Approximately million Americans are

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1 VIRAL HEPATITIS Multicenter Experience Using Simeprevir and Sofosbuvir With or Without Ribavirin to Treat Hepatitis C Genotype 1 in Patients With Cirrhosis Bashar A. Aqel, 1 Surakit Pungpapong, 2 Michael Leise, 3 K. Tuesday Werner, 1 Amy E. Chervenak, 1 Kymberly D. Watt, 3 Jennifer L. Murphy, 2 Kristen Ryland, 2 Andrew P. Keaveny, 2 Ryan McLemore, 1 and Hugo E. Vargas 1 Interferon (IFN)-free regimens are needed to treat hepatitis C virus (HCV) infection. Combined simeprevir (SMV) and sofosbuvir (SOF) with or without ribavirin (RBV) results in high sustained virological response (SVR) rates along with minimal adverse events (AEs) in patients with hepatitis C genotype 1 (HCV GT1). The aim of this study was to report on the virological response, safety, and tolerability of SOF and SMV with or without RBV in compensated and decompensated patients with cirrhosis with HCV GT1 infection. Patients treated with standardized clinical protocol utilizing SMV1SOF with or without RBV at three transplant centers were retrospectively reviewed. A total of 119 patients (61% male, 87% white, 69% subtype 1a, 30% Child-Pugh-Turcott [CPT]-B liver cirrhosis [LC], and 82% were treatment experienced) received treatment and were followed for a median of 38 weeks (range, 12-58). Sustained virological response (SVR) at week 12 (SVR12) was achieved in 78% (92 of 118) of patients (95% confidence interval: 69-85). Lower pretreatment Model for End Stage Liver Disease (MELD) score was a predictor of SVR12 (P ). Baseline viral load, previous treatment status, RBV use, or GT1 subtype did not impact SVR 12. The majority of patients with SVR12 showed stability or improvement in MELD score. Treatment was very well tolerated with mild degrees of AEs. Conclusions: The regimen of SMV1SOF with or without RBV for 12 weeks was very well tolerated and resulted in high SVR12 rates (78%) in HCV GT1 patients with LC. SVR12 was inversely related to pretreatment MELD. SVR12 had favorable short-term impact on MELD score. Long-term impact on disease stability is yet to be determined. Longer treatment duration or the use of different regimen may still be needed in this population. (HEPATOLOGY 2015;62: ) Approximately million Americans are chronically infected with hepatitis C virus (HCV) and are at risk of developing cirrhosis, hepatocellular carcinoma (HCC), or both. Both decision modeling studies and U.S. veterans national studies estimated that 18%-25% of HCV-infected patients will have cirrhosis at time of diagnosis. That estimate will most likely reach a peak of 45% in 2020, leading to a progressive increase in the rates of hepatic decompensation and HCC in the next two decades. 1 As a result of this, HCV infection is the leading indication for liver transplantation (LT) worldwide. 2 The introduction of new direct-acting antiviral agents (DAA) against HCV infection has dramatically altered Abbreviations: AASLD, American Association for the Study of Liver Diseases; AE, adverse event; AVT, antiviral treatment; BOC, boceprevir; CI, confidence interval; CTP, Child-Pugh-Turcott; DAA, direct-acting antiviral agent; egfr, estimated glomerular filtration rate; EOT, end of treatment; EOTR, end-of-treatment response; FDA, U.S. Food and Drug Administration; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HCV GT1, hepatitis C genotype 1; HIV, human immunodeficiency virus; IFN, interferon; IL, interleukin; IL28b, interleukin 28b rs ; ITT, intention to treat; LC, liver cirrhosis; LVD, ledipasvir; LLOD, lower limit of detection; LLOQ, lower limit of quantification; LT, liver transplantation; MELD, Model for End Stage Liver Disease; NS, nonstructural; OR, odds ratio; Peg-IFN, pegylated IFN; PI, protease inhibitor; RAVs, resistance-associated variants; RBV, ribavirin; RVR, rapid virological response; SAE, serious adverse event; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; SVR4, SVR at week 4 after completing treatment; SVR12, SVR at week 12 after completing treatment; SVR24, SVR at week 24; TVR, telaprevir; TW, treatment week. From the 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ; 2 Department of Transplant, Mayo Clinic, Jacksonville, FL; and 3 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN Received March 18, 2015; accepted June 5,

2 HEPATOLOGY, Vol. 62, No. 4, 2015 AQEL ET AL the landscape of treatment for HCV. 3,4 Several interferon (IFN)-free regimens are currently approved to treat the different genotypes and are included in the treatment protocols in the United States. 5 Treatment regimens that contained pegylated IFN (Peg-IFN) and ribavirin (RBV) were not effective and poorly tolerated in the pre-lt setting, with reported sustained virological response (SVR) rates ranging between 24% and 45%. 6 Though the addition of the first-generation protease inhibitor (PI), telaprevir (TVR) or boceprevir (BOC), to Peg-IFN and RBV improved SVR rates (50%-65%), these treatment regimens were complex and associated with high rates of adverse events (AEs), limiting their use in patients with advanced liver disease. 7-9 Simeprevir (SMV), a second-generation nonstructural (NS)3/4 protease inhibitor, and sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor, were approved by the U.S. Food and Drug Administration (FDA) to be used along with Peg-IFN and/or RBV for treatment of hepatitis C genotype 1 (HCV GT1) patients. Patients with cirrhosis treated with SMV/Peg- IFN/RBV had SVR rates as high as 80%-81% (treatment na ıve) and as low as 54% in treatmentexperienced patients. 10,11 In a phase III trial, SOF combined with Peg-INF and RBV showed an SVR rate of 71%-80% in a small subgroup of treatment-na ıve patients with compensated liver cirrhosis (LC). 12 The COSMOS study, a phase II study that investigated the safety and efficacy of the combined use of SMV and SOF with or without RBV, reported SVR rates in excess of 90% even in patients with compensated cirrhosis. 13 This regimen was endorsed by American Association for the Study of Liver Diseases (AASLD)/Infectious Disease Society of America and European Association for the Study of the Liver in their respective guidelines. 14,15 Subsequently, the FDA approved this regimen in November 2014 to treat non-lt patients for 12 weeks in patients without cirrhosis with METAVIR stage F0- F3 and 24 weeks in patients with cirrhosis with META- VIR stage F4. In this study, we report our multicenter experience using SMV1SOF with or without RBV for treatment of HCV GT1 patients with compensated and decompensated LC. Patients and Methods Study Design and Patients. A clinical treatment protocol was developed for treating HCV GT1 patients with cirrhosis at Mayo Clinic Transplant Centers in Arizona, Florida, and Minnesota. This study was a retrospective review of prospectively collected data concerning the safety and efficacy of this protocol. The Mayo Clinic Institution Review Board approved the study. Patients with compensated cirrhosis and those evaluated for LT were considered for treatment. The treatment regimen consisted of SMV and SOF with or without RBV for 12 weeks. Our protocol was put in place preceding the FDA approving 24 weeks of SMV1SOF for treatment of patients with HCV GT1 infection who had cirrhosis. Both SMV and SOF were orally administered together at a daily dose of 150 and 400 mg, respectively. No dose adjustment was allowed. At the discretion of treating physicians, weight-based RBV was used in selected patients. The initial dose of RBV was based on the estimated glomerular filtration rate (egfr) and dose was adjusted depending on hemoglobin levels. All patients had egfr >30 ml/min at time of treatment initiation. egfr rate was calculated using the Modification of Diet in Renal Disease formula. 16 Efficacy Assessments. Plasma HCV-RNA levels were quantified by COBAS TaqMan HCV assay (version 2.0; Roche Molecular Systems, Inc., Indianapolis, IN) with a lower limit of quantification (LLOQ) of IU/mL and a lower limit of detection (LLOD) of 10 IU/mL. HCV RNA was monitored every 2 weeks until undetected, then every 4 weeks thereafter until 24 weeks after completion of treatment. The primary endpoint was the proportion of patients who achieved undetected HCV RNA or SVR 12 weeks after completing treatment (SVR12). SVR12 results were calculated based on intention-to-treat (ITT) analysis. We modeled SVR12 using logistic regression to assess the impact of the following variables: age; gender; race (white vs. nonwhite); genotype subtype; interleukin (IL)228B status (CC vs. non-cc); baseline viral load; RBV use; CTP score; and previous treatment status. Child-Pugh-Turcott (CTP) score and Model for End Stage Liver Disease (MELD) Address reprint requests to: Bashar A. Aqel, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ Aqel.bashar@mayo.edul; fax: Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Dr. Pungpapong received grants from Gilead and Bristol-Myers Squibb.

3 1006 AQEL ET AL. HEPATOLOGY, October 2015 score were exchanged in multivariate models owing to likely collinearity. Changes in CTP and MELD score before and after treatment were assessed as well. R software (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria) was used for all analyses; package car (version ) was used for calculation of the variance inflation factors for regression diagnostics. Package epicalc (version ) was used for calculation of confidence intervals (CIs), with a uniformly set at 0.05 (GNU.org). Safety Assessments. Safety data were collected from all patients from the time of starting treatment until the assessment of the primary endpoint. Standard laboratory tests including MELD score parameters were performed at treatment weeks (TWs) 0, 4, 8, and 12 and post-tws 4, 8, 12, and 24. Clinic visits were conducted at approximately TW4, end of treatment (EOT), and week 12 and 24 after treatment completion. Telephone communications by our advanced practitioners or pre-lt nurse coordinators were conducted frequently throughout the study duration to identify any AEs. Serious AEs (SAEs), including urgent clinic visits and/or hospitalizations, were thoroughly reviewed to identify the causal relationship with treatment regimen. Results A total of 119 patients with HCV GT-1 infection and cirrhosis were treated per protocol with SMV and SOF with or without RBV at the three participating sites. Table 1 summarizes the baseline patient demographic and clinical characteristics. RBV was administered in 24 patients (20%). Genotype 1a was present in 82 patients (69%), and IL-28B polymorphism non-cc was present in 62 patients (71%). High viral load at baseline (viral load >600,000 IU/mL) was present in 32 patients (27%). Eighty patients (67%) were treatment experienced, including 22 of 119 (19%) with previous exposure to either TVR or BOC. At time of treatment, 84 of 119 (71%) patients had CPT class A (CTP-A) cirrhosis, 34 (29%) had CTP class B (CTP-B) cirrhosis, and HCC was present in 18 patients (15%). Fifty-eight patients (49%) had evidence of hepatic decompensation (ascites, variceal bleeding, encephalopathy, or spontaneous bacterial peritonitis), and 82 (69%) were listed for LT. One patient had human immunodeficiency virus (HIV) coinfection. All patients (except 3) completed antiviral treatment (AVT) and were followed for a median of 30 weeks (range, 12-53); no patients were lost to follow-up. To date, all patients have had assessment for SVR12. Table 1. Baseline Patient Demographics and Clinical Characteristics of 119 Patients Characteristic Value Age, mean 6 SD, years Men Women Male sex, no. (%) 73 (61.3) Race, no. (%) Caucasian 103 (87) Non-Caucasian 16 (13) CTP (%) CTP-A 84 (70.5) CTP-B 34 (29) CTP-C 1 HCV genotype, no. (%) 1a 82 (69) 1b 24 (20) Unable to subtype 13 (11) Recipient IL28B polymorphism, no. (%) CC 26 (22) CT or TT 62 (52) Not tested 31 (26) History of previous treatment, no. (%) Na ıve 39 (33) Failed Peg-IFN and RBV 58 (49) Failed Peg-IFN and RBV with first-generation PI 22 (18) Transplanted, no. (%) Yes 9 (7.5) No 110 (92.5) Hepatic decompensation, no. (%) 58 (49) HCC, no. (%) 18 (15) Listed for LT (%) 82 (69) HCV RNA >600,000 IU/mL, no. (%) 32 (27) egfr at treatment initiation Mean 6 SD, ml/min Less than 30 ml/min, no. (%) 0 Abbreviation: SD, standard deviation. Transplantation Status. During the study period, 9 patients (7.5%) underwent LT. Three of those patients had already relapsed before transplant and continue to be viremic post-lt. Six patients received LT after achieving virological response (3 patients with SVR12, 2 with SVR at week 8 after completing treatment, and 1 with SVR at week 4 after completing treatment [SVR4] at time of transplant). Five of these patients continue to be HCV-RNA negative post-transplant after a mean follow-up period of 20 weeks. One patient, who achieved SVR4, relapsed 3 weeks after transplantation. AEs. Table 2 summarizes the AEs reported during the antiviral treatment. Twenty-six patients (22%) had at least one AE. These AEs were mild in severity, requiring only supportive and symptomatic treatment without interruption of AVT. Headache was the most common AE and was observed in 9 patients. Anemia was observed in 6 patients, all receiving RBV. This was managed with RBV dose reduction, and growth factor support was used in 2 patients. Grade 3-4 hyperbilirubinemia developed in 4 of 119 (3%) of patients: Three patients had CTP-B

4 HEPATOLOGY, Vol. 62, No. 4, 2015 AQEL ET AL Event Table 2. AEs and Laboratory Abnormalities Patients With Event, no. (%) Any AE 37 (31) Any AE leading to discontinuation 3 (2.5) SAEs Death (unrelated to the study) 1 (1) Common AEs Fatigue 6 (5) Skin complaints (rash, pruritus, or photosensitivity) 8 (7) Headache 9 (8) Gastrointestinal complaints (nausea, dyspepsia) 1 (0.8) Vertigo 1 (0.8) Insomnia 1 (0.8) Myalgia 1 (0.8) Anemia (RBV group) 6/24 (72) Anemia (non-rbv group) 0/95 (0) Growth factor use (for anemia) 2/6 (33) Grade 2-3 chemical or hematological abnormalities Hemoglobin 8-10 g/dl (RBV group) 6/24 (25) Total bilirubin >3 mg/dl 4/119 (2) Creatinine >2.0 mg/dl 0 (0) Creatinine increase >0.5 mg/dl 8 (7) cirrhosis and 1 had CTP-A and HIV coinfection. Treatment was stopped prematurely in 3 patients: 1 patient at week8and2atweek11oftreatment.inallpatients,bilirubin went back to baseline within 4 weeks of stopping treatment. None of the patients developed events of hepatic decompensation while on treatment. Treatment had minimal impact on egfr, with only 8 patients (7%) having more than a 0.5-mg/dL increase in creatinine level compared to baseline and none of the patients developed creatinine >2.0 mg/dl while on treatment. One patient died during the study period. The patient had decompensated (CTP-B) LC with baseline MELD score of 17 and was not a candidate for LT owing to medical comorbidities. MELD score at baseline was 17. The patient completed 12 weeks of treatment and achieved both EOT response (EOTR) and SVR4. Despite achieving viral clearance, the patient died from complications of hepatic decompensation 6 weeks after completion of treatment. Virological Response. Table 3 summarizes the virological response in our cohort. All patients achieved undetected HCV RNA during treatment, at a median of 4 weeks (range, 2-8). Rapid virological response (RVR) with undetected HCV RNA at TW4 was achieved in 82 of 119 patients. EOTR by ITT analysis was achieved in 100% of patients, including the 1 patient in whom treatment was stopped prematurely at TW8. On-treatment viral kinetics, SVR4, and SVR12 were similar between the 24 patients who received RBV, compared with the remaining 95 patients who did not receive RBV. Nineteen patients developed virological relapse within 4 weeks after treatment completion, resulting in an SVR4 rate of 84% (100 of 119 patients; 95% confidence interval [CI]: ) by ITT analysis. An additional 7 patients relapsed after achieving SVR4 and 1 patient died before reaching the SVR12 time point, yielding an SVR12 rate of 78% (92 of 118 patients; 95% CI: 69-85) by ITT analysis. SVR at week 24 after completing treatment (SVR24) data are available for only 68 patients, and thus far only 1 patient had confirmed virological relapse after achieving SVR12. Whereas SVR4 was a strong predictor of SVR12 with a Kendall s tau correlation coefficient of 0.842, RVR was a weak predictor of SVR12, with a Kendall s tau correlation coefficient of only No resistance-associated variant (RAV) analysis was performed either before treatment initiation or at the time of virological relapse. Impact of Treatment on MELD Score. During the study period, 92 patients achieved SVR12 and 26 patients relapsed after completing treatment. Median MELD score at time of treatment initiation was 13 (range, 8-17). Figure 1 represents a waterfall plot that outlines changes in MELD score in both patients achieving SVR12 and those who relapsed. MELD scores were compared at two time points: at time of treatment initiation and 12 weeks after completion of treatment. For the 3 patients who underwent transplant before that time point, we used the MELD score documented before transplant. In patients achieving SVR12, 27 of 92 (29.3%) showed improvement in MELD, 61 of 92 (66.4%) maintained the same MELD, and only 4 of 92 (4.3%) showed worsening of MELD score during the study period. In patients who relapsed, 10 of 26 patients (38%) showed improvement in MELD, 14 of 26 (54%) maintained stability, and 2 of 26 (8%) showed worsening of MELD during the study period. Factors Influencing SVR12 Rate. Severity of liver disease at baseline had a significant impact on SVR12. SVR12 was inversely related to MELD score at baseline (pretreatment MELD). Patients who relapsed tended to have higher pretreatment MELD with very low rates of relapse in patients with baseline MELD score of 10 or less. Using the univariate analysis model, the odds ratio (OR) for relapse was 1.37 (CI, ; P < 0.001) Table 3. Virological Response N (%) RVR 82/119 (69) EOTR 119/119 (100) SVR4 100/119 (84) SVR12 92/118* (78) One patient died after achieving SVR4.

5 1008 AQEL ET AL. HEPATOLOGY, October 2015 Fig. 2. Relapse by pretreatment MELD score. Those who relapsed tended to have a higher MELD, and relapse rates were very low in patients with pretreatment MELD score of 10 or less. Along the top is the univariate P value and odds ratio for relapse for each point increase in MELD score. Pretreatment continued to be strong predictor for relapse using the multivariate model (P ). analyses to identify factors influencing the SVR12 rate. The addition of RBV, baseline viral load, and recipient interleukin 28b rs (IL28b) polymorphism (CC vs. CT/TT) did not impact the SVR12 rates. Previous treatment status, including the use of the firstgeneration PI, did not impact SVR12 as well. SVR12 rates were similar in patients with genotype 1a, compared to those with genotype 1b (P 5 0.8). SVR12 rates Fig. 1. Waterfall plots outline changes in MELD score from baseline compared to MELD score 12 weeks after completion of treatment in both (A) patients who achieved SVR12 and (B) those who relapsed. Subjects with increased MELD scores are shown in red. Subjects with decreased MELD scores are shown in blue. Each column represents one patient. For the three patients transplanted before the 12 weeks time point, MELD score at time of transplant was used for comparison. for each point increase in baseline MELD score (Fig. 2). Lower pretreatment MELD score continued to be a strong predictor of SVR12 using the multivariate analysis model (P ). However, though patients with advanced liver disease (CTP-B) had lower SVR12 rates than those with well-compensated cirrhosis (CTP-A; 68% vs. 83%), this difference showed a trend of statistical significance on the univariate analysis model with a P value of 0.09, but the difference became less pronounced on the multivariate analysis model (P ; Fig. 3). Figure 4 demonstrates the results of subgroup Fig. 3. Relapse by baseline CTP Score. At the top is the univariate P value in logistic regression for relapse, and the odds ratio based on CTP score. While not statistically significant, relapse rates showed a higher trend in patients with CTP B cirrhosis.

6 HEPATOLOGY, Vol. 62, No. 4, 2015 AQEL ET AL Fig. 4. Proportion of SVR 12 by factor. This plot shows the breakdown of SVR12 by each factor on the left, and the P value from the multivariate model for relapse. were similar in patients who achieved undetected HCV RNA at TW4 (RVR), compared to those with detected HCV RNA at TW4 (P 5 0.8). Discussion In this large, multicenter, real-world experience, we describe the efficacy of an all-oral IFN-free antiviral regimen comprised of SMV1SOF with or without RBV for 12 weeks treating HCV GT1 in patients with advanced liver disease. Overall, this combination treatment was very well tolerated. Three patients (2.5%) discontinued treatment prematurely owing to hyperbilirubinemia: 1 patient completed 8 weeks and 2 completed 11 weeks of therapy, respectively. For the patient cohort as a whole, the SVR12 rate was 78% (95% CI: 69-85) by ITT analysis. The addition of RBV did not impact either on-treatment viral kinetics or SVR12 rate. SVR12 rates were similar among genotype 1 subtypes. Severity of liver disease at baseline had a significant impact on SVR12. Patients with lower MELD score at time of treatment initiation were more likely to achieve SVR12 (P ). Pretreatment MELD was strongly associated with relapse rate. Mean MELD score for patients achieving SVR12 was significantly lower, when compared to mean baseline MELD in those who relapsed (10 and 13, respectively; P < 0.001). There was a linear increase in the rates of relapse with each point increase in baseline MELD score (OR, 1.37; Fig. 2). Whereas SVR12 rates in well-compensated cirrhosis (CTP-A) were higher than in those with more advanced disease (CTP-B; 82% vs. 68%), the difference approached statistical significance on the univariate analysis model (P ), but became less pronounced using the multivariate analysis model (P ; Fig. 3). However, the trend observed using the univariate analysis model combined with an OR of 2.2 (Fig. 3) for achieving SVR12 in patients with CTP-A, we find it reasonable to postulate that the difference was lost owing to a small sample size. Because we had only 1 patient with CTP-C cirrhosis, the safety and efficacy of this regimen in such patients is yet to be determined based on this report. The lower response rate in patients with more advanced liver disease may argue for the need of a more effective treatment regimens or even possibly avoiding treatment in those patients and pursue treatment post-lt where those regimens have been proven to be safe and highly effective. 17 Our analysis showed that viral eradication clearly helps improving hepatic functions and can lead to early improvement in MELD score. Because all patients achieved on-treatment viral clearance, this short-term effect was observed in both patients achieving SVR and patients who relapsed. The short follow-up period limits our ability to assess the long-term impact of SVR12 on those patients. Those changes are starting to mirror the effects that have been described with suppression of hepatitis B in patients with hepatic decompensation, as well as successful treatment of patients with autoimmune hepatitis presenting with acute hepatic decompensation. We postulate that achieving SVR12 will be accompanied by several long-term benefits that may include reversal of hepatic decompensation, reducing the need for LT, and potentially decreased risk of developing HCC. 18 Transplant centers across the nation may soon find the incorporation of this and other novel DAA treatment regimens as part of the solution to the gap between the demand for, and the available number of, liver allografts. 19 SMV and SOF combination therapy was more effective, better tolerated, and associated with significantly fewer AEs, compared to Peg-IFN-based regimens. 7,8,13 Those features would allow this regimen and several other all-oral DAA regimens to treat patients with various degrees of hepatic decompensation. 17,20,21 Significant grade 3-4 hyperbilirubinemia was rare and only observed in 4 patients in our cohort. It predominantly affected patients with more advanced liver disease (3 patients had CTP-B cirrhosis). As expected, this was a reversible phenomenon and the bilirubin level returned back to their baseline in all patients within 12 weeks after treatment discontinuation.

7 1010 AQEL ET AL. HEPATOLOGY, October 2015 Our report is among the growing experience that documents the safety and efficacy of all-oral IFNfree antiviral regimens to treat HCV GT1 in patients with cirrhosis. 5,20,21 Most of those studies addressed HCV treatment in patients with compensated CTP-A cirrhosis with very limited data regarding the efficacy of those regimens in patients with CTP-B cirrhosis. In the ION-2 study, ledipasvir (LDV)/SOF combination therapy was evaluated in patients with and without cirrhosis in whom previous treatment with Peg-INF and RBV (with or without first-generation PIs). 22,23 This regimen was given for 12 and 24 weeks and was well tolerated in all treatment groups. In patients with cirrhosis, patients treated with 24 weeks had higher SVR rates (100%), compared with those treated for only 12 weeks (86%), supporting the current recommendation for 24 weeks treatment in patients with cirrhosis. In the SIRIUS study, a doubleblind, placebo-controlled French study, patients with a previous nonresponse to Peg-INF, RBV plus TVR or BOC, were randomized to receive 12 weeks of LVD/ SOF plus RBV or LDV/SOF with placebo for 24 weeks. SVR rates were similar in both groups: 96% and 97%, respectively. This observation was further supported by a meta-analysis of treatment-na ıve and -experienced patients with cirrhosis who were treated with LDV/SOF in phase II and III studies. In this analysis, both LDV/SOF for 24 weeks and LDV/SOF plus RBV for 12 weeks had similar efficacy. Both regimens were well tolerated, though there was a higher rate of anemia in patients receiving RBV. 20,21 In the TURQUOISE-II study, patients with CTP-A cirrhosis were treated with a regimen of ombitasvir, paritaprevir/ritonavir, and dasabuvir with RBV for 12 or 24 weeks. 24 This regimen was well tolerated and demonstrated high efficacy with an overall SVR12 rate of 90.2% for the 12-week arm and 96.9% in patients in the 24-week arm. Though treatment discontinuation rate for AEs was low at only 2.1%, significant anemia was observed in 7.2% of patients in the 12-week arm and 11% in the 24-week arm. Patients with previous nonresponse to Peg-INF and those with genotype 1a had lower response to 12- week treatment. Though our report supports the safety of this regimen in patients with decompensated CTB-B cirrhosis, efficacy was low with a SVR12 rate of only 68%. Those rates are lower when compared to the limited data available regarding the efficacy of DAAs in patients with decompensated cirrhosis. The SOLAR-2 multicenter study reported the efficacy of LDV/SOF with RBV for 12 and 24 weeks in HCV GT1 and GT4 patients with decompensated CTP-B and -C cirrhosis. SVR12 was achieved in 87% of patients given the 12-week treatment course and 89% in those given the 24-week treatment arm. Similar to what we observed in our study, baseline CTP and MELD scores improved in more than 50% of treated patients. Grade 3 or 4 AEs were more common in the 24-week arm (34%), compared to 15% in the 12-week arm. Most patients were maintained on a low dose of RBV (600 mg/day). Five patients died during the study period, but none of the deaths were attributed to AVT. Our study is one of the largest reports to date using an all-oral IFN- and RBV-free antiviral regimen to treat patients with HCV GT1 and LC. Whereas RBV was used in only 24 patients, its addition did not influence on-treatment virological response or SVR12 rates. This finding has been reported by several other studies. 13,22,25 The efficacy of SMV and SOF combination demonstrated in those reports suggests that RBV might not be essential in this regimen, but its use may be considered until results from larger phase III trials will more definitively address this question (NCT and NCT ). The ability to eliminate RBV from any future treatment regimens will simplify such regimens, obviate the risk of anemia, and allow better tolerance, especially in those patients with decompensated liver disease. Our study had several noteworthy observations in regard to viral kinetics. On-treatment virological response (RVR) was not a predictor of SVR12, similar to what has been reported previously in several other studies, and thus its use as a futility rule should be abandoned in the era of all-oral IFN-free DAA treatment regimens. 13 Though SVR4 continues to be a strong predictor of SVR12, we found that 6% of relapses in our cohort occurred after achieving SVR4. Furthermore, we report on 1 patient with a late relapse that occurred after achieving SVR12. Though this represents a rare event, we believe that it provides a rationale for checking SVR24 in patients with cirrhosis. Despite the increasing evidence that viral negativity for a minimum of 4 weeks on treatment is a strong predictor of SVR post-lt, 26 our cohort included 1 patient who completed HCV treatment, achieved SVR4, but yet relapsed post-lt. There are several limitations that should be considered in the interpretation of this report, including the retrospective element in the design with the relatively limited 12-week treatment duration, and the lack of data on RAVs. We demonstrated that the SMV and SOF combination regimen was equally effective in patients with genotype 1a and genotype 1b infections with SVR12 of 79.3% and 83.3%, respectively (P 5 0.8). Although the difference was not statistically

8 HEPATOLOGY, Vol. 62, No. 4, 2015 AQEL ET AL significant, the analysis was likely underpowered owing to the small number of patients with genotype 1b and high number of patients in whom genotype subtype could not be defined (11%). Because our clinical protocol for treatment with SMV1SOF was implemented before FDA approval for this regimen, the treatment duration was fixed at 12 weeks. Subsequent to the development of our protocol, pooled data from the COS- MOS study showed that in patients with cirrhosis, an SVR rate of (96%) was achieved when patients were treated for 24 weeks. As a consequence, the FDA approved a 24-week SMV1SOF treatment regimen for HCV treatment-na ıve and -experienced patients with cirrhosis. 13,27 The 78% SVR rate in the real-world setting of our patient cohort (compared to the COSMOS study) supports this recommendation. Finally, given that the presence of the Q80K polymorphism does not preclude treatment with SMV1SOF per AASLD guidelines (SVR rate was as high as 88% in patients with HCV genotype 1a and the Q80K polymorphism), 13 RAV analysis was not part of our clinical protocol either before treatment initiation or at the time of virological relapse. The lack of these data precludes us from determining the impact of RAV on virological rebound or relapse in our patients. In summary, we found that the all-oral IFN-free regimen consisting of SMV and SOF, with or without RBV, for 12 weeks was well tolerated and demonstrated an SVR12 rate of 78% by ITT among patients with cirrhosis infected with HCV GT1. SVR12 was lower in patients with more advanced liver disease and was inversely related to pretreatment MELD (0.018). Though viral clearance was associated with short-term improvement in MELD score, long-term impact of SVR12 is still to be determined. Our data support the FDA recommendation to extend duration of therapy of SMV1SOF to 24 weeks in patients with cirrhosis. The use of this regimen may be limited by the cost and availability of other effective all-oral treatment regimens. References 1. Jacobson IM, Davis GL, El-Serag H, Negro F, Trepo C. Prevalence and challenges of liver diseases in patients with chronic hepatitis C virus infection. Clin Gastroenterol Hepatol 2010;8: ; quiz, e Younossi ZM, Kanwal F, Saab S, Brown KA, El-Serag HB, Kim WR, et al. The impact of hepatitis C burden: an evidence-based approach. Aliment Pharmacol Ther 2014;39: Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology 2014;146: Pawlotsky JM. New hepatitis C therapies. Semin Liver Dis 2014;34: Pawlotsky JM. Hepatitis C treatment: the data flood goes on an update from the Liver Meeting Gastroenterology 2015;148: Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol 2008;49: Manns MP, McCone J, Jr., Davis MN, Rossaro L, Schiff E, Shiffman ML, et al. Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials. Liver Int 2014;34: Hezode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology 2014;147: e Pungpapong S, Aqel BA, Koning L, Murphy JL, Henry TM, Ryland KL, et al. Multicenter experience using telaprevir or boceprevir with peginterferon and ribavirin to treat hepatitis C genotype 1 after liver transplantation. Liver Transpl 2013;19: Forns X, Lawitz E, Zeuzem S, Gane E, Bronowicki JP, Andreone P, et al. 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9 1012 AQEL ET AL. HEPATOLOGY, October 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: Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370: Sulkowski MS, Jacobson IM, Nelson DR. Daclatasvir plus sofosbuvir for HCV infection. N Engl J Med 2014;370: CurryMP,FornsX,ChungRT,TerraultNA,BrownR,Jr.,FenkelJM,etal. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology 2015;148: e Janssen Inc. Olysio (simeprevir) prescribing information. Titusville, NJ: Janssen Inc.; 2014.