The Use of Protease Inhibitors for the Treatment of Hepatitis C in Liver Transplant Recipients: Is a Bird in the Hand Worth Two in the Bush?

Transcription

1 The Use of Protease Inhibitors for the Treatment of Hepatitis C in Liver Transplant Recipients: Is a Bird in the Hand Worth Two in the Bush? Christina Guerra, PharmD PGY-1 Pharmacy Resident University Health System, San Antonio, TX The University of Texas at Austin College of Pharmacy University of Texas Health Science Center at San Antonio February 22, 2013 Learning Objectives: 1. Describe the impact of hepatitis C on liver transplantation 2. Evaluate the literature regarding the utilization of protease inhibitors in the liver transplant population 3. Propose a strategy for the future treatment of liver transplant recipients with hepatitis C virus genotype 1

2 HEPATITIS C VIRUS I. Epidemiology A. Global 1-3 i. Approximately million people are infected worldwide ii. 3 to 4 million new infections occur each year iii. Over 350,000 deaths annually B. United States 4-5 i. Approximately 4 to 7 million Americans have chronic hepatitis C (HCV) infection ii. 17,000 Americans are estimated to become infected with HCV each year C. Texas 6 i. As of 2009, approximately 368,000 people in Texas have HCV infection ii. Approximately 80% of cases are chronic infections II. Disease course 1,7-8 Figure 1. Disease Course of HCV. III. Genotypes 2,5-8 A. 6 genotypes have been identified B. Genotype 1 i. Most common genotype in the United States (US) and western Europe ii. Accounts for 80% of HCV patients in the US Figure 2. Locations of Highest Incidence of HCV by Genotype. 9 Source: ClevelandClinicMedED.com Page 1

3 TREATMENT OF HCV I. Definitions of virologic response 7,10 A. Rapid virologic response (RVR): undetectable viral load (VL) at week 4 of treatment B. Early virologic response (EVR): VL decreases by at least 2 log IU/mL from baseline at week 12 of treatment C. Extended rapid virologic response: undetectable VL at treatment weeks 4 and 12 D. Sustained virologic response (SVR): VL remains undetectable 24 weeks following treatment cessation; considered to be synonymous with cure E. Null response: VL does not decrease by at least 2 log IU/mL by week 12 of treatment F. Partial response: VL decreases by at least 2 log IU/mL from baseline by week 12 of treatment, but still detectable at week 24 of treatment G. Virologic breakthrough: initially undetectable VL during treatment that becomes detectable despite continued treatment H. Relapse: VL is undetectable during treatment, but becomes detectable after treatment cessation II. Factors affecting response to treatment 7,11-15 Figure 3. Virologic Response Terms. 10 Source: hepatitis.va.gov Figure 4. Variables Affecting Response to HCV Treatment. III. Evolution of standard of care of treatment for HCV genotype 1 5,7-8 A. Agents: i. Interferon (IFN) ii. Ribavirin (RBV) iii. Pegylated interferon (PegIFN) iv. Protease inhibitors (PI) Page 2

4 Mean SVR Rate in Genotype % 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% IFN IFN + RBV PegIFN + RBV PegIFN + RBV + PI Treatment Regimen Figure 5. Development of HCV Treatment. B. Development of HCV treatment (See Figure 5) i a. IFN b. Mean SVR rate in patients with genotype 1: ~5% ii a. Combination treatment of IFN and RBV b. Mean SVR rate in patients with genotype 1: ~30% iii a. IFN reformulated to PegIFN b. Combination treatment of PegIFN and RBV ( dual therapy ) c. Mean SVR rate in patients with genotype 1: 40-50% iv a. Addition of PI to PegIFN and RBV ( triple therapy ) b. Mean SVR rate in patients with genotype 1: 60-70% C. Limitations of therapy with PegIFN and RBV 2,16 i. Unacceptable rate of SVR for patients with genotype 1 infection ii. Subcutaneous dosage form of PegIFN iii. Discontinuation in approximately 30% of patients due to lack of tolerability 17 a. Hemolytic anemia: 14%; neutropenia: 3-11%; thrombocytopenia: 1-8% b. Fatigue: 40-49%; myalgia: 32-42% c. Injection site reaction: 10-28% d. Headache: 35-48% e. Nausea: 24-29%; diarrhea: 14-16% f. Alopecia: 10-25% g. Depression: 17-22% D. Direct-acting antiviral (DAA) agents: PI (See Appendix A) i. Available agents: telaprevir (TVR), boceprevir (BOC) Page 3

5 Mean SVR Rate in Genotype 1 Mean SVR Rate in Genotype 1 100% 90% 80% 70% 60% 50% 40% 100% 90% 80% 70% 60% 50% 40% 30% 30% 20% 20% 10% 10% 0% Naïve PegIFN + RBV PegIFN + RBV + TVR Population Experienced 0% PegIFN + RBV Naïve PegIFN + RBV + BOC Population Experienced Figure 6. Results of Early Clinical Trials of TVR (on left) and BOC (on right) in Genotype 1 Treatment-Naïve and Treatment-Experienced Patients (See Appendices B and C) ii. Mechanism of action: inhibition of the nonstructural protein 3/4A (NS3/4A) protease necessary for HCV RNA replication and virion assembly iii. Administration a. Must be administered with PegIFN and RBV b. TVR 18,27 1. Must be taken with at least 20 g of fat 2. 2 tablets every 8 hours (6 tablets per day) 3. Regimens for treatment-naïve patients and prior relapsers a) Undetectable VL at weeks 4 and 12 1) Triple therapy (TT) for 12 weeks then dual therapy for 12 weeks 2) 24 weeks total b) VL <1000 IU/mL at weeks 4 and/or 12 1) TT for 12 weeks then dual therapy for 36 weeks 2) 48 weeks total 4. Regimen for prior partial and null responders a) TT for 12 weeks then dual therapy for 36 weeks b) 48 weeks total 5. Regimens for treatment-naïve patients with compensated cirrhosis a) Undetectable VL at weeks 4 and 12 1) TT for 12 weeks then dual therapy for 36 weeks 2) 48 weeks total c. BOC 19, Must be taken with food 2. 4 capsules every 8 hours (12 capsules per day) 3. Lead-in period (LI) with PegIFN and RBV for 4 weeks 4. Regimens for treatment-naïve patients a) Undetectable VL at weeks 8 and 24 1) LI for 4 weeks then TT for 24 weeks 2) 28 weeks total b) Detectable VL at week 8 and undetectable VL at week 24 1) LI for 4 weeks then TT for 32 weeks then dual therapy for 12 weeks 2) 48 weeks total Page 4

6 5. Regimens for prior partial responders and prior relapsers a) Undetectable VL at weeks 8 and 24 1) LI for 4 weeks then TT for 32 weeks 2) 36 weeks total b) Detectable VL at week 8 and undetectable at week 24 1) LI for 4 weeks then TT for 32 weeks then dual therapy for 12 weeks 2) 48 weeks total 6. Regimens for null responders and patients with compensated cirrhosis a) LI for 4 weeks then TT for 44 weeks b) 48 weeks total iv. Discontinuation of therapy a. Inadequate virologic response within a certain amount of time suggests unlikelihood of SVR b. Continuation of therapy in setting of poor response may trigger the development of treatmentemergent resistance c. Futility rules: 1. TVR a) If VL > 1000 IU/mL at treatment week 4 or 12: discontinue triple therapy b) If detectable VL at treatment week 24: discontinue triple therapy 2. BOC a) If VL > 100 IU/mL at treatment week 12: discontinue triple therapy b) If detectable VL at treatment week 24: discontinue triple therapy v. Tolerability issues a. PegIFN and RBV remain the backbone of treatment b. Fatigue (TVR: 56%; BOC: 55-58%) c. Anemia (TVR: 36%; BOC: 45-50%) d. Nausea (TVR: 39%; BOC: 43-46%) e. Skin reactions (TVR: 56%; BOC: 16-17%) vi. Patient populations in which use of these agents is off-label 1. Patients with decompensated cirrhosis 2. Patients coinfected with human immunodeficiency virus or hepatitis B virus 3. *Liver transplant recipients* IMPACT OF HCV ON LIVER TRANSPLANTATION I. HCV is the most common indication for liver transplantation 12,29-36 A. ~31% of adult patients waiting for a liver transplant in the US B. ~26% of adult liver transplant recipients in the US listed HCV as the primary cause of their liver disease C. ~40% of liver transplant recipients at University Hospital are HCV-positive II. Recurrence of HCV after liver transplantation 12-13,30,33-37 A. If detectable HCV VL at time of transplant, VL becomes detectable within a few days after transplantation B. Accelerated rate of fibrosis progression i % of transplant recipients with preexisting HCV develop cirrhosis within 5 years of transplant compared to 3-20% of immunocompetent patients who develop cirrhosis within 20 years ii % risk of decompensation within 1 year of cirrhosis diagnosis for transplant recipients compared to less than 5% of immunocompetent patients C. HCV accounts for approximately two-thirds of graft failures D. Decreased rate of patient survival i. 3 year survival rate of transplant recipients that develop decompensated cirrhosis: 10% ii. 3 year survival rate of immunocompetent patients that develop decompensated cirrhosis: 60% iii. Rate of 5-year survival among liver recipients with HCV ~25% lower than those without HCV Page 5

7 TREATMENT OF HCV IN POTENTIAL LIVER TRANSPLANT CANDIDATES I. Treatment goals 12-13,16,30,36 A. Achieve SVR B. Improve liver disease C. Prevent worsening of liver disease D. Postpone need for transplantation E. *Prevent recurrent HCV in the allograft following transplantation* II. Eligibility for IFN-containing treatment regimens 12-13,30,35-36,39 A. Poor candidates i. Lack of tolerability likely ii. At high risk of complications: liver failure, infection, death iii. Examples: a. Patients with decompensated cirrhosis b. Patients with higher MELD scores B. Ideal candidates i. Higher potential for tolerability of regimen ii. Preserved hepatic function iii. Examples a. Candidates with potential to receive a graft from a living donor b. Candidates with a MELD waiting list upgrade for hepatocellular carcinoma III. Study by Everson et al. 40 A. Objective i. To evaluate the safety and efficacy of the pre-transplant administration of a low accelerating dose regimen of PegIFN and RBV for the prevention of HCV recurrence post-transplant ii. Post-transplant virologic response (PTVR): undetectable VL 12 weeks after transplant iii. Combined virologic response (CVR): undetectable VL 12 weeks after end of treatment B. Patient population (n=79) i. Chronic HCV infection a. Genotype 1: n=44 b. Genotype 2/3: n=32; genotype 4: n=2; genotype 6: n=1 ii. Listed for liver transplantation with a predictably short time until transplantation iii. Likely to tolerate therapy C. Multicenter randomized controlled trial i. Patients with genotypes 1, 4, and 6 randomized 2:1 to treatment:observation (n=31:n=16) ii. All patients with genotypes 2 and 3 received treatment (n=32) iii. Treatment consisted of a low accelerating dose regimen of PegIFN and RBV D. Pertinent efficacy results i. 22% (13/59) of treated patients achieved CVR compared to none of the untreated patients ii. 59% (n=26/44) of treated transplant recipients achieved undetectable VL by the time of transplant a. 42% (n=11/26) achieved PTVR b. 50% (n=13/26) relapsed c. 8% (n=2/26) died within 12 weeks after transplant iii. Response to varying treatment lengths a. <8 weeks of treatment 1. 25% (n=2/8) achieved undetectable VL at time of transplant 2. None achieved PTVR b. 8 to 16 weeks of treatment 1. 68% (n=15/22) achieved undetectable VL at time of transplant 2. 18% (n=4/22) achieved PTVR Page 6

8 c. Greater than 16 weeks of treatment 1. 64% (n=9/14) achieved undetectable VL at time of transplant 2. 50% (n=7/14) achieved PTVR E. Safety results i. 19% (n=11/59) of treated patients experienced cytopenias ii. 12% (n=7/59) of treated patients experienced infections iii. 5 treated patients and 2 untreated patients died before liver transplantation F. Take home points i. Treatment with PegIFN and RBV prior to transplant can prevent post-transplant HCV recurrence in those most likely to tolerate therapy a. No PTVR achieved in patients receiving less than 8 weeks of treatment b. Treatment for greater than 16 weeks was associated with best rates of PTVR ii. Treatment is associated with risk of side effects a. Most notably cytopenias and infections b. Incidence of side effects may be increased among general liver transplant recipient population IV. Phase 3 studies of TVR and BOC (See Appendix C) A. Patients with decompensated cirrhosis were not included B. SVR rates among cirrhotic patients i. Trials with TVR: 42-66% SVR in TVR groups compared to 10-33% SVR with PegIFN + RBV groups ii. Trials with BOC: 47-59% SVR in BOC groups compared to 0-38% SVR with PegIFN + RBV groups V. CUPIC multicenter study in France: experience with triple therapy in setting of compensated cirrhosis 41 A. Objective: to study the safety and efficacy of triple therapy with PI for at least 16 weeks B. Patient population (n=455) i. Compensated cirrhosis ii. Genotype 1 HCV iii. Non-responders, partial responders, relapsers C. Preliminary efficacy results: undetectable level of viral load i. Week 8 of treatment: 85% (n=224/265) on TVR; 37% (n=55/149) on BOC ii. Week 12 of treatment: 86% (n=219/254) on TVR; 61% (n=88/144) on BOC iii. Week 16 of treatment: 86% (n=177/205) on TVR; 71% (n=86/126) on BOC D. Preliminary safety results i. Infections in 8.8% (n=26/296) of TVR group; 2.5% (n=4/159) of BOC group ii. Asthenia in 4.7% (n=14/296) of TVR group; 5.7% (n=9/159) of BOC group iii. Serious adverse effects in 48.6% (n=144/296) of TVR group and 38.4% (n=61/159) of BOC group iv. 14.5% (n=43/296) of TVR group and 7.4% (n=12/159) of BOC group discontinued therapy due to adverse effects E. Take home points: i. PIs were associated with on-treatment virologic response in patients with compensated cirrhosis a. More patients reached an undetectable viral load with TVR than BOC b. Gap in virologic response between treatment groups narrowed as treatment duration increased ii. High rate of side effects in compensated liver dysfunction iii. High rate of discontinuation due to adverse effects with triple therapy VI. Summary of pre-transplant treatment of HCV A. Limited literature in patients with compensated cirrhosis B. No literature on the use of triple therapy in patients with decompensated cirrhosis C. Treating with dual or triple therapy is difficult due to high rate of adverse effects and discontinuation D. Therapy resulting in undetectable VL at the time of transplant provides the patient with the best chance of avoiding recurrence following transplantation Page 7

9 TREATMENT OF HCV IN LIVER TRANSPLANT RECIPIENTS I. Treatment goals 12-13,16,29-30 A. Achieve SVR B. Maintain function and extend survival of transplanted graft C. Extend patient survival II. Dual therapy of PegIFN and RBV post-transplantation 42 A. SVR rates of 20-30% in transplant recipients with genotype 1 B. Tolerability i. Poses a major difficulty for this population due to propensity to develop anemia ii. Dose reduction required in 65-75% of patients iii. Approximately 25% of patients discontinue treatment due to adverse effects 3,30,32,35,36, 39 III. Concerns of treatment with triple therapy in this population A. Triple therapy not yet approved in liver transplant recipients B. Increased risk of adverse effects and lack of tolerability C. Concern for drug interactions between PI and backbone immunosuppressant agents cyclosporine (CsA) and tacrolimus (TAC) i. Calcineurin inhibitors (CNI) and mammalian target of rapamycin (mtor) inhibitors a. Primarily metabolized by cytochrome P450 3A4 (CYP450 3A4) b. Substrates of P-glycoprotein (P-gp) ii. PI a. CYP450 3A4 substrates and inhibitors b. P-gp substrates and inhibitors IV. Pharmacokinetic studies of PI with CNI A. Healthy volunteers: 2 small studies Table 1: Magnitude of Increase in CNI Pharmacokinetics After a Single Dose of TVR or BOC Protease Cyclosporine Tacrolimus Inhibitor C max AUC t 1/2 C max AUC t 1/2 TVR 1.35 fold 4.3 fold 4 fold 9.3 fold 70 fold 5 fold BOC 2 fold 2.7 fold 1.25 fold 10 fold 17 fold 2 fold V. Experiences using triple therapy in liver transplant recipients Page 8

10 Table 2. Abstracts of Experience with PI in Liver Transplant Recipients. Study Pereira et al. 45 Rogers et al. 46 Pungpapong et al. 47 Burton et al. 48 Kwo et al. 49 McCashland et al. 50 Schlitsky et al. 51 N Response to Prior HCV Treatment Unknown Pts 1 and 2: null-responders Pt 3: partial-responder 3 null-responders; 3 partial-responders; 1 pt with poor tolerance 9 null-responders; 3 treatment-naïve pts Null-responders Unknown Pt 1: partial-responder Pts 2 and 3: null-responders PI TVR TVR TVR TVR TVR TVR BOC CNI TAC + EVL TAC CsA CsA CsA CsA CsA Change to CsA No No Yes Yes Yes Yes Unknown CNI Dose CNI Interval Efficacy Results TAC 0.5 mg; EVL 0.25 mg Weekly (TAC); every 3 days (EVL) Undetectable VL in 2 pts after 5 weeks of therapy and in 1 pt after 12 weeks of therapy Based on level; target level increased by 30% BID changed to twice per week Pt 1: achieved RVR, undetectable VL 4 months after therapy completion; Pt 2: null response; Pt 3: relapse % of original CsA dose BID changed to daily Undetectable VL: 17% of pts at week 4, 100% at week 12; acute rejection due to low CsA levels: 1 pt Reduced to 25% of total daily dose Daily changed to every other day Undetectable VL in 92% of pts at week 4; VL increased following decline in 2 pts; no acute rejection Based on level Based on level Based on level Based on level Undetectable VL in 3 pts at week 12; 1 pt reached futility at week 4 but had undetectable VL at week 24 Based on level; 4 pts: every other day 6 pts: daily 2 pts met futility rules at week 4; 2 pts achieved RVR; undetectable VL in all pts (3) completing 12 weeks of therapy; undetectable VL in 1 pt at week 24; no rejection Based on level 1 pt attained undetectable VL and 1 pt experienced a 2 log decrease in VL by day 19; 1 pt experienced delayed response Worsening anemia Mild renal insufficiency All required RBV dose 7 pts required RBV dose requiring EPO in pts 1 due to CsA toxicity; 3 pts hospitalized; reduction, EPO, GCSF, Only fatigue D/C of treatment in reduction; 2 pts with Safety and 2; pancytopenia cytopenias common; TVR 5 pts required and blood; all with rash; experienced; no 1 pt due to skin rash anemia; 2 pts with Results resulting in D/C in pt D/C in 1 pt due to severe blood; no episodes 1 pt with perianal pain; treatment D/C; no CsA and headache depression; 1 pt with 2; 1 pt without anemia; 5 pts required of rash all CsA levels in target toxicity leukopenia; no skin rash adverse effects EPO; 2 pts required GCSF range Most centers combined TVR-based triple therapy with CsA Patients studied were primarily treatment-experienced TVR has a greater effect on TAC pharmacokinetics than CsA pharmacokinetics Take Home o Required decreased TAC dose and extension of dosing interval to weekly or twice weekly dosing Points o Required decreased CsA dose and extension of dosing interval to daily or every other day Promising preliminary rates of viral response with triple therapy Lack of tolerability due to anemia and leukopenia is a concern Patients experiencing anemia and leukopenia required EPO and GSF BID, twice daily; BOC, boceprevir; CsA, cyclosporine; D/C, discontinuation; EPO, erythropoietin; EVL, everolimus; pt, patient; GCSF, granulocyte colony-stimulating factor; TAC, tacrolimus; TVR, telaprevir; VL, viral load Page 9

11 Table 3. Experience with TVR in Liver Transplant Recipients. 52 Study Werner et al. Liver Transpl. 2012;18: Objective To study the feasibility of TVR-based triple therapy for HCV genotype 1 in liver transplant patients in terms of efficacy, drug-drug interactions, and safety Study Design Single center retrospective pilot study in Germany Enrollment 9 consecutive patients being treated for the recurrence of HCV after liver transplantation All HCV genotype 1 Mean age: 60.9 years old Mean time since liver transplant: 52 months (range: months) Patient Population 2 females; 7 males Mean BMI: 27.1 kg/m 2 Mean baseline HCV VL 6.64 log 10 IU/mL (range: log 10 IU/mL) Patient IL28B Genotype CT CT CT CT CT TT CT CT CT Baseline VL (log 10 IU/mL) Compensated Liver Function Yes Yes Yes Yes Yes Yes Yes No Yes Baseline Immunosuppressants TAC TAC+MMF TAC TAC+CCS SIR+CCS CsA+MMF+CCS CsA+MMF+CCS CsA+CCS CsA IFN+RBV IFN+RBV+AMT PegIFN+RBV PegIFN+RBV PegIFN+RBV IFN+RBV PegIFN+RBV Pre-Transplant HCV Treatment None None (NR)* (NR)* (NR) (relapse) (NR) (NR) (D/C) Prior Post-Transplant HCV PegIFN+RBV PegIFN+RBV PegIFN+RBV PegIFN+RBV PegIFN+RBV PegIFN+RBV PegIFN+RBV PegIFN+RBV None Treatment (NR)* (NR) (NR) (relapse) (NR) (NRx2)* (NR) then TVR (breakthrough) HCV Treatment PegIFN + RBV + TVR x 12 weeks TAC and SIR were adjusted to a single weekly dose, while CsA was kept as a daily dose CNI Adjustment 22-fold reduction in TAC, 7-fold reduction in SIR, and 2.5-fold reduction in CsA Trough levels of TAC, SIR, and CsA were above target range 28%, 45%, and 13%, respectively, of exposure time Pharmacokinetic Analysis Trough levels of TAC, SIR, and CsA were below target range 32%, 54%, and 21%, respectively, of exposure time Trough levels of TAC, SIR, and CsA were within target range 40%, 1%, and 66%, respectively, of exposure time Week 4: undetectable VL in 4 patients; VL close to LLOQ in patients 4, 8, 9 Efficacy Results Week 8: undetectable VL in 7 patients Week 12: undetectable VL in all except patient 4 EPO Use Yes Yes No No No Yes Yes Yes Yes Blood Transfusion 2 units 4 units None None None 8 units 2 units 2 units 6 units GCSF Use Yes No No No No No No Yes No Safety RBV Reduction No Yes N/A N/A No Yes Yes Yes Yes Results Reason for D/C N/A N/A Side effects Bacterial PNA N/A N/A N/A N/A N/A 5 hospitalizations: bacterial PNA, TAC overdose with renal failure, Yersinia-induced enteritis, DM exacerbation, increased LFTs from NASH Hb <10 g/dl: 6 patients; Hb <8 g/dl: 4 patients; WBC <2500/µL: 6 patients; WBC <1500/µL: 3 patients; Plt <50,000/µL: 4 patients Other Mild skin reactions: 3 patients SCr increase >1.5 mg/dl: 3 patients Patient population included treatment-experienced individuals with poor response IL28B genotypes and compensated liver disease Most significant drug interaction between TVR and TAC; least difficulty in maintaining very narrow target immunosuppressant levels with CsA Take Home Points High rate of virologic response with triple therapy; 8 of 9 patients achieved undetectable VL by week 12 of treatment; SVR data unknown All patients on TAC and CsA experienced side effects; 6 of 9 patients experienced anemia and required EPO; 6 of 9 patients experienced leukopenia and 2 patients required GCSF *then low-dose PegIFN; AMT, amantadine; CCS, corticosteroids; CsA, cyclosporine; D/C, discontinuation; DM, diabetes mellitus; EPO, erythropoietin; GCSF, granulocyte colony-stimulating factor; Hb, hemoglobin; LLOQ, lower limit of quantification; MMF, mycophenolate mofetil; NASH, nonalcoholic steatohepatitis; NR, non-response; Plt, platelets; SCr, serum creatinine; SIR, sirolimus; TAC, tacrolimus; TVR, telaprevir; VL, viral load; WBC, white blood cells Page 10

12 Table 4: Experience with BOC in Liver Transplant Recipients. 38 Study Coilly et al. Antimicrob Agents Chemother. 2012;56(11): Objective To evaluate interactions and safety of BOC in HCV recurrence following liver transplantation Study Design Single center pilot study in France Enrollment 5 consecutive patients All males with HCV genotype 1 Mean age: 62.6 years old Mean BMI: 24.8 kg/m 2 Patient Population Mean MELD score at baseline: 9.2 Mean time since liver transplant: 48.6 months (range: months) Mean baseline HCV VL 6.87 log 10 IU/mL (range: log 10 IU/mL) Patient IL28B Genotype CC CT CT CC TT Baseline VL (log 10 IU/mL) CsA CsA CsA TAC TAC Baseline CNI 50 mg (AM); 125 mg (AM); 25 mg BID 1 mg daily 2 mg BID 25 mg (PM) 100 mg (PM) Other Baseline Immunosuppressants Response to Previous HCV Treatment HCV Treatment Main Immunosuppressant Dose at Week 12 Prednisone 5 mg daily Relapser Prednisone 5 mg daily EVL MMF 500 mg BID NR pre-transplant PegIFN + RBV x 4 weeks PegIFN + RBV + BOC CsA CsA 75 mg (AM); 25 mg BID 50 mg (PM) 0.5 mg BID Pharmacokinetic Reduction in clearance: CsA (~50%); TAC (~80%); EVL: (~52%) Analysis Mean time to steady state for immunosuppressant: 4.2 days (range: 3 7 days) Week 4: mean decrease in VL of 2.2 log 10 IU/mL (range: log 10 IU/mL) Efficacy Results: Week 8: undetectable VL in patients 1, 4, 5 Virologic Response Week 12: undetectable VL in patients 1, 3, 4, 5; VL of patient 2 at 1.08 log 10 IU/mL Mean decrease in VL of 6.64 log 10 IU/mL (range: log 10 IU/mL) Anemia experienced by all of patients o Mean decrease in Hb level from baseline to week 12: 3.12 g/dl o All patients required EPO Safety Results o 3 patients required a reduction in RBV dose o 1 patient required a blood transfusion No significant worsening of renal function Patient population primarily included treatment-experienced individuals with low MELD scores and poor response IL28B genotypes Most significant drug interaction between TVR and TAC o Clearance of TAC most affected Take Home Points o Dose of TAC decreased by 70-88% o Dose of CsA decreased by 33-44%; 1 patient did not require CsA dose decrease High rate of virologic response with triple therapy; 4 of 5 patients achieved undetectable VL by week 12 All patients experienced anemia and required EPO BOC, boceprevir; CNI, calcineurin inhibitor; CsA, cyclosporine; EPO, erythropoietin; EVL, everolimus; Hb, hemoglobin; NR, non-response; RBV, ribavirin; TAC, tacrolimus; VL, viral load None MMF 250 mg BID Treatment-naïve Relapser NR CsA 25 mg BID EVL 0.25 mg BID TAC 0.5 mg 2 days in 3 TAC 0.5 mg daily Page 11

13 VI. Take home points gained from published experiences A. Triple therapy can be safely utilized in transplant recipients for the treatment of HCV i. Promising preliminary results in difficult-to-treat population ii. Most results published are not in terms of SVR, but are presented in terms of EVR iii. Close therapeutic drug monitoring of immunosuppressant medications is essential iv. High risk for severe anemia and leukopenia B. PI choice i. Published experiences primarily with TVR ii. Less significant effect on the pharmacokinetics of CNI expected with BOC C. CNI choice i. Published experience primarily with CsA ii. Less pronounced pharmacokinetic effect expected with CsA iii. Less difficulty maintaining target level with CsA iv. More ease with new dosing schedule of CsA compared with new dosing schedule of TAC v. Potential benefit to switching patients managed on TAC to CsA prior to PI initiation CONCLUSIONS I. Triple therapy is an option for the treatment of HCV after liver transplantation II. III. IV. Pertinent patient characteristics to consider A. Prior treatment experience B. IL28B genotype C. Current viral load and stage of fibrosis D. Expected ability to tolerate therapy Treat patients with rapidly progressive fibrosis or high viral load A. If on TAC, consider switch to CsA or decrease TAC to once weekly dosing B. If on CsA, decrease dose by 30-50% C. Frequently monitor therapeutic drug levels of CsA or TAC D. Monitor for anemia, leukopenia, skin rash, rejection, kidney dysfunction, and infection E. Be prepared for patient requiring EPO and/or GCSF Consider postponing treatment in stable patients A. Continue to monitor viral load B. Continue to monitor measures of fibrosis C. Consider starting treatment upon the arrival of new agents to market FUTURE DIRECTIONS I. Therapy changes in the pipeline A. Future agents i. Numerous agents at different stages of development ii. Expected arrival to market as early as iii. Examples: daclatasvir, asunaprevir, sofosbuvir, ABT450/r, ABT333, ABT267 B. IFN-free regimens to minimize side effects and increase probability of tolerability Page 12

14 II. Effect of new agents on treatment decisions A. Expectations i. Decrease in potential for drug interaction ii. Similar to PI in percentage of patients attaining SVR B. Decision to treat with BOC or TVR i. Decreased risks involved with postponing HCV treatment ii. Drug interaction potential iii. Increased difficulty of monitoring iv. Risk of limiting future treatment options III. Possible expansion of literature A. Size of studies B. Patient population i. Decompensated cirrhosis ii. Liver transplant recipients iii. Patients with co-infections Page 13

15 REFERENCES 1. World Health Organization. Hepatitis C. Available from: en/index.html. Accessed November 18, Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345(1): Wilby KJ, Greanya ED, Ford JE, et al. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012;11(2): Centers for Disease Control and Prevention. Overview and statistics. Available from: hepatitis. Accessed November 18, Poordad F. Hepatitis C treatment options: the evolution. Presentation at: University Transplant Center Grand Rounds. 2012, Mar 16; San Antonio, Texas. Available from: Transplant_Dec21_Poordad.html. Accessed January 2, Texas Department of State Health Services. Hepatitis C in Texas. Available from: state profiles/pdf/texas_profile.pdf. Accessed November 18, Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis c virus infection: 2011 practice guideline by the American Association for the Study of Liver Disease. Hepatology. 2011;54(4): Alam I. Hepatitis C achieving SVR: a new era of treatment. Presentation at: University Transplant Center Grand Rounds Mar 16; San Antonio, Texas. Available from: Flash/Transplant/T52_Alam.html. Accessed October 31, O Shea RS. Hepatitis C. Available from: management/hepatology/hepatitis-c. Accessed November 18, United States Department of Veterans Affairs. Hepatitis C. Available from: provider/guidelines/2012hcv-definitions-of-response.asp. Accessed November 18, Beinhardt S, Rutter K, Stattermayer A, et al. Revisiting the predictors of a sustained virologic response in the era of direct-acting antiviral therapy for hepatitis C virus. Clin Infect Dis. 2013;56(1): Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol. 2012;26(4): Terrault NA, Merenguer M. Treating hepatitis C infection in liver transplant recipients. Liver Transpl. 2006;12(8): Thomas DL. Predicting the response to the treatment of hepatitis C virus infection. Clin Liver Dis. 2012;1(2): Vierling JM. Hepatitis C virus viral assays in the direct-acting antiviral era. Clin Liver Dis. 2013;17(1): Saxena V, Terrault N. Hepatitis C virus treatment and liver transplantation in the era of new antiviral therapies. Curr Opin Organ Transplant. 2012;17(3): Lexi-Drugs Online TM. Lexi-Comp Online TM [database online]. Hudson, OH: Lexi-Comp, Inc.; Available at Accessed January 5, Boceprevir (Victrelis ). Package Insert. Merck & Co., May Telaprevir (Incivek ). Package Insert. Vertex Pharmaceuticals, Inc., December McHutchinson JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360: Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360: Jacobson IM, McHutchinson JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364: Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365: Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364: Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: Jesudian AB, Jacobson IM. Telaprevir for chronic hepatitis C virus infection. Clin Liver Dis. 2013;17(1): Page 14

16 28. Kwo PY. Boceprevir and treatment of chronic hepatitis C. Clin Liver Dis. 17(1): Biggins SW, Terrault NA. Management of recurrent hepatitis C in liver transplant recipients. Infect Dis Clin N Am. 2006;20(1): Burton JR, Everson GT. Management of the transplant recipient with chronic hepatitis C. Clin Liver Dis. 2013;17(1): Charlton M. Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents a potentially lethal cocktail. Hepatology. 2011;54(1): Kiser JJ, Burton JR, Anderson PL, et al. Review and management of drug interactions with boceprevir and telaprevir. Hepatology. 2012;55: Pan Q, Peppelenbosch MP, Janssen HLA, et al. Telaprevir /boceprevir era: from bench to bed and back. World J Gastroenterol. 2012;18(43): Schiano TD, Martin P. Management of HCV infection and liver transplantation. Int J Med Sci. 2006;3(2): Wiesner RH, Sorrel M, Villamil F. Report of the first International Liver Transplantation Society Expert Panel Consensus Conference on liver transplantation and hepatitis C. Liver Transpl. 2003;9(11):S Arjal RR, Burton JR, Villamil F, et al. Review article: the treatment of hepatitis C virus recurrence after liver transplantation. Aliment Pharmacol Ther. 2007;26: Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology. 2002;122(4): Coilly A, Furlan V, Roche B, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother. 2012;56(11): Mutimer D. Understanding the switchbacks: the impact of direct antivirals on the minimization of hepatitis C virus recurrence after transplantation. Liver Transpl. 2012;18:S Everson GT, Terrault NA, Lok AS, et al. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology. 2012;000(000): Hezode C. The first year: evidence from the French national access program. Presentation at: European Association for the Study of the Liver Clinical Symposium. 2012; Apr Barcelona, Spain. Available from: Accessed February 3, Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatology. 2008;29: Garg V, Heeswijk R, Lee JE, et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology. 2011;54: Hulskotte E, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology. 2012;56: Pereira AP, Shin HJ, Safdar A, et al. Post liver transplant therapy with telaprevir for recurrent hepatitis C. Abstract presented at: American Transplant Congress June 4; Boston, Massachusetts. 46. Rogers CC, Stevens DR, Kim M, et al. Telaprevir can be used safely with concomitant tacrolimus in the posttransplant setting. Abstract presented at: American Transplant Congress June 4; Boston, Massachusetts. 47. Pungpapong S, Murphy J, Henry T, et al. Initial experience utilizing telaprevir with peginterferon and ribavirin for treatment of hepatitis C genotype 1 after liver transplantation. Abstract presented at: American Transplant Congress June 4; Boston, Massachusetts. 48. Burton JR, Everson GT. Initial experience with telaprevir for treating hepatitis C virus in liver recipients: virologic response, safety, and tolerability. Abstract presented at: American Transplant Congress June 6; Boston, Massachusetts. 49. Kwo PY, Ghabril M, Lacerda MA, et al. Use of telaprevir plus PEG interferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C. Abstract presented at: European Association for the Study of the Liver Clinical Symposium Apr 18-22; Barcelona, Spain. 50. McCashland TM, Olivera-Martinez MA, Garcia-Saenz de Sicilia M, et al. Early experience with triple drug therapy (telaprevir, pegylated interferon α2a and ribavirin) in patients on cyclosporine a for hepatitis c recurrence after liver transplantation. Abstract presented at: International Liver Transplant Society Annual International Congress May 17; San Francisco, California. 51. Schilsky M, Sam T, Tichy E, et al. Boceprevir, peginterferon, and ribavirin (PEGIFN/RIB) as triple antiviral therapy for severe recurrent hepatitis C post liver transplant: an early single center experience. Abstract presented at: American Transplant Congress June 4; Boston, Massachusetts. Page 15

17 52. Werner CR, Egetemeyr DP, Lauer UM, et al. Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl. 2012;18: Barreiro P, Vispo E, Poveda E, et al. Hepatitis C therapy: highlights from the 2012 annual meeting of the European Association or the Study of the Liver. Clin Infect Dis. 2013;56(4): Bourliere M, Khaloun A, Wartelle-Bladou C, et al. Chronic hepatitis C: treatments of the future. Clin Res Hepatol Gastroenterol. 2011;35(2):S Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368: Lok AS. HCV NS5A inhibitors in development. Clin Liver Dis. 2013;17: Membreno FE, Espinales JC, Lawitz EJ. Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis. 2013;17: Pockros PJ. Non-nucleoside analogue polymerase inhibitors in development. Clin Liver Dis. 2013;17: Pockros PJ. Nucleoside/nucleotide analogue polymerase inhibitors in development. Clin Liver Dis. 2013;13: Poordad F, Lawitz E, Kowdley KV, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Eng J Med 2013;368: Rockstroh JK. Will there be an interferon-free HCV therapy for all: upcoming reality or just a vision? European Association for the Study of the Liver Conference Report Apr 18-22; Barcelona, Spain. Available from: Accessed December 20, Page 16

18 APPENDICES Appendix A Generic (Brand Name) Telaprevir (Incivek ) Boceprevir (Victrelis ) Manufacturer Vertex Pharmaceuticals, Inc. Merck & Co., Inc. Dosage Forms 375 mg tablet 200 mg capsule FDA-Approved Indication Pharmacokinetics Treatment of HCV genotype 1 in combination with PegIFN alfa and ribavirin in adult patients with compensated liver disease Metabolism: hepatic (CYP3A4) Metabolism: hepatic (aldo-ketoreductase, CYP3A4/5) Protein binding: 59-76% Protein binding: 75% Half-life: 9-11 hours at steady state Half-life: 3.4 hours Tmax: 4-5 hours Tmax: 2 hours Elimination: Feces (82%); Urine (1%) Elimination: Feces (79%); Urine (9%) Dosing 750 mg PO every 8 hours 800 mg PO every 8 hours Administration With food containing >20 g of fat With food Most Common Adverse Effects Fatigue (56%), anemia (36%), nausea (39%), rash (56%), pruritus (47%) Appendix B: Phase 2 Studies Patient Population Control Group (n=75) Group 1 (n=79) Group 2 (n=79) Conclusion Appendix C: Phase 3 Studies PROVE-1 Trial 20 Fatigue (55-58%), anemia (45-50%), nausea (43-46%), abnormal taste (35-44%), chills (33-34%) Genotype 1; treatment-naïve; no evidence of decompensated liver disease or cirrhosis PegIFN α-2a + RBV for 48 weeks and placebo for the first 12 weeks PegIFN α-2a + RBV for 24 weeks and TVR for the first 12 weeks PegIFN α-2a + RBV for 48 weeks and TVR for the first 12 weeks 41% achieved SVR 61% achieved SVR 67% achieved SVR 11% of patients discontinued treatment due to adverse effects 21% of patients discontinued treatment due to adverse effects The addition of TVR significantly improved SVR rates in treatment-naïve patients with genotype 1 HCV PROVE-2 Trial 21 Patient Population Genotype 1; treatment-naïve; no evidence of cirrhosis Control Group (n=85) PegIFN α-2a + RBV for 48 weeks and placebo for the first 12 weeks 46% achieved SVR Group 1 (n=84) PegIFN α-2a + RBV + TVR for 12 weeks 60% achieved SVR Group 2 (n=83) PegIFN α-2a + RBV for 24 weeks and TVR for the first 12 weeks 69% achieved SVR Group 3 (n=82) PegIFN α-2a + TVR for 12 weeks 36% achieved SVR Conclusion Triple therapy with TVR significantly improved SVR rates in treatment-naïve patients with genotype 1 HCV Patient population Control Group (n=365) Group 1 (n=365) Group 2 (n=365) Conclusion ADVANCE Trial 22 Genotype 1; treatment-naïve; no evidence of decompensated liver disease PegIFN α-2a + RBV for 48 weeks and placebo for the 44% first 12 weeks achieved SVR PegIFN α-2a + RBV for 24 weeks if VL 89% TVR for 12 was undetectable at weeks 4 and 12 achieved SVR weeks PegIFN α-2a + RBV for 48 weeks if VL 54% was detectable at week 4 or week 12 achieved SVR TVR for 8 PegIFN α-2a + RBV for 24 weeks VL was 83% weeks and undetectable at weeks 4 and 12 achieved SVR placebo for PegIFN α-2a + RBV for 48 weeks if VL 50% 4 weeks was detectable at week 4 or week 12 achieved SVR Triple therapy with TVR was associated with significantly improved SVR rates in treatment-naïve patients with genotype 1 HCV with most patients receiving 24 total weeks of therapy 33% (n=7/21) of cirrhotics achieved SVR 62% (n=13/21) of cirrhotics achieved SVR 53% (n=14/26) of cirrhotics achieved SVR Page 17

19 ILLUMINATE Trial 23 Patient population Genotype 1; treatment-naïve; no evidence of decompensated liver disease Extended rapid virologic response: 92% 82% (n=31/38) of Group 1 (n=162) PegIFN α-2a + No additional therapy after 24 weeks achieved SVR cirrhotics achieved SVR RBV for 24 Extended rapid virologic response: 88% 88% (n=29/33) of Group 2 (n=160) weeks and PegIFN α-2a + RBV for 24 more weeks achieved SVR cirrhotics achieved SVR TVR for the Group 3 (n=118) first 12 weeks No extended rapid virologic response: 64% 55% (n=23/55) of PegIFN α-2a + RBV for 24 more weeks achieved SVR cirrhotics achieved SVR Triple therapy with TVR for 12 weeks followed by therapy with Peg-IFN and RBV for 12 weeks was Conclusion noninferior to triple therapy for 12 weeks followed by dual therapy for 24 weeks in terms of SVR rates in treatment-naïve patients with genotype 1 HCV Patient Population Control Group (n=133) Group 1 (n=266) Group 2 (n=264) Conclusion REALIZE Trial 24 Genotype 1; did not achieve SVR to 1 previous course of PegIFN + RBV; no evidence of decompensated liver disease PegIFN α-2a + RBV for 48 weeks 17% 10% (n=1/10) of achieved SVR cirrhotics achieved SVR PegIFN α-2a + RBV for 48 weeks and 64% 44% (n=11/25) of TVR for the first 12 weeks achieved SVR cirrhotics achieved SVR PegIFN α-2a + RBV for 48 weeks and 66% 40% (n=10/25) of TVR for weeks 5-16 achieved SVR cirrhotics achieved SVR Regardless of the presence of a lead-in phase, the addition of TVR significantly improved SVR rates in patients with genotype 1 HCV who had a previous relapse, a partial response, or no response to previous treatment Patient Population Control Group (n=133) Group 1 (n=266) Group 2 (n=264) Conclusion Patient Population Control Group (n=180) Group 1 (n=162) Group 2 (n=161) Conclusion SPRINT-2 Trial 25 Genotype 1; treatment-naïve; no evidence of decompensated liver disease PegIFN α-2a + RBV + placebo for 44 38% more weeks achieved SVR No additional therapy 96% PegIFN α-2a PegIFN α-2a after 28 weeks achieved SVR + RBV + + RBV BOC for 24 PegIFN α-2a + RBV + for 4 weeks 72% more weeks placebo for 20 more achieved SVR 38% (n=9/24) of cirrhotics achieved SVR 41% (n=14/34) of cirrhotics achieved SVR weeks PegIFN α-2a + RBV + BOC for 44 more 66% 52% (n=22/42) of weeks achieved SVR cirrhotics achieved SVR The addition of BOC significantly improved SVR rates in treatment-naïve patients with genotype 1 HCV, with similar rates among groups of 24 and 44 weeks of BOC RESPOND-2 Trial 26 Genotype 1; previous treatment for HCV; no evidence of decompensated liver disease PegIFN α-2a + RBV + placebo for 44 21% 0% (n=0/10) of more weeks achieved SVR cirrhotics achieved SVR No additional therapy PegIFN α-2a PegIFN α-2a + after 36 weeks + RBV + 59% 35% (n=6/17) of RBV for 4 BOC for 32 PegIFN α-2a + RBV + achieved SVR cirrhotics achieved SVR weeks more weeks placebo for 12 more weeks PegIFN α-2a + RBV + BOC for 44 more 66% 77% (n=17/22) of weeks achieved SVR cirrhotics achieved SVR The addition of BOC significantly improved SVR rates in previously treated patients with genotype 1 HCV Page 18