Simeprevir and Sofosbuvir With or Without Ribavirin to Treat Recurrent Genotype 1 Hepatitis C Virus Infection After Orthotopic Liver Transplantation

Transcription

1 ORIGINAL ARTICLE Simeprevir and Sofosbuvir With or Without Ribavirin to Treat Recurrent Genotype 1 Hepatitis C Virus Infection After Orthotopic Liver Transplantation Neil E. Crittenden, 1 Laura A. Buchanan, 6 * Christina M. Pinkston, 5 Barbra Cave, 1,9 Ashutosh Barve, 1,9,10 Luis Marsano, 1,9,10 Craig James McClain, 1,2,9,10 Christopher M. Jones, 3,9 Michael R. Marvin, 3,9 Eric G. Davis, 3,9 Candice B. Kuns-Adkins, 6 Roberto Gedaly, 7,8 Guy Brock, 5 Malay B. Shah, 7,8 Jens Rosenau, 6,8 * and Matthew C. Cave 1,2,4,9,10 Departments of 1 Medicine, Division of Gastroenterology, Hepatology, and Nutrition, 2 Pharmacology and Toxicology, 3 Surgery, Division of Transplantation, 4 Biochemistry and Molecular Genetics, and 5 School of Public Health and Information Sciences, University of Louisville, Louisville, KY; Departments of 6 Medicine, Division of Digestive Health, 7 Surgery, Division of Transplantation, and 8 Healthcare Transplant Center, University of Kentucky, Lexington, KY; 9 KentuckyOne Health Transplant Center, Louisville, KY; and 10 Robley Rex Veterans Affairs Medical Center, Louisville, KY Although combination simeprevir (SIM) plus sofosbuvir (SOF) is an approved regimen for genotype 1 chronic hepatitis C virus (HCV), data regarding its safety and efficacy in liver transplant recipients remain limited. A multicenter retrospective study was performed to determine the efficacy and tolerability of a 12-week regimen of SIM/SOF with or without ribavirin (RBV) in 56 consecutive liver transplant recipients in 2014; 79% of patients had genotype 1a, 14% had cirrhosis, and 73% were treatment experienced. Sustained virological response at 12 weeks (SVR12) was 88% by intention to treat analysis (95% confidence interval, 84%-90%). Four patients relapsed, but no on-treatment virological failures occurred. The Q80K polymorphism did not impact SVR12, but there was a trend toward decreased sustained virological response with advanced fibrosis (P ). HCV RNA was detectable at treatment week 4 in 21% of patients, and those who had detectable levels were less likely to achieve SVR12 (58% versus 95%; P ). Five patients had baseline Child-Pugh class B cirrhosis, and 2 of them died (1 following early discontinuation of therapy). An additional discontinuation resulted from a severe photosensitivity reaction in a patient on concomitant cyclosporine. Seven patients receiving RBV developed progressive anemia requiring intervention. Immunosuppression dose modifications were minimal. SIM/SOF for 12 weeks was effective and well tolerated by compensated liver transplant recipients especially when administered without concomitant RBV or cyclosporine. SIM/SOF appears to have a niche as the only 12-week RBV-free treatment regimen currently recommended by guidelines for compensated transplant recipients. However, 12 weeks may not be the optimal duration of therapy for those with detectable virus at week 4 or possibly for those with cirrhosis. These data require confirmation by prospective randomized clinical trials. Liver Transplantation AASLD. Received September 7, 2015; accepted February 20, Abbreviations: AASLD, American Association for the Study of Liver Diseases; AE, adverse event; BMI, body mass index; CI, confidence interval; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; IQR, interquartile range; ITT, intention to treat; LLOQ, lower limit of quantification; OR, odds ratio; RBV, ribavirin; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virological response; SVR12, sustained virological response at 12 weeks; TW, treatment week; WBC, white blood cell. Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation in the United States. (1) Recurrence of HCV in the allograft following transplantation is universal. Posttransplant HCV is associated with accelerated progression of fibrosis, and 10%-30% of patients were reported to have recurrent cirrhosis after 5 years. (2) Although recurrent HCV may lead to graft loss, only 5% of retransplants were historically performed for this indication, presumably due to the recognition of poor ORIGINAL ARTICLE 635

2 LIVER TRANSPLANTATION, May 2016 outcomes. (3) For these reasons, and others, treatment of HCV in the organ transplant recipient is assigned the highest priority in the most recent HCV guidance from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA). (4) With great interest, we followed the phase 2 data from the COSMOS trial showing high sustained virological response (SVR) rates in nontransplant genotype 1 patients using combination simeprevir (SIM) plus sofosbuvir (SOF) therapy. (5) SIM is a HCV NS3/4A protease inhibitor, whereas SOF is a nucleotide-analogue NS5B polymerase inhibitor. Several studies including COSMOS and the as of yet unpublished OPTIMIST-1 and OPTIMIST-2 trials have established the safety and efficacy of this regimen in the nontransplant setting. (6,7) There are 2 liver transplant centers located in Kentucky: KentuckyOne Health Transplant Care (a joint program between Jewish Hospital and the University of Louisville), and the University of Kentucky Healthcare Transplant Center. Subsequent to the approval of SIM and SOF and prior to the approval by the US Food and Drug Administration (FDA) of fixed-dose combination ledipasvir/sof in October 2014, both Address reprint requests to Matthew C. Cave, M.D., Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Kosair Charities Clinical and Translational Research Building, Room 509, 505 South Hancock Street, Louisville, KY Telephone: ; FAX: ; matt.cave@louisville.edu *These authors contributed equally to this work. Barbra Cave has been involved with research and/or the speaker s board for Abbvie, Bristol-Meyers Squibb, Gilead Sciences Inc., and Janssen Pharmaceuticals Inc. Luis Marsano has participated in research for Gilead Sciences Inc. Matthew C. Cave has been involved with research and/or consulting and/or the speaker s board for Abbvie, Bristol-Meyers Squibb, Conatus Pharmaceuticals Inc., Gilead Sciences Inc., Intercept Pharmaceuticals Inc., Janssen Pharmaceuticals Inc., Kadmon Pharmaceuticals LLC., Lumena Pharmaceuticals Inc., Merck and Co., Inc., and Novartis. Neil E. Crittenden, Laura A. Buchanan, Christina M. Pinkston, Ashutosh Barve, Craig James McClain, Christopher M. Jones, Michael R. Marvin, Eric G. Davis, Candice B. Kuns-Adkins, Roberto Gedaly, Guy Brock, Jens Rosenau, and Malay B. Shah have no conflict of interests to report. Additional supporting information may be found in the online version of this article. Copyright VC 2016 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /lt Potential conflict of interest: Nothing to report. centers exclusively treated recurrent genotype 1 HCV with SIM/SOF with or without ribavirin (RBV). The purpose of this retrospective analysis is to examine the safety, efficacy, and predictors of SVR using pooled data from these transplant centers during this initial period of time. Adding incrementally to the published literature, the effect of the Q80K variant after transplant was examined for a subset of this population. The HCV NS3 Q80K variant has been observed in 28%-47% of patients with HCV genotype 1a, (8) and its presence has been observed to limit the effectiveness of SIM in combination with pegylated interferon and RBV. However, the potential importance of this baseline resistance polymorphism for patients treated with SIM/SOF following liver transplantation is unknown. Patients and Methods DESIGN AND SELECTION OF PARTICIPANTS A multicenter retrospective study was conducted at the 2 aforementioned transplant centers involving the University of Louisville and the University of Kentucky. Inclusion criteria were as follows: orthotopic liver transplant recipient with genotype 1 HCV allograft infection treated with SIM/SOF with or without RBV between February 2014 (date of first insurance approval) and October 2014 (corresponding to FDA approval of fixed-dose combination ledipasvir/sof). Both cirrhotic and noncirrhotic patients were included. Both treatment na ıve and experienced patients were included, and only 2 patients had prior experience with a protease inhibitor. A biopsy was requested in all patients but was not mandatory for treatment initiation. Exclusion criteria were consistent with contraindications listed in the prescribing information for SIM, SOF, and RBV at that time. In general, these included factors such as pregnancy, glomerular filtration rate (GFR) < 30 ml/ minute, and contraindicated concomitant medication. A significant drug-drug interaction between SIM and cyclosporine became apparent during the study, and some patients on cyclosporine were treated with SIM/ SOF prior to the recognition of this important drugdrug interaction. Likewise, at study initiation, SIM was not recommended in patients with Child-Pugh class C cirrhosis. However, the label was subsequently changed, and SIM is no longer recommended for patients with class B or C cirrhosis. (9) Some patients with class B cirrhosis were enrolled prior to this label change. 636 ORIGINAL ARTICLE

3 LIVER TRANSPLANTATION, Vol. 22, No. 5, 2016 ETHICAL CONSIDERATIONS Institutional review board approval was obtained at each institution. TREATMENT PROTOCOL All patients, including those with cirrhosis, were treated with daily SOF (400 mg) and SIM (150 mg) for 12 weeks. Current FDA guidance recommends a 24-week treatment duration in general for patients with cirrhosis treated with SIM/SOF. However, the patients with cirrhosis included in this analysis initiated therapy prior to this FDA guidance. The addition of RBV was at the discretion of the individual transplant center. Although most patients did not receive RBV, a subset of patients at the Louisville site who tested positive for the Q80K NS3 viral resistance polymorphism were treated with weight-based and creatinine clearance based RBV, due to reports of decreased efficacy of SIM in patients treated with pegylated interferon plus RBV-based combination therapy. (10) ASSESSMENT OF TOLERABILITY Multidisciplinary teams involving physicians, advanced practice providers, nurses, pharmacists, and liver transplant coordinators followed patients closely. At the University of Kentucky, patients were followed per HCV treatment protocol with office visits at treatment initiation, weeks 4 and 12 on treatment, and at week 24 after treatment. Laboratory testing (monitoring of immunosuppression trough levels, hepatic, renal, and hematologic function) was done weekly for the first 4 weeks, at weeks 8 and 12 of treatment, and at weeks 4 and 12 after treatment. Self-reported adverse events (AEs) were captured with a standardized questionnaire. At the Louisville site, frequency of follow-up visits and of laboratory testing was individualized at the discretion of the treating provider, but in general, routine laboratory tests included routine monitoring of immunosuppression trough levels and hepatic, renal, and hematologic function. Because rash was reported in other SIM studies and anemia is known to occur with RBV therapy, rash and anemia were monitored in all patients at the Louisville site. Other AEs were documented in the patient chart as reported by the patient, but the standardized side effect questionnaire administered at the University of Kentucky was not administered at the University of Louisville. Key safety and tolerability endpoints included deaths, discontinuations, anemia requiring intervention, immunosuppression dose modifications, as well other serious AEs such as severe photosensitivity rash. Frequency of patient-reported side effects was also a secondary endpoint. ASSESSMENT OF EFFICACY The primary efficacy endpoint was sustained virological response at 12 weeks (SVR12) by intention to treat (ITT) analysis. SVR12 was defined as HCV RNA below the lower limit of quantification (LLOQ) at 12 weeks after the end of treatment. At both institutions, plasma HCV RNA levels were quantified by the COBAS AmpliPrep/COBAS TaqMan HCV Test, version 2.0 (Roche Molecular Systems, Inc., Pleasanton, CA), with a LLOQ of 15 IU/mL. Viral load monitoring was physician specific, but in general, it was prior to treatment, at treatment week (TW) 4, end of treatment, and at 12 weeks after treatment. Secondary efficacy endpoints included the impact of baseline host/virological factors, treatment factors, and on-treatment viral kinetics on SVR12 rates. Baseline host factors included fibrosis stage and prior treatment experience. Baseline virological factors included genotype (1a versus 1b) and baseline NS3 Q80K virological resistance (using the HCV RNA NS3 genotype test from Quest Diagnostics which had a limit of detection of 500 IU/mL). Treatment factors included the use of RBV. Viral kinetics included HCV RNA testing at TW 4. STATISTICAL ANALYSIS The primary endpoint was measured using ITT analysis. Categorical variables were analyzed using a Fisher s exact test and presented as counts and percentages. Continuous variables were checked for normality and, if appropriate, analyzed with nonparametric Kruskal- Wallis tests. These variables are presented as medians and interquartile ranges (IQRs). Rates and 95% confidence intervals (CIs) of SVR12 were constructed using exact binomial estimates and were plotted to compare the subgroup analyses. Odds ratio (OR) and 95% CIs were calculated with logistic regression models. All analyses were completed using Base SAS, version 9.4 (SAS Institute, Cary, NC). Statistical significance was based on a P value < ORIGINAL ARTICLE 637

4 LIVER TRANSPLANTATION, May 2016 TABLE 1. Demographic and Clinical Characteristics at Baseline University of Louisville (n 5 38) University of Kentucky (n 5 18) Overall (n 5 56) P Value Host factors Age, years 61 (6) 60 (8) 61 (7) 0.98 Weight, pounds; median (IQR) 192 (46) 192 (50) 192 (48) >0.99 BMI, kg/m 2 ; median (IQR) 29 (6) 30 (8) 29 (7) 0.69 Race (Caucasian); n (%) 31 (82) 17 (94) 48 (86) 0.41 Sex, male; n (%) 28 (74) 14 (78) 42 (75) >0.99 Time after LT, months; median (IQR) 53 (80) 72 (55) 55 (74) 0.41 Diagnosis leading to transplant; n (%) 0.17 HCV 27 (71) 9 (50) 36 (64) HCV and alcohol cirrhosis 3 (8) 4 (22) 7 (12) HCV and HCC 8 (21) 4 (22) 12 (21) HCV, alcohol cirrhosis, and HCC 0 (0) 1 (6) 1 (2) Cirrhosis; n (%) 3 (8) 5 (28) 8 (14) 0.10 Treatment experience; n (%) <0.001 Na ıve 4 (11) 11 (61) 15 (27) Experienced 34 (89) 7 (39) 41 (73) Baseline clinical characteristics; median (IQR) WBC, k/ml 4.9 (2.1) 5.2 (3.1) 5.0 (2.4) 0.75 Hemoglobin, g/dl 12.8 (2.6) 13.0 (4.6) 12.9 (3.0) 0.76 Creatinine, mg/dl 1.3 (0.7) 1.1 (0.5) 1.3 (0.5) 0.23 Bilirubin, mg/dl 0.8 (0.8) 0.6 (0.4) 0.7 (0.5) 0.02 Platelet, k/ml 138 (80) 130 (63) 142 (83) Viral factors Baseline HCV RNA, IU/mL; median (IQR) 4,800,000 5,190,000 4,800, (8,100,000) (11,820,000) (9,150,000) HCV genotype; n (%) a 29 (76) 15 (83) 44 (79) 1b 9 (24) 3 (17) 12 (21) HCV genotype 1a; n (%) Q80K 1 14 (48) 4 (27) 18 (41) Q80K 14 (48) 4 (27) 18 (41) Q80K unknown 1 (3) 7 (47) 8 (18) Immunosuppression; n (%) 0.31 Cyclosporine 3 (8)* 2 (11) 5 (9) Tacrolimus 25 (66) 15 (83) 40 (71) Mycophenolic acid 1 (3) 0 (0) 1 (2) Sirolimus 9 (24) 1 (6) 10 (18) NOTE: Data are presented as n (%) or median (IQR). *One patient on cyclosporine was also on low-dose corticosteroids. Two patients on tacrolimus were also on low-dose corticosteroids. Results BASELINE DEMOGRAPHICS AND CHARACTERISTICS Fifty-six consecutive orthotopic liver transplant recipients initiating antiviral therapy were eligible for evaluation (38 from University of Louisville, 18 from University of Kentucky). No patient had fibrosing cholestatic hepatitis. All had HCV genotype 1 infection and were treated with a combination of SIM and SOF with or without RBV. Table 1 summarizes their baseline characteristics and demographics. Overall, 75% of patients were male and 86% were Caucasian, with a median age of 61 years (IQR, 7 years). The median time after transplant was 55 months with a range of months. Between the 2 centers, there were 8 patients with cirrhosis (Child-Pugh A, n 5 3; Child- Pugh B, n 5 5). Most were treatment experienced (73%). Baseline demographics and characteristics were similar between centers, although patients at the University of Louisville site were more likely to be treatment experienced (89% versus 39%; P < 0.001), have a higher median baseline bilirubin (1.5 versus 0.7 mg/ dl; P ), and have a known Q80K viral genotype (97% versus 53%; P ). Two patients were protease inhibitor experienced. Immunosuppression regimens are provided in Table 1. The majority of patients (71%) received a tacrolimus-based regimen. Only 5% received corticosteroids while on therapy. 638 ORIGINAL ARTICLE

5 LIVER TRANSPLANTATION, Vol. 22, No. 5, 2016 TABLE 2. ITT SVR12 Rates and 95% CIs Characteristic SVRs Total Rate %, 95% CI P Value RBV >0.99 With (60-98) Without (74-96) Genotype a (75-96) 1b (52-98) Fibrosis stage 0.18 F0-F (80-99) F3-F (56-94) Fibrosis stage genotype 1a 0.61 F0-F (75-99) F3-F (60-98) Fibrosis stage genotype 1b 0.15 F0-F (59-100) F3-F (15-95) Prior treatment history 0.37 Na ıve (52-96) Experienced (77-97) Q80K polymorphism 0.49 and genotype 1a (65-98) (81-100) Genotype 1a and Q80K1* >0.99 With RBV (55-98) Without RBV (48-100) HCV RNA at TW Undetected (85-99) Detected (28-85) NOTE: Q80K polymorphism status was not obtained in 8 patients. Of these, 5 of 8 achieved SVR. DETERMINATION OF EFFICACY Fifty-three of the 56 patients completed therapy. There were 2 deaths, both occurring in patients with baseline Child-Pugh B cirrhosis. One of these patients died shortly after therapy discontinuation, and 1 death occurred after therapy completion but before SVR12 was obtained. The latter patient achieved an end-oftreatment response. One additional patient on concomitant cyclosporine discontinued treatment due to a severe photosensitivity reaction. These patients were considered treatment failures in the ITT analysis. By ITT analysis, SVR12 was 88% (n 5 49/56; 95% CI, 84%-90%). Using ITT analysis, SVR12 at the University of Louisville (n 5 35/38, 92%) and the University of Kentucky (n 5 14/18, 78%) were not statistically different (P ). Subgroup analyses were performed to identify factors influencing SVR12 rate and are summarized in Table 2 and Supporting Fig. 1. SVR12 was not impacted by viral genotype (eg, 1a versus 1b; P ), baseline presence of the Q80K viral resistance polymorphism (P ), the use of RBV (P > 0.99), or prior treatment experience (P ). Significantly increased SVR12 rates were observed in patients who were undetectable at TW 4 versus those who were detectable (95% versus 58%; P ). Thus, although 42% of patients with detectable virus at TW 4 failed therapy, only 5% with undetectable virus at TW 4 failed therapy. Patients with advanced fibrosis (METAVIR F3-F4) had numerically lower SVR12 compared to those with F0- F2 fibrosis (80% versus 94%; P ), but this trend did not reach statistical significance. Rates of SVR12 were also low among those with genotype 1b and advanced fibrosis (60%; 95% CI, 15%-95%) and unknown Q80K polymorphism status treated without RBV (57%, 95% CI, 18%-90%). Excellent SVR12 rates were observed in treatment-experienced patients (90%, 95% CI, 77%-97%) subgroups. Small subgroups had 100% SVR12 rates including patients with genotype 1b and no or early fibrosis; patients with genotype 1a who were Q80K1 and treated without RBV; patients who were genotype 1a Q80K ; and patients who were genotype 1a, but in whom Q80K was not obtained and who were not treated with RBV. Both patients who had prior experience with a protease inhibitor achieved SVR12. All 3 on concomitant lowdose corticosteroids achieved SVR12. DETERMINATION OF SAFETY AND TOLERABILITY Treatment was discontinued in 2 patients. One of these had Child-Pugh class B cirrhosis at baseline and died shortly after treatment discontinuation with hepatic decompensation. This patient developed hepatorenal syndrome 3 weeks after initiating treatment, and treatment was discontinued due to progressive decline in GFR. Therapy was stopped at that time, but the patient s hepatic decompensation worsened resulting in death. Although this death was not initially felt not to be treatment-related, because hepatic decompensation was later noted during postmarketing surveillance of SIM and this medication is now no longer recommended for class B patients with cirrhosis, the impact of SIM on the patient s death now cannot be excluded with confidence. The second treatment discontinuation was due to a severe photosensitivity reaction consisting of blistering on the face, which occurred 31 days after treatment initiation. This patient was on concomitant cyclosporine and was nonadherent. No other severe rashes were reported. Another patient died 26 days after treatment completion but prior to obtaining SVR12. Per the death certificate, the cause of death was cerebral ORIGINAL ARTICLE 639

6 LIVER TRANSPLANTATION, May 2016 Immunosuppression TABLE 3. Immunosuppression Changes Change Required None Decrease Increase Primary Immunosuppression, n Cyclosporine Tacrolimus Mycophenolic acid Sirolimus anoxia without a specified cause. The death was not thought to be treatment-related, but this patient also had Child-Pugh B cirrhosis at baseline. In addition to rash, development of anemia was closely monitored at both centers. Thirteen of 15 patients treated with RBV experienced anemia defined as a hemoglobin decline to <10 g/dl. In those treated with RBV compared to those treated without RBV, the OR for developing anemia was 23.1 (95% CI, ), whereas the OR for developing anemia requiring intervention was 73.2 (95% CI, ). Decisions to intervene and change treatment were provider-dependent and occurred in 7 patients. RBV was either decreased or eventually stopped in 5 of those patients. Epoetin-a was started for 4 patients, whereas 3 patients received blood transfusions. According to patient questionnaires at the University of Kentucky site, other adverse effects were experienced in 14 of the 18 patients. Of the 14 patients who had adverse effects, the incidence of each adverse effect was noted as follows: fatigue, 71% (n 5 10); headache, 36% (n 5 5); nausea, 36% (n 5 5); skin reaction to sunlight, 21% (n 5 3); insomnia, 21% (n 5 3); loss of appetite, 21% (n 5 3); red eyes, 14% (n 5 2); pruritus, 14% (n 5 2); rash, 7% (n 5 1); muscle aches, 7% (n 5 1); dizziness, 7% (n 5 1); mouth sores, 7% (n 5 1); and others, 28% (n 5 4). Patients at the Louisville site reported fatigue, headaches, insomnia, mild rash, and Clostridium difficile infection. Thus, treatment was fairly well tolerated, especially in those not on concomitant RBV or cyclosporine. DETERMINATION OF DRUG-DRUG INTERACTIONS WITH IMMUNOSUPPRESSANT MEDICATIONS There was no predictability in immunosuppression adjustments, and adjustments did not differ by institution (Table 3). Tacrolimus was used in 40 of 56 patients and required no change in 23 patients, an overall dose increase in 8, and a dose decrease in 9 patients. Sirolimus wasusedin10patientswithnoadjustmentin4patients; an overall dose increase in 3 patients; and a dose decrease in 3 patients. Cyclosporine was used in 5 patients, and 2 of these developed severe photosensitivity reactions also associated with sunscreen nonadherence. Discussion This retrospective study confirms that high SVR rates can be achieved with an all-oral interferon-free combination of SIM and SOF with and without RBV after liver transplantation in a real-world setting. Our ITT overall SVR rate of 88% corresponds to previously reported response rates in the nontransplant and posttransplant setting. (11-13) The transplant centers affiliated with the University of Kentucky and University of Louisville started using SIM and SOF in February 2014 on the basis of the results of the COSMOS trial and with endorsement of a 12-week regimen with or without RBV by guidelines of the AASLD and the IDSA in the nontransplant setting starting in January All patients were started on treatment prior to the release of the FDA recommendation in November 2014 to treat patients with cirrhosis for 24 weeks. The COSMOS trial, a multicenter randomized open-label trial, included 167 patients assigned to 4 different groups. (5) Two groups received 12 weeks, whereas the other 2 groups received 24 weeks of SIM and SOF with or without RBV; 92% of patients achieved SVR12 using an ITT analysis. Neither the use of RBV nor the treatment duration had a significant effect on the SVR rate. Also, the presence of the NS3 Q80K mutation at baseline did not impact the SVR rate. All 6 patients with virological relapse had genotype 1a. Four had the Q80K mutation, and 3 had been treated with SIM and SOF with RBV. However, in the PILLAR trial (10) which tested SIM with interferon and RBV in treatment-na ıve genotype 1 patients, a higher SVR rate in patients without the Q80K polymorphism was noted. On the basis of these data, 2 different treatment strategies were chosen at our 2 centers. The University of Louisville added RBV to 640 ORIGINAL ARTICLE

7 LIVER TRANSPLANTATION, Vol. 22, No. 5, 2016 the treatment of genotype 1a patients with the Q80K mutation. The Q80K mutation had a significant impact in the PILLAR study, and a nonstatistically significant but clinically evident disproportionate number of viral relapses in patients with the Q80K mutation in the COSMOS trial was noted. The University of Kentucky decided to treat all patients without RBV due to concerns about a negative clinical impact of hemolytic anemia related to RBV accumulation in posttransplant patients with nephrotoxic immunosuppression and the risk of rash. Our results demonstrate a trend toward lower SVR in patients with advanced fibrosis (80% versus 94%; P ) and a significantly lower SVR in those with detectable HCV RNA at TW 4 (95% versus 58%; P ), confirming recently reported results. (11,12) Pungpapong et al. (12) have published a 90% overall SVR12 rate in 123 patients, and as in our cohort, the addition of RBV did not impact the response rate. Gutierrez et al. (11) reported a 93% overall SVR rate in 65 patients, but advanced fibrosis was associated with diminished antiviral efficacy in liver transplant recipients with genotype 1a (SVR12 67%). In that cohort, patients with advanced fibrosis had a higher rate of detectable HCV RNA at week 4, but the impact of positive HCV RNA at week 4 on the overall SVR rate was not reported. Notably, 2 of our patients developed photosensitivity reactions with blisters on sun-exposed skin, and both were on cyclosporine-based immunosuppression. In an interim analysis of an ongoing SIM study, concomitant use of SIM (plus daclatasvir and RBV) with cyclosporine at steady-state resulted in an approximately 6-fold increase in plasma concentrations of SIM compared with historical data of SIM in the absence of cyclosporine. This interaction may have been caused by inhibition of organic ion-transporting polypeptide 1B1, p-glycoprotein, and cytochrome P450 3A by cyclosporine. The AEs in our patients confirm clinically that SIM should not be administered in combination with cyclosporine as per the current SIM prescribing information, (14) although insufficient adherence with sun protection was certainly a contributing factor. Overall, our results are in line with previously reported safety data. Pungpapong et al. (12) reported that 72% of their 25 patients receiving RBV had anemia requiring intervention, which is similar to our experience of 66% of patients with anemia on RBV treatment requiring intervention. Except for 1 death possibly due to drug-induced lung injury in Pungpapong s report, (12) only mild AEs were reported. Gutierrez et al. (11) reported photosensitivity reactions in 5 patients, but none of those led to treatment discontinuation and concomitant cyclosporine was not reported. As in our study, no significant changes of immunosuppression drug levels were observed in other studies. (11,12) This is consistent with pharmacokinetic data showing that a single-dose coadministration of tacrolimus or cyclosporine with SIM resulted only in <20% decrease or increase of tacrolimus or cyclosporine drug exposure (area under the curve), respectively (see SIM prescribing information). Several other treatment options exist to treat genotype 1 recurrent HCV infection in liver transplant recipients. The first all-oral interferon-free study using SOF daily and RBV mg daily for 24 weeks in 40 post liver transplant patients included 33 patients with genotype 1 and showed an overall SVR12 of 70%. (15) However, this is currently not a recommended regimen in the AASLD-IDSA HCV treatment guidelines. (4) In addition to SIM/SOF with or without RBV for 12 weeks, several other treatment regimens are recommended. Importantly, all other currently recommended 12-week treatment regimens require RBV, whereas other RBV-free regimens require 24 weeks of treatment. Thus, SIM/SOF is the only currently available 12-week treatment option for RBV ineligible liver transplant recipients. CORAL-1 was a multicenter clinical trial evaluating a fixed-dose combination of paritaprevir, ritonavir, and ombitasvir plus twice-daily dasabuvir and RBV for 24 weeks. This regimen achieved an SVR24 rate of 96% in 34 genotype 1 liver transplant recipients without advanced fibrosis and is recommended by AASLD-IDSA guidelines. (4,16) However, due to drug-drug interactions between ritonavir and calcineurin inhibitors, major prospective dose adjustments were needed for cyclosporine and tacrolimus. Regimens combining SOF plus an NS5A inhibitor (either daclatasvir or ledipasvir) for 12 weeks with RBV or for 24 weeks without RBV are also recommended by the AASLD-IDSA guidelines. SOLAR-1 included 111 noncirrhotic and 51 cirrhotic liver transplant recipients with recurrent genotype 1 HCV infection randomized 1:1 to 12 versus 24 weeks of fixed-dose combination SOF/ledipasvir plus RBV therapy. (17) SVR ranged from 96% to 98%, and the therapy was safe and well tolerated. Although our results are encouraging, several important limitations remain. First, this is a relatively small retrospective study reporting high SVR12. This limits the ability to perform subgroup analysis and also ORIGINAL ARTICLE 641

8 LIVER TRANSPLANTATION, May 2016 to identify baseline or on-treatment factors associated with response or lack thereof. Thus, the data should be interpreted with caution until larger prospective studies have been performed. For example, although our analysis suggested that neither the presence of the Q80K polymorphism nor coadministration of RBV impacted SVR, randomized prospective studies are nonetheless required to definitively answer these questions. The treatment protocol varied slightly between each center in this multicenter study. For example, 47% of patients at 1 site were not tested for Q80K baseline polymorphism, illustrating that complete data were not available for the entire cohort. The SIM/SOF regimen is also not appropriate for all posttransplant patients, most notably those with GFR < 30 ml/minute based on the SOF label (18) and those with hepatic decompensation based on the SIM label. (14) When this study was initiated, SIM was not recommend for patients with Child-Pugh C cirrhosis, but following reports of sometimes fatal hepatic decompensation occurring on therapy during postmarketing surveillance, the label was changed to indicate it was not recommended for Child-Pugh B-C cirrhosis. Five Child-Pugh B patients were enrolled in this study prior to the label change. One of these patients died from progressive hepatic decompensation shortly after initiating therapy, whereas another died after completing therapy but prior to reaching 12 weeks after treatment completion. Consistent with FDA guidance, the AASLD-IDSA guidelines do not currently recommend SIM for patients with hepatic decompensation regardless of their transplant status. (4) Concern regarding the use of currently available protease inhibitors in decompensated liver disease was echoed in the recent label change for the protease inhibitor containing regimen ombitasvir/paritaprevir/ritonavir/dasabuvir to now being contraindicated in Child-Pugh class B-C cirrhosis. (19) This regimen is also not recommended by the AASLD-IDSA guidelines for the treatment of decompensated liver transplant recipients. (4) The deaths reported in the present study could be consistent with these emerging safety concerns regarding the use of protease inhibitors in patients with baseline hepatic decompensation. In summary, our study demonstrated the efficacy and safety of the SIM/SOF regimen after transplant. Although RBV did not increase SVR rates, it did increase toxicity (anemia) suggesting that in the absence of stronger data, RBV may not need to be routinely included as a component of this regimen. Importantly, SIM/SOF is the only RBV-free 12-week treatment regimen currently recommended by the AASLD-IDSA HCV treatment guidelines for posttransplant patients. (4) Twelve weeks might not be the optimal treatment duration in patients who remain virus positive at 4 weeks, or in those with advanced fibrosis. On the basis of other studies, alternate therapies should also be considered in patients with compensated cirrhosis with genotype 1a Q80K 1 HCV infection. Thus, SIM/SOF is an attractive treatment regimen especially for RBV intolerant/ineligible, compensated, posttransplant genotype 1 patients preferring a 12-week duration of therapy. Prospective data from randomized clinical trials are required to confirm the results of this retrospective study. Acknowledgements: The authors thank Erica Rose and Nancy Bellis at the KentuckyOne Health Transplant Care Center and Tonia Carr and Sarah Hughes at the University of Kentucky. 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