethnicity, presence of cirrhosis, details of comorbidities and prior HCV treatment history. Clinical evidence of cirrhosis was given if one or more of the following criteria were fulfilled: biopsy showing cirrhosis (Metavir score F4), transient elastography (Fibroscan®, Echosens, France) >12.5 kPa, ultrasound confirming cirrhosis, clinical evidence of cirrhosis (e.g., presence of ascites, esophageal varices). Fibrosis stage was determined according to results of histology (histologic scoring), transient elastography (‘F0-F1’: <7kPa; ‘F2’: >7 - ≤9.5 kPa; ‘F3’: >9.5 – 12.5 kPa; ‘F4’: >12.5 kPa) and/or acoustic radiation force impulse imaging (ARFI; ‘F0-F1’: <1.27; ‘F2’: ≥1.27 -1.44; ‘F3’: >1.45-1.72; ‘F4’: >1.72). Fibrosis-4 (FIB-4) and AST to Platelet Ratio Index (APRI) scores were calculated in all patients treated for 8 weeks without documented fibrosis stage. HCV RNA was assessed at baseline, end of treatment and 12 weeks after completion of therapy. Samples were tested at local sites using different assays. Assays were performed according to manufacturers’ instructions. HCV RNA negativity was defined as HCV RNA below the lower limit of quantification of the respective quantitative PCR-based assays. The primary effectiveness endpoint was the proportion of patients with SVR12, which was defined as HCV RNA negativity 12 weeks after end of treatment.

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Statistics This analysis includes data through June 30, 2016 including all queries answered by July 26, 2016. The statistical analysis was descriptive to reflect the clinical routine as intended by the clinicians. Summary statistics (mean, median, standard deviation, 25th percentile, 75th percentile, number of values) or frequencies and proportions were assessed dependent on the scale level of the data. In advance, all relevant variables needed to describe the sample were defined in a statistical analysis plan. Univariate and multivariate analyses (logistic regression model (LR), with 95% confidence interval for the odds ratio (OR) were calculated. Variables included in univariate analyses were selected by the study steering committee based on findings from clinical trials as well as other cohort studies. Significant variables in univariate analyses were included in multivariate analysis. Differences were considered significant for p values ≤ 0.05. In case of missing data only the available data were analyzed, i.e. missing data were ignored. Analyses were calculated using SPSS Windows Release 22.0.0.2 (IBM©, USA).

Results Disposition of genotype 1 patients who initiated treatment with LDV/SOF for 8 or 12 weeks is shown in Figure 1. In total, 2,404 patients were included in the present study. Thereof, 968 and 1,415 patients initiated a 8 week and 12 week treatment, respectively. Baseline characteristics are shown in Table 1. As expected given prescribing recommendations, the majority of patients treated for 8 weeks with LDV/SOF were non-cirrhotic (97.6%) and were treatment-naïve (92.3%). HIV co-infection was present in 9.1% of patients, and 10.1% were receiving opioid substitution therapy. The majority (75.3%) had baseline viral loads < 2 million IU/mL, and only 3.0% had HCV RNA > 6 million IU/mL at baseline. In the LDV/SOF 12 week group, most patients (59.6%) were treatment-experienced, and 13.9% had cirrhosis

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at baseline. HIV co-infection was present in 11.4% of patients, and 7.5% were receiving opioid substitution therapy. The majority (58.0%) had baseline viral loads < 2 million IU/mL, and 14.6% had HCV RNA > 6 million IU/mL at baseline. Among patients treated for 8 and 12 weeks, respectively, 90.3% (875/968) and 33.3% (471/1,415) met all criteria for 8 weeks of treatment according to the SmPC (i.e. treatment-naïve, no cirrhosis). 86.2% (834/968) and 25.9% (367/1,415) of the patients treated for 8 and 12 weeks, respectively, met all criteria for 8 weeks of treatment according to the EASL guideline recommendations (i.e. treatmentnaïve, no cirrhosis, and viral load <6 million IU/ml). Effectiveness The overall SVR rate of the safety population (ITT1) was 84.6% (2,034/2,404). In the ITT effectiveness (ITT2) and the PP population the SVR rates amounted to 94.5% (2,034/2152) and 98.2% (2,029/2,066), respectively. In the 8 week treatment group, 94.0% (824/877) of the ITT2 and 98.3% (821/835) of the PP achieved SVR12, while in the 12 week treatment group, 94.9% (1,210/1,275) of the ITT2 population and 98.1% (1,208/1,231) of the PP population achieved SVR12. SVR12 rates by baseline characteristics in the PP population are shown in Table 2. SVR12 rates were 94.2% (742/788) and 98.7% (739/749) in the ITT2 and PP populations, respectively, in patients treated with LDV/SOF for 8 weeks according to the SmPC. In patients treated with LDV/SOF for 8 weeks according to the EASL recommendations, SVR12 rates were 94.4% (710/752; ITT2) and 98.6% (707/717; PP), respectively. In patients treated with LDV/SOF for 8 weeks, SVR12 was lower in patients who were treated outside the SmPC, e.g. treatment experienced or cirrhotic patients. The SVR rate in treatment-experienced vs. treatment-naive patients was 95.7% vs. 98.6%, respectively and 90.5% in cirrhotic vs. 98.5% in non-cirrhotic patients, respectively.

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Other baseline factors including baseline viral load, age, HIV co-infection, opioid substitution therapy (OST), and HCV genotype as well as subtype did not influence the high rates of SVR12 neither in the 8 week group nor the 12 week group. Overall, relapse rates were low and similar in both treatment groups (Table 3). A total of 1.5% (30/2,066) of patients relapsed post-treatment, 1.4% (12/835) after 8 weeks and 1.5% (18/1,231) after 12 weeks of treatment. Relapse rates in patients who met the SmPC criteria for 8 weeks of treatment were similar among patients treated for 8 (1.2%; 9/749) and 12 (1.8%; 7/397) weeks, respectively. In patients meeting the EASL criteria for 8 weeks, relapse rates were 1.3% (9/717) and 1.9% (6/318), respectively. Of the 12 patients who relapsed following 8 weeks of treatment with LDV/SOF, two patients were previously treated with IFN-based regimens; two patients had cirrhosis at baseline, one with Child Pugh Turcotte (CPT) A and one with CPT B. The patient with CPT A was one of the previously IFN-based treated patients. The patient with CTP B also received proton pump inhibitors. Baseline viral load was <6 million IU/mL in all patients with relapse after 8 weeks of treatment. Baseline viral load was >6 million IU/mL in 16.7% (3/18) of patients who relapsed following 12 weeks of treatment. In patients treated for 8 weeks, relapse rates were higher in patients with cirrhosis at baseline compared with non-cirrhotic patients (9.5% [2/21] vs. 1.2% (10/814], respectively) and in treatment-experienced compared with treatment-naïve patients (2.9% [2/70] vs. 1.3% [10/765], respectively). Rates of relapse were also higher in HIV-infected patients treated for 8 weeks compared with HIV-negative patients (4.1% [3/74] vs. 1.2% [9/761], respectively). There was no difference in relapse rate according to baseline viral load in the 8 week treatment group, but the number of patients with baseline HCV RNA >6 million IU/mL was small. There were only limited resistance data available in patients who relapsed. In the 8 week group 2 patients with relapse had resistance data at follow up (1x NS5A/NS5B; 1x 44D, 174S, 122N), 1 patient at baseline (NS5B). In the 12 week group 5 patients with

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relapse had resistance testing during follow up (3x NS5A; 1x NS5A/NS5B; 1x no mutation), 2 of those had testing at baseline without any resistance-associated substitutions (RASs). In univariate regression analysis, SVR12 was associated with the absence of cirrhosis (odds ratio [OR]: 0.14, 95% confidence interval [95% CI]: 0.03-0.68, p=0.015) and female gender (OR=4.04, 1.22-15.90, p=0.024) (Table 4). Both factors were confirmed in multivariate analysis (cirrhosis OR: 0.13, 95% CI: 0.03-0.65; p=0.013; female gender OR: 4.55; 1.2516.53; p=0.021). In patients treated for 12 weeks, only absence of cirrhosis was associated with SVR 12 (OR: 0.20, 95% CI: 0.09-0.48, p<0.001). In patients without fibrosis assessment with elastography or liver biopsy no patients with APRI-scores >1.5 or FIB-4 scores >3.25 experienced a virological relapse (Tables 2 and 3, Supplementary Table 1). Accordingly, higher APRI or FIB-4 scores were not associated with lower SVR rates, but 100% SVR12 (ITT) was only observed in patients with APRI-scores >1.5 or FIB-4 scores >3.25. Safety and tolerability More adverse events (AEs) were documented in patients receiving 12 weeks therapy regimen (50.4%) compared to patients receiving 8 weeks of treatment (40.4%; Table 5). The rate of AEs leading to discontinuation was overall low and comparable between the two treatment arms (8 weeks: 0.3% versus 12 weeks: 0.1%) The rate of documented severe adverse events (SAEs) was lower in patients treated with LDV/SOF for 8 weeks (1.7%) vs. 12 weeks (2.8%). Overall, 10 patients (0.4%) died during the study period (Supplementary Table 2), none of the deaths were considered treatment related by the physician.

Discussion Overall, ≥85% of patients who received treatment with LDV/SOF for 8 weeks or for 12 weeks in this large real-world cohort had a documented SVR12 (ITT1) and >98% of patients with follow-up data available were HCV RNA negative after therapy (PP). The majority of patients treated with LDV/SOF for 8 weeks were non-cirrhotic and treatment naïve in accordance

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with treatment guidelines. The presence of cirrhosis was predictive of SVR12 in both the 8 and 12 week treatment groups, and was associated with significantly lower rates of response and higher rates of relapse in patients treated for 8 weeks. This supports the treatment recommendations that patients with cirrhosis should be treated with LDV/SOF for longer than 8 weeks (12 or 24 weeks, depending on patient characteristics), or with the addition of RBV for 12 weeks. With the analysis of the APRI-score and the FIB-4-score we excluded that patients with undiagnosed advanced cirrhosis or early cirrhosis were under-treated. Overall, we consider this finding as a major strength of this real-world cohort. Many physicians judged the fibrosis state on commonly accepted clinical criteria without histology or elastography and apparently performed extremely well – without putting patients at an increased risk for relapse. The data of the APRI-score and the FIB 4-score of our cohort support the thesis that relevant cirrhosis can be ruled out sufficiently even in the absence of elastography or results from liver biopsy reflecting the situation in many non-specialised centres. The SVR12 rate of 98.3% (PP) in patients treated for 8 weeks in our cohort compares favourably with that seen in a similar population of patients included in the ION-3 study (94%) (Kowdley et al., 2014). A number of other real-world studies have also demonstrated similar SVR rates following 8 weeks of treatment in treatment-naive, noncirrhotic patients, including those from the US TRIO Network (95%) (Curry 2015), a US Veterans Affairs analysis (94.3%) (Ioannou et al., 2016), the international HCV-TARGET database (96%) (Terrault et al., 2016) and the German GECCO cohort (93.5%) (Ingiliz et al., 2016). Overall SVR rates for 8 weeks of LDV/SOF were somewhat lower only in a large realworld US veterans cohort (91.7%) (Backus, 2016 AP&T). Although a high SVR rate (93.2%) was seen after 8 weeks treatment in those patients who met US prescribing recommendations for this regimen (i.e. treatment-naive, non-cirrhotic [FIB-4 ≤ 3.25], and baseline HCV RNA <6 million IU/mL), for patients who met these criteria but who received 12 weeks of treatment, the SVR rate was significantly higher (96.6%; P = 0.001). This led the authors to conclude that a 12 week duration may be preferred in order to optimise a patient’s likelihood of SVR (Backus AP&T 2016 and Hepatol 2016). However, this finding is 12

not in agreement with data from the HCV-TARGET database, where patients with similar baseline characteristics achieved similar SVR rates after 8 weeks (96% (95% CI: 94-99)) to those treated for 12 weeks (98% (95% CI: 95-99). The reason for this discrepancy is unclear, but may reflect differences in the characteristics of the study cohorts. For example, the US veterans cohort included a higher proportion of African Americans (39.7% in the 8 week cohort), compared with 22% in the HCV-TARGET cohort. In the US study, rates of SVR were markedly lower in 8 weeks vs. 12 weeks of LDV/SOF in African American (89.5% vs. 94.3%, respectively) and African American race was found to be predictive of decreased likelihood of SVR in the overall cohort, but not in patients with viral load < 6 Million IU/ml and those who completed 12 week of treatment (Backus Hepatol 2016). A pooled analysis of data from the ION studies showed that, although black patients had similar rates of SVR to non-black patients following 8 weeks of treatment with LDV/SOF, they were more likely to relapse post-treatment (9% vs. 4%, respectively) (Wilder 2015). The reasons behind these findings remain to be clarified. However, overall, data from the current study are in accordance with an increasing number of real-world studies, which show that in patients who fit the recommended criteria, treatment for 8 weeks with LDV/SOF is highly effective in clinical practice. Recently, favourable results with 8 week treatment duration were shown for the combination of Ombitasvir, Paritaprevir and Dasabuvir in non-cirrhotic patients with genotype 1b infection, too (Welzel 2016). Furthermore it supports the recommendation not to include patients with >F3 fibrosis in the 8 week treatment regimen. Nevertheless, there is evidence that the 8 week treatment regimen is underutilized in routine practice. For example around half of patients treated for 12 weeks in the US veteran study met the criteria for 8 weeks treatment (Backus Hepatol 2016), while less than half of patients eligible for 8 weeks of treatment received 12 weeks in this study as well as in the HCV-TARGET, TRIO and US Veterans Affairs cohorts (Terrault 2016; Curry 2016; Ioannou 2016). Longer treatment in patients was not associated with improvements in SVR in the US Veterans Affairs cohort; eligible patients who received 8 weeks of treatment

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achieved a SVR of 95.1% (95% CI 94.0-96.0), whereas those who received 12 weeks of treatment achieved a very similar SVR of 95.8% (95% CI 94.7-96.8) (P = 0.6) (Ioannou 2016). One of the strength of the current study is that more than 65% of those who are eligible for 8 weeks of treatment received this regimen, reducing a potential selection bias. The data from the majority of studies, including the current study, should encourage confidence in this regimen in appropriate patients, thereby avoiding unnecessary treatment extension and potentially improving adherence. Of note, nearly 44% of all treated patients within this analysis fulfilled all 3 criteria (treatment naïve, non-cirrhotic and < 6 million IU /mL RNA) and this group will potentially grow as in most countries the treatment in the beginning focused on advanced fibrosis stages and is now slowly opened to lower fibrosis stages. Data from another German cohort show an increase in treated patients below F 3 from 14% in 2014 to 52% in 2016 (Petersen 2017). Patients without cirrhosis treated for 8 weeks achieved very high rates of SVR12 (98.3% vs. 90.5% in cirrhotics) and low rates of relapse (1.2 vs. 9.5% in cirrhotics) in our cohort, and as expected cirrhosis was found to be a significant predictor of SVR12. Cirrhosis was also a predictor of SVR12 in patients treated for 12 weeks with LDV/SOF. This may reflect the characteristics of the cirrhotic patients treated in the current study. Treatment recommendations state that LDV/SOF for 12 weeks may be considered for patients with compensated cirrhosis ‘deemed at low risk for clinical disease progression and who have subsequent retreatment options’. It is possible that a proportion of the cirrhotic patients treated with LDV/SOF in the current study did not fulfil these criteria. Opioid substitution therapy was not a negative predictive factor for SVR in patients treated for 8 or 12 weeks, indicating that these patients reach similar SVR rates as patients without substitution therapy. Overall, rates of post-treatment relapse were low following both 8 weeks and 12 weeks of treatment groups in our cohort. In patients treated for 8 weeks, the relapse rate was 1.4%, lower than that reported in patients treated for 8 weeks in ION-3 (5%) (Kowdley 2014) and in 14

the real-world HCV-TARGET cohort (4%) (Terrault 2016). In patients treated for 8 weeks, relapse rates were markedly lower in treatment-naïve vs. treatment experienced patients (1.3% vs. 2.9%, respectively) and particularly in non-cirrhotic vs. cirrhotic patients (1.2% vs. 9.5%, respectively), emphasizing the importance of patient selection for the shorter treatment duration. Relapse rates were also higher for HIV-infected patients treated for 8 weeks (4.1% vs. 0.7% after 12 weeks of treatment) although HIV infection was not predictive of SVR in this patient group. Overall, this is a similar rate of relapse as reported in the ION-4 study, where HIV-infected patients were treated with LDV/SOF for 12 weeks (Naggie 2015). One consideration which remains to be fully clarified is whether including baseline HCV RNA < 6 million IU/mL as a selection criterion for 8 weeks of treatment with LDV/SOF is justified. This cut off was derived from a post hoc analysis of data from ION-3 which found that relapse rates in patients with a baseline viral load < 6 million IU/mL were similar with 8 and 12 weeks of therapy (2% for both) while patients with a baseline viral load ≥ 6 million had a greater risk of relapse with 8 weeks of therapy than with 12 weeks (10% versus 1%, respectively). Although adopted by US prescribing guidelines and EU treatment guidelines, there have been queries around the scientific rationale, and specifically the statistical justification, for restricting 8 weeks of LDV/SOF to patients with baseline viral load < 6 million IU/mL (O’Brien 2016). In the current study, neither SVR rates nor relapse rates appeared to vary consistently according to baseline viral load in any treatment group. Although there were few patients in the 8 week treatment group with baseline viral load > 6 million IU/mL (n=21), all achieved SVR and no relapse was seen. In addition, baseline HCV RNA > 6 million IU/mL was not found to be predictive of SVR12 in the current study. In this analysis, Roche Cobas® Taqman® HCV Test was predominantly used to determine HCV RNA load (66.5%), the Abbott m2000rt Real-Time PCR assay was used for 22.8 % of patients, in 5.1% the assay was not reported and 5.6% utilized different other assays. As the Abbott assay is believed to result in slightly lower viral loads (Cloherty 2015), the proportion of patients with viral load > 6 million IU/mL may be underestimated in this cohort. In patients included in the

15

US veterans study, patients with baseline viral load > 6 million IU/mL had significantly lower rates of SVR compared with those with baseline viral load < 6 million IU/mL (73.8% vs. 92.7%, respectively; P<0.001), but no information on the assays that were used to determine viral load is available in the publication (Backus 2016). In line with our results, data from TRIO showed similar response rates in treatment-naive, non-cirrhotic patients treated for 8 and 12 weeks irrespective of baseline viral load (Curry 2016). Omeprazole and other PPIs have the potential to reduce serum concentrations of LDV and could therefore impact on SVR. An analysis of data from the HCV TARGET network suggested that PPI use at baseline was associated with a reduction in SVR (Terrault 2016). In keeping with a recent analysis of real world data (Tapper 2016), the use of PPIs did not appear to impact on SVR12 in our study. However, only few patients (38/2485) in our cohort were reported to be receiving PPIs and therefore patient numbers were small limiting the possibility to draw conclusions, but on the other hand showing that physicians were able to reduce PPI use. The majority of patients treated with LDV/SOF for 8 weeks in our cohort were genotype 1 infected, non-cirrhotic and treatment naïve, suggesting that the prescription of this regimen in Germany is largely in accordance with treatment guidelines. However, a small proportion were treatment-experienced, had cirrhosis, and therefore should not have received the shorter treatment duration. This reflects the real-world nature of our study, where prescribing practice may vary. Our results strongly support treatment according to the SmPC. Our study has the well-known limitations associated with uncontrolled, observational, retrospective studies. Although registry studies often suffer from inconsistencies in data and the risk of investigator bias, the DHC-R has been designed to include data control, with onsite monitoring and analysis of data quality by plausibility checking. In addition, as all treatment and monitoring was at the physicians’ discretion, local practice means that not all data are available for all patients. Nevertheless, data from the DHC-R reflects real-world

16

treatment in Germany and therefore provides important information of effectiveness and safety of treatment in this setting. Our results confirm those seen in other real world studies which indicate that in clinical practice, LDV/SOF is, as in clinical trials, a highly effective, safe, well-tolerated treatment option with few adverse effects. In addition, 8 weeks of treatment with LDV/SOF resulted in high rates of SVR12 and low relapse rates in treatment-naive, non-cirrhotic patients selected according to SmPC recommendations, irrespective of other baseline factors such as HCV subtype, patient age, HIV status, OST or baseline viral load.

17

Acknowledgements The German Hepatitis C-Registry (DHC-R) is a project of the German Liver Foundation (Deutsche Leberstiftung) managed by Leberstiftungs-GmbH Deutschland in cooperation with the

Association

of

German

gastroenterologists

in

private

practice

(bng,

Bund

Niedergelassener Gastroenterologen) with financial support from the German Center for Infection Research (DZIF) as well as from the companies AbbVie Deutschland GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Gilead Sciences GmbH, Janssen-Cilag GmbH, MSD Sharp & Dohme GmbH, and Roche Pharma AG. The authors thank all study investigators, study nurses, and participating patients. Special thanks to Dr. Yvonne Serfert and Bianka Wiebner from Leberstiftungs-GmbH Deutschland for the management of the DHC-R.

References Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:1889-1898. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:14831493. Backus LI, Belperio PS, Shahoumian TA, Loomis TP, Mole LA. Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine medical practice. Aliment Pharmacol Ther. 2016; 44:400-410. Backus LI, Belperio PS, Shahoumian TA, Loomis TP, Mole LA. Real World Effectiveness of Ledipasvir/Sofosbuvir in 4365 Treatment-Naïve Genotype 1 Hepatitis C Infected Patients. Hepatology. 2016;64:405-416.

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Cloherty G, Cohen D, Sarrazin C, Wedemeyer H, Chevaliez S, Herman C. HCV RNA assay sensitivity impacts the management of patients treated with direct acting antivirals. Antivir Ther. 2015;20(2):177-83. Curry MP, Bacon B, Dieterich D, Flamm SL, Guest L, Kowdley KV, et al. Effectiveness of 8 or 12 week LDV-SOF in Treatment-Naïve Patients with Non-Cirrhotic, Genotype 1 Hepatitis C: Real-World Experience from the TRIO Network. Poster presented at the 66th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, Nov 13-17 2015. European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol 2015;63:199-236. Ingiliz P, Christensen S, Kimhofer T, Hueppe D, Lutz T, Schewe K, et al. Sofosbuvir and Ledipasvir for 8 weeks for the treatment of chronic hepatitis C virus infection in HCV-monoinfected and HIV-HCV co-infected individuals- Results from the German hepatitis c cohort (GECCO-01). Clin Infect Dis. 2016;63:1320-1324. Ioannou GN, Beste LA, Chang MF, Green PK, Lowey E, Tsui JI, et al. Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Healthcare System. Gastroenterology 2016;151:457-471. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370:1879-1888. O'Brien TR, Feld JJ, Kottilil S, Pfeiffer RM. No scientific basis to restrict 8 weeks of treatment with ledipasvir/sofosbuvir to patients with hepatitis C virus RNA <6,000,000 IU/mL. Hepatology 2016;63:28-30. Petersen J, Wursthorn K, Olah K, Lorenzen T, Plettenberg A, Unger S et al. Strong decrease of patients with advanced liver disease and more adherence problems to HCV therapy as 19

DAA regimen enter third year of existence in Germany. Poster FRI-252 presented at The International Liver Congress 2017 of the European Association for the Study of the Liver. 2017 Apr 19-23; Barcelona, Spain. Tapper EB, Bacon BR, Curry MP, Dieterich DT, Flamm SL, Guest LE et al., Evaluation of Proton Pump Inhibitor Use on Treatment Outcomes with Ledipasvir and Sofosbuvir in a Real-World Cohort Study. Hepatology 2016;64:1893-1899. Terrault NA, Zeuzem S, Di Bisceglie AM, Lim JK, Pockros PJ, Frazier LM, et al. Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated of Sustained Virologic Response. Gastroenterology 2016;151:1131-1140. Welzel TM, Zeuzem S, O Dumas E, Asselah T, Shaw D, Hazzan R, et al. Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, phase 3b trial. The Lancet Gastroenterology & Hepatology 2017;2:494-500. Wilder JM, Jeffers LJ, Ravendhran N, Shiffman ML, Poulos J, Sulkowski MS, et al. Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data. Hepatology 2016;63:437-444.

20

Tables.

21

Table 1. Demographic and clinical characteristics of the patients at baseline (safety population, ITT1) LDV/SOF 8 weeks (n=968)

12 weeks (n=1,415)

47.4 (459)

56.9 (805)

7.3 (71)

11.0 (156)

Gender, % (n) Male Age, years, % (n) >70 ≤70 Median (IQL)

92.7 (897)

89.0 (1,259)

50.0 (40.5-59.0)

54.0 (47.0-62.0)

Ethnicity, % (n) 97.6 (945)

97.7 (1,382)

Africa

0.4 (4)

0.7 (10)

Asia

1.5 (15)

1.2 (17)

Hispanic

0.4 (4)

0.4 (6)

Caucasian

Treatment history 7.7 (75)

59.6 (844)

Prior IFN

7.7 (75)

58.5 (828)

Prior DAA

-

11.4 (162)

Other

-

2.1 (30)

GT 1a

44.8 (434)

48.3 (683)

GT 1b

50.5 (489)

45.9 (650)

Experienced

HCV Genotype (GT), % (n)

Other/unknown Cirrhosis, % (n)

4.7 (45)

5.8 (82)

2.4 (23)

13.9 (197)

Fibrosis stage, % (n) 27.8 (269)

20.4 (288)

F2

9.1 (88)

11.2 (158)

F3

2.1 (20)

6.6 (94)

F4

2.4 (23)

13.9 (197)

58.7 (568)

47.9 (678)

≤2,000,000

75.3 (729)

58.0 (820)

>2,000,000 – ≤6,000,000

19.9 (193)

25.8 (365)

3.0 (29)

14.6 (207)

24.3 (21.9-27.0)

25.6 (22.6-27.8)

10.1 (98)

7.5 (106)

0.9 (9)

0.5 (7)

F0 - F1

Fibrosis stage not determined Baseline viral load, IU/mL

>6,000,000 2

BMI, Kg/m , median (IQL) OST, % (n) Active Substance use, % (n) Bilirubin mg/dL, median (IQL) ALT, IU/L, median (IQL) Platelets, x109/L, median (IQL)

0.5 (0.4-0.7)

0.6 (0.4-0.7)

56.0 (37.0-90.0)

58.0 (40.0-92.0)

221.5 (185.0-262.0)

206.0 (162.0-252.0)

Albumin, g/dL, % (n/N) <35

6.2 (27/436)

8.2 (49/597)

≥35

93.8 (409/436)

91.8 (548/597)

70.5 (682)

75.5 (1068)

Psychiatric diseases

14.5 (140)

17.4 (246)

Cardiovascular diseases

20.4 (197)

26.9 (380)

Comorbidities, % (n)

22

Diabetes

4.4 (43)

8.3 (118)

HIV co-infection, % (n)

9.1 (88)

11.4 (161)

Proton-pump inhibitors, % (n)

1.0 (10)

1.9 (27)

90.3 (875/968)

33.3 (471/1,415)

SmPC criteria for 8 weeks no cirrhosis/treatmentnaïve

EASL criteria for 8 weeks No cirrhosis/treatment86.2 (834/968) 25.9 (367/1,415) naïve, viral load ≤6,000,000 Abbreviations: LDV/SOF, ledipasvir/sofosbuvir; HCV, hepatitis c virus; RNA, ribonucleic acid; ALT, alanine aminotransferase; BMI, body mass index; DAAs, direct-acting antivirals; OST, opioid substitution therapy; PPI, proton pump inhibitors; IQL, interquartile range

23

Table 2. SVR rates according to treatment duration, % (n/N) (Per Protocol population)

LDV/SOF 8 weeks

LDV/SOF 12 weeks

98.3 (821/835)

98.1 (1,208/1,231)

Male

97.1 (373/384)

97.7 (665/681)

Female

99.3 (448/451)

98.7 (543/550)

≤70 yrs

98.3 (756/769)

98.4 (1,073/1,019)

>70 yrs

98.5 (65/66)

96.4 (135/140)

98.6 (754/765)

97.7 (471/482)

Experienced

95.7 (67/70)

98.4 (737/749)

Prior IFN

95.7 (67/70)

98.4 (724/736)

Prior DAA

100 (4/4)

98.6 (141/143)

-

100 (22/22)

GT 1a

98.0 (350/357)

98.3 (563/573)

GT 1b

98.9 (436/441)

97.8 (575/588)

94.6 (35/37)

100 (70/70)

Yes

90.5 (19/21)

94.3 (165/175)

No

98.5 (802/814)

98.8 (1,043/1,056)

98.8 (238/241)

99.6 (245/246)

F2

97.5 (79/81)

98.6 (141/143)

F3

94.4 (17/18)

97.6 (83/85)

F4

90.5 (19/21)

94.3 (165/175)

<0.5 (F0-1)

98.7 (220/223)

n.a.

≥0.5 - 1.5

98.2 (164/167)

n.a.

>1.5 - <2 (F2-3)

100 (14/14)

n.a.

≥2 (F4)

100 (13/13)

n.a.

unknown

100 (57/57)

n.a.

<1.45 (F0-2)

99.2 (235/237)

n.a.

≥1.45 - ≤3.25

97.3 (145/149)

n.a.

Overall Gender

Age

Treatment history Naïve

Other HCV Genotype (GT), % (n)

Other/unknown GT1 subtype Cirrhosis

Baseline fibrosis stage F0 – F1

APRI

FIB-4

24

>3.25 (F3-4)

100 (31/31)

n.a.

unknown

100 (57/57)

n.a.

≤2,000,000

98.2 (615/626)

98.5 (711/722)

>2,000,000 – ≤ 6,000,000

98.3 (170/173)

97.2 (314/323)

100 (21/21)

98.2 (166/169)

Yes

95.9 (71/74)

98.7 (133/136)

No

98.6 (750/761)

98.2 (1,075/1,095)

Yes

98.7 (76/77)

96.8 (90/93)

No

98.3 (745/758)

98.2 (1,118/1,138)

98.7 (739/749)

98.0 (389/397)

98.6 (707/717)

97.8 (311/318)

Baseline viral load, IU/mL

>6,000,000 HIV co-infection

Opioid substitution therapy

SmPC criteria for 8 weeks no cirrhosis/treatmentnaïve EASL criteria for 8 weeks No cirrhosis/treatmentnaïve, viral load ≤6,000,000

Abbreviations: SVR, sustained virological response; LDV/SOF, ledipasvir/sofosbuvir; IFN, Interferon; DAA, directacting antivirals; HCV, hepatitis c virus; RNA, ribonucleic acid; APRI, AST to Platelet Ratio Index; FIB-4, Fibrosis 4; HIV, human immunodeficiency virus infection; n.a., not analysed

25

Table 3. Relapse rates according to treatment duration, % (n/N) (Per Protocol population) LDV/SOF 8 weeks

LDV/SOF 12 weeks

1.4 (12/835)

1.5 (18/1,231)

Male

2.6 (10/384)

2.1 (14/681)

Female

0.4 (2/451)

0.7 (4/550)

≤70 yrs

1.4 (11/769)

1.5 (16/1,091)

>70 yrs

1.5 (1/66)

1.4 (2/140)

Overall Gender

Age

Treatment history 1.3 (10/765)

1.7 (4/482)

Experienced

2.9 (2/70)

1.3 (10/749)

Prior IFN

2.9 (2/70)

1.4 (10/736)

Prior DAA

0 (0/4)

1.4 (2/143)

Other

0 (0/1)

0 (0/22)

GT 1a

1.7 (6/357)

1.4 (8/573)

GT 1b

0.9 (4/441)

1.7 (10/588)

5.4 (2/37)

0 (0/70)

Yes

9.5 (2/21)

4.0 (7/175)

No

1.2 (10/814)

1.0 (11/1,056)

1.2 (3/241)

0.4 (1/246)

F2

2.5 (2/81)

0.7 (1/143)

F3

5.6 (1/18)

2.4 (2/85)

F4

9.5 (2/21)

4.0 (7/175)

1.3 (3/223)

n.a.

0.6 (1/67)

n.a.

>1.5 - <2 (F2-3)

-

n.a.

≥2 (F4)

-

n.a.

unknown

-

n.a.

<1.45 (F0-2)

0.8 (2/237)

n.a.

≥1.45 - ≤3.25

1.3 (2/149)

n.a.

Naïve

HCV Genotype (GT), % (n)

Other/unknown GT1 subtype Cirrhosis

Baseline fibrosis stage F0 – F1

APRI <0.5 (F0-1) ≥0.5 - 1.5

FIB-4

26

>3.25 (F3-4)

-

n.a.

unknown

-

n.a.

≤2,000,000

1.4 (9/626)

1.1 (7/722)

>2,000,000 – ≤6,000,000

1.7 (3/173)

2.3 (7/323)

0 (0/21)

1.8 (3/169)

Yes

4.1 (3/74)

0.7 (1/136)

No

1.2 (9/761)

1.6 (17/1,095)

Yes

1.3 (1/77)

2.2 (2/93)

No

1.5 (11/758)

1.4 (16/1,138)

1.2 (9/749)

1.8 (7/397)

1.3 (9/717)

1.9 (6/318)

Baseline viral load, IU/mL

>6,000,000 HIV co-infection

Opioid substitution therapy

SmPC criteria for 8 weeks no cirrhosis/treatmentnaïve EASL criteria for 8 weeks No cirrhosis/treatmentnaïve, viral load ≤6,000,000

Abbreviations: LDV/SOF, ledipasvir/sofosbuvir; IFN, Interferon; DAA, direct acting antivirals; HCV, hepatitis c virus; RNA, ribonucleic acid; APRI, AST to Platelet Ratio Index; FIB-4, Fibrosis 4; HIV, human immunodeficiency virus infection; n.a., not analysed

27

Table 4. Univariate and multivariate logistic regression analysis for predictors of SVR (Per Protocol population) A) univariate regression analysis yes (n SVR/N)

no (n SVR/N)

p-value

Odds Ratio (95%-CI)

Baseline viral load ≥ 6 million IU/ml (820)

21/21

785/799

0.998

-

Cirrhosis (835)

19/21

802/814

0.015

0.142 (0.030-0.680)

Treatment experienced (835)

67/70

754/765

0.091

0.326 (0.089-1.197)

HIV co-infection (835)

71/74

750/761

0.111

0.347 (0.095-1.273)

OST (835)

76/77

745/758

0.787

1.326 (0.171-10.277)

Age >70 years (835)

65/66

756/769

0.915

1.118 (0.144-8.679)

Gender female (835)

448/451

373/384

0.024

4.404 (1.220-15.902)

HCV GT1b (798)

436/441

350/357

0.346

260.294 (0.002-27300000)

Baseline viral load ≥6 million IU/ml (1,214)

167/170

1024/1044

0.893

1.087 (0.320-3.699)

Cirrhosis (1,231)

165/175

1043/1056

0.000

0.206 (0.089-0.477)

Treatment experienced (1,231)

737/749

471/482

0.392

1.434 (0.628-3.277)

HIV co- infection (1, 231)

133/136

1075/1095

0.758

0.825 (0.242-2.813)

OST (1, 231)

90/93

1118/1138

0.322

0.537 (0.156-1.840)

Age > 70 years (1, 231)

135/140

1073/1091

0.123

0.453 (0.165-1.240)

Gender female (231)

543/550

665/681

0.172

1.866 (0.762-4.569)

HCV GT1b (1,161)

575/588

563/573

0.570

0.090 (0.000-369.742)

yes (n SVR/N)

no (n SVR/N)

p-value

Odds Ratio (95%-CI)

Cirrhosis

19/21

802/814

0.013

0.130 (0.026-0.645)

Gender female

448/451

373/384

0.021

4.547 (1.251-16.534)

Subgroup (N) LDV/SOF 8W

LDV/SOF 12 W

B) multivariate regression analysis Subgroup (N=835) LDV/SOF 8W

Factors which were statistically significant are highlighted in bold. Abbreviations: SVR, sustained virological response; LDV/SOF, ledipasvir/sofosbuvir; W, weeks; HCV, hepatitis c virus; GT, genotype; RNA, ribonucleic acid; HIV, human immunodeficiency virus infection; OST, opioid substitution therapy; 95%-CI, 95% confidence interval for the odds ratio

28

Table 5. Adverse events (safety population (ITT1)) Event

LDV/SOF 8 weeks n=968

LDV/SOF 12 weeks n=1,415

AEs, % (n)

40.4 (391)

50.4 (713)

SAEs, % (n)

1.7 (16)

40 (2.8)

SAEs classified as ‘severe’,

1.4 (14)

27 (1.9)

Discontinuation, % (n)

0.3 (3)

0.1 (2)

Deaths, % (n)

0.5 (5)

0.4 (5)

% (n)

Abbreviations: LDV/SOF, ledipasvir/sofosbuvir; AE, adverse event; SAE, severe adverse event

29

Figure Legends Figure 1. Patient disposition Abbreviations: ITT, Intention-to-Treat; PP, Per-Protocol; FU1, Follow up after 12 to 24 weeks

30

N=2,404 Intention-to-treat 1 analysis group (ITT1) GT1 patients with LDV/SOF treatment started between Feb 1st, 2014 and Sep 30th, 2015 (safety population)

N=968 8 week treatment completed (ITT1) treatment duration 50 – 61 days

N=1,415 12 week treatment completed (ITT1) treatment duration 70 – 98 days

N=2,152 ITT 2 analysis group LDV/SOF 8 or 12 week treatment completed and FU1 (effectiveness population)

N=877 8 week treatment (ITT2) treatment completed and FU1

N=231 No follow-up data

N=1,275 12 week treatment (ITT2) treatment completed and FU1

N=2,066 Per Protocol analysis group (PP) LDV/SOF 8 or 12 week treatment completed and FU1 (per protocol population)

N=835 8 week treatment (PP) treatment completed and FU1

N=21 other treatment duration

N=86 lost-to-follow-up or missing data / non-compliant patients

N=1,231 12 week treatment (PP) treatment completed and FU1

31

Highlights -

Large real-world cohort of HCV therapy 8 weeks of treatment duration with ledipasvir/sofosbuvir Very high SVR rates

32

33