Chronic infection with hepatitis C virus (HCV)

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1 VIRAL HEPATITIS Concordance of Sustained Virological Response 4, 12, and 24 Weeks Post-Treatment With Sofosbuvir- Containing Regimens for Hepatitis C Virus Eric M. Yoshida, 1 Mark S. Sulkowski, 2 Edward J. Gane, 3 Robert W. Herring, Jr., 4 Vlad Ratziu, 5 Xiao Ding, 6 Jing Wang, 6 Shu-Min Chuang, 6 Julie Ma, 6 John McNally, 6 Luisa M. Stamm, 6 Diana M. Brainard, 6 William T. Symonds, 6 John G. McHutchison, 6 Kimberly L. Beavers, 7 Ira M. Jacobson, 8 K. Rajender Reddy, 9 and Eric Lawitz 10 Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR) defined as HCV RNA levels below a designated threshold of quantification 24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at post-treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved directacting antiviral agents. The aim of this study was to assess the concordance between SVR at various post-treatment time points in phase III clinical trials of sofosbuvir (SOF)-containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1-6. The concordance between SVR at 4 weeks post-treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed posttherapy, 77.6% did so within 4 weeks of completing therapy. Conclusion: Data from phase III studies demonstrate that with SOF-based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine cure rates in trials and in clinical practice. (HEPATOLOGY 2015;61:41-45) Chronic infection with hepatitis C virus (HCV) is a curable disease, and the absence of detectable virus in the blood 6 months after completion of treatment is widely regarded as being indicative of cure. In the interferon (IFN) era, clinical studies of HCV treatment have, by convention, used a 24-week sustained virological response (SVR24) defined as absence of HCV RNA after completion of treatment as a primary efficacy endpoint. Achievement of SVR24 has been associated with a reduced risk of developing complications of liver disease (including hepatocellular carcinoma [HCC]), as well as a reduction in overall mortality, and has been used historically as a regulatory endpoint for approval. 1,2 More recently, SVR after the end of treatment (SVR12) has been established as an appropriate Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; LLOQ, lower limit of quantification; NPV, negative predictive value; Peg-IFN, pegylated interferon; PPV, positive predictive value; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response (SVR); SVR4, SVR at 4 weeks after treatment end; SVR12, SVR at after treatment end; SVR24, SVR at after treatment end. From the 1 University of British Columbia, Vancouver, Canada; 2 Viral Hepatitis Center, Johns Hopkins University School of Medicine, Baltimore, MD; 3 New Zealand Liver Transplant Unit, Auckland, New Zealand; 4 Quality Medical Research, PLLC, Nashville, TN; 5 University Pierre et Marie Curie, Paris, France; 6 Gilead Sciences, Inc., Foster City, CA; 7 Asheville Gastroenterology Associates, Asheville, PA; 8 Cornell University School of Medicine, New York, NY; 9 University of Pennsylvania School of Medicine, Philadelphia, PA; 10 Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, TX. Received June 25, 2014; accepted August 12, Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/ /hep.27366/suppinfo. This analysis was supported by Gilead Sciences, Inc. (Foster City, CA). 41

2 42 YOSHIDA ET AL. HEPATOLOGY, January 2014 endpoint for demonstrating efficacy in trials containing regimens that include pegylated interferon (Peg-IFN) with a protease inhibitor for weeks of treatment. 3 Sofosbuvir (SOF; Gilead Sciences, Inc., Foster City, CA) an oral, HCV-specific, nucleotide polymerase inhibitor with clinical efficacy in patients with HCV genotypes 1-6 is approved currently for use in combination with other agents for treatment of chronic HCV infection. 4-7 The present analysis assessed the concordance between SVR 4 weeks posttreatment (SVR4) and SVR12, and between SVR12 and SVR24 in patients with chronic HCV who received SOF-containing regimens with and without Peg-IFN in SOF phase III trials. Patients and Methods Patients with HCV genotype 1 or 4-6 receiving SOF in combination with Peg-IFN and ribavirin (RBV) for, patients with HCV genotype 2 receiving SOF in combination with RBV for, and patients with genotype 3 receiving SOF in combination with RBV for in SOF phase III trials who had a virological outcome of SVR4, SVR12, SVR24, breakthrough, or relapse were included in this analysis (Fig. 1 and Supporting Fig. 1). 4-6 SOF was administered at 400 mg once-daily, and RBV dose was based on body weight (1,000 mg/day for <75 kg and 1,200 mg/day for 75 kg in a divided dose) in all patients; all patients with genotype 1 or 4-6 also received Peg-IFN-2a 180 mg once-weekly. All patients with HCV genotype 1 or 4-6 included in this analysis were enrolled in the NEUTRINO trial (ClinicalTrials.gov identifier: NCT ); all patients with genotype 2 were enrolled in the FISSION (NCT ), POSITRON (NCT ), FU- SION (NCT ), or VALENCE (NCT ) trial, and all patients with genotype 3 were enrolled in the VALENCE trial (Fig. 1 and Supporting Fig. 1). 4-6 NEUTRINO was an open-label, single-arm trial in which 327 treatment-na ıve patients with genotype 1 or 4-6 (98% with genotype 1 or 4) received of SOF plus Peg-IFN/RBV. 6 FISSION was an open-label noninferiority trial in which 499 patients with genotype 2 or 3 were randomized to receive SOF plus RBV for (n 5 256; 73 enrolled as genotype 2) or Peg-IFN/RBV for (n 5 243). 6 POSITRON was a blinded trial in which 278 patients with genotype 2 or 3 in whom Peg-IFN therapy was not an option were randomized to receive SOF plus RBV (n 5 207; 109 with genotype 2) or placebo (n 5 71) for. 5 FUSION was a blinded trial in which 201 patients with genotype 2 or 3 previously treated with Peg-IFN were randomized to receive SOF plus RBV for 12 (n 5 103; 39 enrolled as genotype 2) or 16 weeks (n 5 98). 5 VALENCE was a double-blind trial in which 419 treatment-experienced (58%) or - na ıve patients with genotype 2 or 3 were initially randomized to receive SOF plus RBV (n 5 334) or placebo (n 5 85) for. 4 After emerging data suggested that patients with genotype 3 benefited from > of treatment, the trial was amended to extend SOF plus RBV treatment to in patients with genotype 3 (n 5 250) and to offer treatment in an alternative protocol to patients randomized to placebo. (An additional 11 patients with genotype 3 had completed treatment before their treatment could be extended; for safety analyses, they were included with patients with genotype 2, but were analyzed separately for efficacy.) A total of 73 patients with genotype Address reprint requests to: Eric M. Yoshida, M.D., F.R.C.P. (C.), Division of Gastroenterology, Vancouver General Hospital, Diamond Health Care Center, 5th Floor, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9, Canada. eric.yoshida@vch.ca; fax Copyright VC 2014 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Dr. Yoshida received grants, lecture fees, and/or speaker honoraria from Hoffman LaRoche, Vertex, Gilead, Merck, Schering, Astellas, Pfizer, Boehringer Ingleheim, Janssen, and Novartis. Dr. Sulkowski consults, advises, and received grants from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Idenix, and Tobira. Prof. Gane advises and is on the speakers bureau for Gilead and Novartis. He advises Merck, Idenix, and Achillion and is on the speakers bureau for Janssen. Dr. Reddy advises and received grants from Gilead, Bristol-Myers Squibb, Vertex, Janssen, Merck, and AbbVie. Dr. Beavers advises, is on the speakers bureau for, and received grants from Gilead; she advises and is on the speakers bureau for Janssen and Genentech; she is on the speakers bureau and received grants from Vertex; she received grants from Bristol-Myers Squibb, GlaxoSmithKline (GSK), Roche, and Idenix. Dr. Lawitz advises, is on the speaker s bureau for, and received grants from Gilead, Janssen, Merck, and Vertex; he advises and received grants from AbbVie, Achillion, Idenix, Novartis, and Santaris; he advises BioCryst, Biotica, Enanta, and Theravance; he is on the speakers bureau for Kadmon; he received grants from Boehringer Ingleheim, Bristol-Myers Squibb, GSK, Presidio, and Roche. Dr. Jacobson consults, advises, is on the speakers bureau for, and received grants from Bristol-Myers Squibb, Gilead, Genentech, Janssen, and Vertex; he consults and received grants from AbbVie, Boehringer Ingelheim, and Merck; he consults for Achillion and Idenix; he received grants from Novartis. Drs. McNally, Symonds, Brainard, Wang, McHutchison, Ma, Stamm, Chuang, and Ding own stock in and are employed by Gilead.

3 HEPATOLOGY, Vol. 61, No. 1, 2014 YOSHIDA ET AL. 43 Fig. 1. Patient analysis flow chart by HCV genotype (GT) and study. *Includes 3 patients subsequently found to have GT 1. 2 received SOF plus RBV for. In all trials, the primary endpoint was SVR12. The analyses for concordance included all patients with known virological outcomes (e.g., SVR4, SVR12, and SVR24 on-treatment virological failure or relapse) in the studies. Thus, patients were excluded if they were lost to follow-up during treatment or in the follow-up period, or if they discontinued treatment before HCV RNA suppression (Fig. 1). This analysis included 324 treatment-na ıve patients with HCV genotype 1 or 4-6 receiving SOF plus Peg-IFN/RBV for (all from NEUTRINO), 291 treatmentna ıve and -experienced patients with genotype 2 receiving SOF plus RBV for, and 248 treatment-na ıve and -experienced patients with genotype 3 receiving SOF plus RBV for (all from VALENCE). For the calculation of final SVR rates, any patient who received a dose of study drug was included, resulting in more patients for analysis: genotype 1 or 4-6, n 5 327; genotype 2, n 5 294; and genotype 3, n In all trials, HCV RNA levels were measured by the COBAS AmpliPrep/COBAS TaqMan HCV Test (v2.0) for use with the High Pure System (Roche Molecular Systems, Pleasanton, CA), with a lower limit of quantification (LLOQ) of 25 IU/mL, and HCV genotype was determined by the VERSANT HCV Genotype 2.0 Assay Line Probe Assay (Siemens AG, Erlangen, Germany). 4-6 Results SVR by HCV Genotype. SVR4, SVR12, and SVR24 rates by HCV genotype are shown in Fig. 2. For patients with genotype 1 or 4-6 treated with SOF plus Peg-IFN/RBV for, SVR4, SVR12, and SVR24 rates were 92.4%, 90.5%, and 90.5%, respectively; for patients with genotype 2 treated with SOF plus RBV for, the corresponding rates were 94.2%, 91.8%, and 91.8%, and for patients with genotype 3 treated with SOF plus RBV for, the rates were 87.2%, 85.2%, and 84.4%. Concordance of SVR4 and SVR12. Concordance of SVR4 and SVR12, and positive predictive value (PPV) and negative predictive value (NPV) of SVR4 for SVR12 are shown in Table 1. Similar concordance was observed across all HCV genotypes. Overall, SVR12 was achieved in 779 of 796 patients (98.0%) with SVR4, including 296 of 302 (98.0%) with HCV genotype 1 or 4-6, 270 of 276 (97.8%) with genotype 2, and 213 of 218 (97.7%) with genotype 3. The PPV of SVR4 for SVR12 was 98.0% and the NPV was 100%. Concordance of SVR12 and SVR24. Concordance of SVR12 and SVR24, and PPV and NPV of Fig. 2. SVR rates 4 (SVR4), 12 (SVR12), and 24 (SVR24) weeks after treatment end according to genotype (GT). Treatments for each GT are those for which SOF is approved: for GT 1 or 4-6, SOF plus Peg-IFN/RBV for ; for GT 2, SOF plus RBV for ; for GT3, SOF plus RBV for.

4 44 YOSHIDA ET AL. HEPATOLOGY, January 2014 SVR12 for SVR24 are shown in Table 2. Overall, SVR24 was achieved in 777 of 779 patients (99.7%) with SVR12, including 296 of 296 (100%) with HCV genotype 1 or 4-6, 270 of 270 (100%) with genotype 2, and 211 of 213 (99.0%) with genotype 3. The PPV of SVR12 for SVR24 was 99.7% and the NPV was 100%. Timing of. Relapse was defined as being negative for HCV RNA at the end of treatment and subsequently having HCV RNA above the LLOQ. In all cases, relapse, rather than reinfection, was confirmed with viral sequencing. The timing of relapses in the post-treatment period in the phase III SOF studies is shown in Table 3. Overall, a total of 85 of 863 patients experienced virological relapse. Of these patients, 66 (77.6%) had relapse by post-treatment week 4, 17 (20.0%) had relapse between weeks 4 and 12, and 2 (2.3%) had relapse between weeks 12 and 24. The 2 patients who relapsed between posttreatment weeks 12 and 24 were both in VALENCE with HCV genotype 3 and were treatment experienced without cirrhosis (Supporting Table 1). Discussion Table 1. Concordance of SVR4 and SVR12 SVR12 (n) Summary (%) Genotype Regimen SVR4 (n) Yes No PPV NPV Yes No 0 22 Yes No 0 15 Yes No 0 30 This post-hoc analysis of data from the SOF phase III registrational studies supports the use of SVR12 as the primary efficacy endpoint in SOF-containing regimens with or without Peg-IFN. When SOF combined with RBV or Peg-IFN/RBV was used according to current indications and dosing recommendations, 98.0% of patients who achieved SVR4 also achieved SVR12 and 99.7% of those who achieved SVR12 also Table 2. Concordance of SVR12 and SVR24 SVR24 (n) Summary (%) Genotype Regimen SVR12 (n) Yes No PPV NPV Yes No 0 28 Yes No 0 21 Yes No 0 35 Genotype Regimen Table 3. Timing of EOT and FU Week 4 (n) Abbreviations: EOT, end of treatment; FU, follow-up. FU Weeks 4 and 12 (n) FU Weeks 12 and 24 (n) achieved SVR24. This is consistent with the results of the SPARE trial, in which there was 100% concordance between SVR12 and SVR 24 in GT1 patients with unfavorable treatment characteristics who received SOF and RBV for. 8 The high degree of concordance between SVR12 and SVR24 across HCV genotypes 1-6 confirms that SVR12 is an appropriate endpoint for assessing efficacy of therapy with SOF-containing regimens. Although most patients (77.6%) who relapsed did so within the first 4 weeks after treatment was completed, 20.0% of patients who relapsed did so between post-treatment weeks 4 and 12, indicating that SVR4 is not a suitable primary endpoint for primary efficacy analyses. Although it would be of interest to determine what factors may predict a relapse between weeks 12 and 24, there were not enough patients (only 2.3% relapsing after achieving SVR12) for any meaningful analysis. There are a couple of limitations of this analysis which may affect generalizability of the results. First, there were relatively few patients with HCV genotypes 4-6 as a result of the lower prevalence of these genotypes and thus lower enrollment in the clinical studies. However, the concordance between SVR12 and SVR24 was 100% for these patients, suggesting that the high concordance with SOF-based regimens may also be generalized to these less-prevalent genotypes. Second, these trials used a highly sensitive assay to detect HCV RNA and determine relapse. Commercial assays available in clinical practice may have higher limits of detection, which could theoretically affect the ability to detect relapse. However, across the clinical trials included in this analysis, patients who relapsed after post-treatment week 12 did so with HCV RNA levels that substantially exceeded the lower limit of detection of any available assay. It is important to emphasize that the focus of this analysis was an assessment of the appropriateness of SVR12 as a primary efficacy endpoint in clinical trials and not an assessment of the appropriate duration for follow-up of patients after HCV treatment in clinical practice. Although patients who achieve SVR have improved clinical outcomes, current treatment

5 HEPATOLOGY, Vol. 61, No. 1, 2014 YOSHIDA ET AL. 45 guidelines recommend continued monitoring for HCC in patients with cirrhosis who achieve SVR. 9 Future long-term virological outcome follow-up studies in regimens of shorter duration and in IFN-free protocols will be important to determine the long-term durability of SVR. To date, of the 480 patients in the SOF phase III studies who enrolled in the long-term registry study for patients who achieved SVR24, 435 (91%) and 90 (19%) have week 24 and 48 data, respectively, and the virological response was durable in 100%. 10 In conclusion, this analysis validates that SVR12 is an appropriate efficacy endpoint for the evaluation of regimens containing SOF plus Peg-IFN/RBV and SOF plus RBV. It is unknown whether new direct-acting antiviral based regimens, particularly those with shorter durations and/or with drugs with lower barriers to resistance, will demonstrate similar concordance. Acknowledgment: Editorial assistance was provided by Matt Stenger and Geoff Marx of BioScience Communications (New York, NY) and was funded by Gilead Sciences, Inc. (Foster City, CA). References 1. Dieperink E, Pocha C, Thuras P, Knott A, Colton S, Ho SB. All-cause mortality and liver-related outcomes following successful antiviral treatment for chronic hepatitis C. Dig Dis Sci 2014;59: van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308: Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013;144: Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al.; VALENCE investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370: Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368: Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368: Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; Osinusi A, Meissner EG, Lee YJ, Bon D, Heytens L, Nelson A, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013;310: Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. HEPATOLOGY 2009:49: Cheng W, Shafran S, Beavers K, Mo H, McNally J, Brainard DM, et al. Long term follow-up of patients treated with sofosbuvir in the FISSION, POSITRON, FUSION and NEUTRINO phase 3 studies. J Hepatol 2014;60(Suppl):S449. Supporting Information Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/ /hep.27366/suppinfo.