Applied Health Economics and Health Policy

Applied Health Economics and Health Policy Cost-Effectiveness Analysis of Boceprevir for the Treatment of Chronic Hepatitis C Virus Genotype 1 Infection in Portugal Elamin H. Elbasha, Jagpreet Chhatwal, Shannon A. Ferrante, Antoine C. El Khoury, Pedro A. Laires Correspondence: Elamin H. Elbasha, Merck & Co., Inc., UG1C-60, PO Box 1000, North Wales, PA19454-1099 USA e-mail: elamin_elbasha@merck.com Electronic Supplementary Material

Appendix: treatment-related inputs The label-based treatment regimens include recommendations for different subsets of the population based on prior treatment experience with peginterferon alfa and ribavirin, baseline fibrosis status, and response to treatment. For certain subsets of the population, the recommended treatment strategies in the label differ from those studied in SPRINT-2 and RESPOND-2 clinical trials. This appendix briefly describes the results of the post-hoc analyses that we conducted in order to estimate the treatment-related inputs of the model. These steps were necessary to parameterize our model in order to evaluate the costeffectiveness of label-based regimens. The analyses were conducted for the following subgroups: non-cirrhotic (with baseline Metavir score of F0, F1, F2 or F3) patients who were previously untreated, non-cirrhotic patients who were previously treated, cirrhotic patients who are previously untreated, cirrhotic (with baseline Metavir score of F4) patients who were previously treated, and null responders. Input values associated with the label-based recommended treatment strategy for noncirrhotic untreated patients were based on the reported data of patients randomized to the BOC/RGT arm in SPRINT-2. In SPRINT-2, black and non-black patients were randomly assigned to the treatment arms separately and data collected from each cohort was analyzed separately. Hence, there are separate estimates for the input values for the models associated with the non-black and black cohorts. Input values associated with the label-based recommended treatment strategy for cirrhotic patients are based on the reported data of patients randomized to the BOC/ arm in SPRINT-2 who had a baseline Metavir score of F4. The label-based treatment recommendation for cirrhotic patients is the same as the BOC/ treatment arm. Because less than 10% of patients in SPRINT-2 were cirrhotic, separate input values based on the race cohort were not obtained the same input values were applied to both the non-black and black cohorts. Input values for non-cirrhotic previously treated patients were based on the reported data of patients randomized to the BOC/RGT arm whereas inputs for cirrhotic previously treated patients and null responders were obtained from the BOC/ arm in RESPOND-2. Patients who fulfill the strict definition of prior treatment null responders (i.e., having less than a 2 log 10 drop in HCV-RNA by treatment week 12 during prior therapy with 1

peginterferon alfa and ribavirin) were not studied in RESPOND-2. Instead, we assumed prior null responders are patients with less than a 1 log 10 HCV-RNA decline by treatment week 4 during current therapy. The post-hoc analysis deviates from the primary analysis in several ways. First, patients with missing baseline Metavir score were excluded from the post-hoc analysis. Second, the label introduced an additional futility rule (at week 12 for untreated patients and at week 24 for previously treated patients). Further, the stopping rule at week 12 that is recommended for previously treated patients in the label (having HCV-RNA greater than or equal to 100 IU/mL) is different from that implemented in RESPOND-2 (having detectable HCV-RNA). To mimic what would have happened in the clinical trials if a label-based stopping rule had been implemented, patients who failed were assumed to cease therapy immediately. On the other hand, if a patient had failed a stopping rule in the trial but passed a label-based rule, the patient would not have ceased treatment in the post-hoc analysis. Patients who passed a label-based rule at week 12 and had missing measurements at week 24 were assumed to complete the full course of treatment, but would not achieve an SVR. The additional stopping rule suggested in the label impacted some of the outcomes such as discontinuation rates and SVR rates. Finally, there was a difference in the length of therapy with BOC for non-cirrhotic untreated patients in the BOC/RGT arm of SPRINT-2 who had detectable HCV-RNA at TW 8 (24 weeks of BOC) and the label recommendation for this group (32 weeks of BOC). We assumed that the additional 8 weeks of BOC will not affect treatment outcomes such as SVR rates but would increase the cost of therapy. Thus our approach was biased against boceprevir-based regimens. 2

Table A1. Treatment outcomes of previously untreated patients who were enrolled in SPRINT-2 Non-Cirrhotic patients Cirrhotic patients Outcome Conditional probability of discontinuation a (%) (N=287) Non-black cohort Black cohort Both cohorts RGT (N=292) (N=52) RGT (N=45) (N=13) BOC/ (N=24) for other reasons, before week 4 13/287 (4.5) 11/292 (3.8) 5/52 (9.6) 3/45 (6.7) 0/13 (0.0) 0/24 (0.0) for other reasons, week 4 12 9/274 (3.3) 13/281 (4.6) 3/47 (6.4) 5/42 (11.9) 0/13 (0.0) 1/24 (4.2) for futility reasons at week 12 112/265 (42.3) 19/268 (7.1) 29/44 (65.9) 9/37 (24.3) 6/13 (46.2) 5/23 (21.7) for other reasons, week 12 24 10/153 (6.5) 17/249 (6.8) 1/15 (6.7) 2/28 (7.1) 0/7 (0.0) 0/18 (0.0) for futility reasons at week 24 14/143 (9.8) 26/232 (11.2) 1/14 (7.1) 4/26 (15.4) 1/7 (14.3) 4/18 (22.2) for other reasons, after W 24 20/129 (15.5) 14/206 (6.8) 4/13 (30.8) 2/22 (9.1) 0/6 (0.0) 2/14 (14.3) Conditional probability of only 28- weeks therapy a, ratio (%) Sustained virologic response, ratio (%), pdf 105/287 (36.6) Beta(104.16,180.54) 160/206 (77.7) 12/22 (54.5) 199/292 (68.2) Beta(200.91,93.89) 11/52 (21.2) Beta(13.09,48.80) 20/45 (44.4) Beta(18.79,23.49) 5/13 (38.5) Beta(5.39,8.63) 10/24 (41.7) Beta(9.76,13.66) Anemia b, ratio (%) 89/339 (26.3) 162/337 (48.1) 89/339 (26.3) 162/337 (48.1) 3/13 (23.1) 13/24 (54.2) Receipt of erythropoietin given anemia b, ratio (%) 67/89 (75.3) 138/162 (85.2) 67/89 (75.3) 138/162 (85.2) 3/3 (100) 12/13 (92.3) Mean duration of anemia b, days 104.5 88.5 104.5 88.5 113.3 89.8 Mean duration of erythropoietin use b, days 104.9 87.5 104.9 87.5 236 152.8 a Conditional on continuing treatment at that time. b Assumed to be the same for both cohorts. = peginterferon-ribavirin regimen, RGT = Response Guided Therapy; BOC/ peginterferon ribavirin-boceprevir regimen; pdf = probability distribution function assumed for the Monte Carlo simulations. 3

Table A2. Selected treatment outcomes of previously treated patients who were enrolled in RESPOND-2 and other studies Outcome Conditional probability of discontinuation a (%) for other reasons, before week 4 for other reasons, week 4 12 for futility reasons at week 12 for other reasons, week 12 24 for futility reasons at week 24 for other reasons, after W 24 Sustained virologic response, ratio (%), pdf Non-Cirrhotic patients Cirrhotic patients Null responders (N=66) RGT (N=132) (N=10) BOC/ (N=22) (N=9) BOC/ (N=49) 0/66 (0.0) 6/132 (4.6) 1/10 (10.0) 1/22 (4.6) 0 (0.0) 3/49 (6.1) 2/66 (3.0) 4/126 (3.2) 0/9 (0.0) 0/21 (0.0) 0 (0.0) 2/46 (4.3) 30/64 (46.9) 11/122 (9.0) 7/9 (77.8) 1/21 (4.8) 1062/2312 (45.9) 22/45 (48.9) 2/34 (5.9) 5/111 (4.5) 0/2 (0.0) 1/20 (5.0) 0 (0.0) 1/22 (4.5) 9/32 (28.1) 14/106 (13.2) 2/2 (100.0) 1/19 (5.3) 0 (0.0) 0 (0) 1/32 (4.4) 3/92 (9.7) 0 (0.0) 2/18 (11.1) 0 (0.0) 1/17 (5.9) 16/66 (24.2) Beta(17.93,56.02) 85/132 (64.4) Beta(102.75,56.82) 0/10 (0.0) ) Beta(15.96,6367.0) 17/22 (77.3) ) Beta(16.24,4.78) 117/1198 (9.8 ) Beta(124.91,1154.12) 19/49 (38.8) Beta(18.80,29.69) Anemia, ratio (%) 15/76 (19.7) 61/149 (40.9) 15/76 (19.7) 70/150 (46.7) 372/2312 (16.1) 80/168 (47.6) Receipt of erythropoietin given anemia, ratio (%) 15/15 (100) 60/61 (98.4) 15/15 b (100) 70/70 (100) 15/15 b (100) 68/80 (85.0) Mean duration of anemia, days 75.0 109.6 75.0 b 132.7 b 75.0 b 132.7 b Mean duration of erythropoietin use, days 66.1 137.4 66.1 b 131.9 b 66.1 b 131.9 b a Conditional on continuing treatment at that time. b Assumed to be the same as that for all previously treated patients of the corresponding arm. = peginterferon-ribavirin regimen, RGT = Response Guided Therapy; PRB peginterferon ribavirin-boceprevir regimen; pdf = probability distribution function assumed for the Monte Carlo simulations. 4

Health state costs Portuguese-specific annual direct costs of HCV health states were estimated based on a national expert panel conducted through Delphi method. The expert panel consisted of 8 Portuguese clinical experts vastly experienced in HCV treatment at the national level, representing north, center, and south of Portugal. This section includes the results. Table 3. Unit cost and mean resource use by health state (per year) Cost Items Unit Cost, Mean annual resource use Hospitalizations F0-F3 F4 DC1 DC2 HCC1 HCC2 LT1 LT2 Hospital Admission 0.00 0.00 2.00 2.21 2.50 2.29 1.00 Hospital Readmission 0.23 0.2 Consultations General Practitioner 31.00 1.00 0.75 2.00 2.00 1.71 1.57 0.33 0.3 Gastroenterology/Infectious Diseases 158.65 2.00 2.13 4.57 4.57 5.14 4.57 0.33 0.0 Internal Medicine 164.87 0.00 0.00 0.14 0.14 0.14 0.14 0.00 0.0 Psychiatry 46.74 0.00 0.00 0.07 0.07 0.01 0.01 0.33 0.4 Transplantation 161.76 0.00 0.13 0.36 0.76 0.63 0.46 8.33 4.7 Ophthalmology 44.90 0.00 0.00 0.00 0.14 0.00 0.00 0.17 0.3 Nurse consultation 31.00 0.38 0.38 0.71 1.57 1.00 1.29 4.67 2.7 Nutritionist 81.96 0.25 0.25 0.64 0.71 1.14 1.29 2.00 1.7 Pain consultation 51.6 0.00 0.00 0.00 0.00 0.96 1.03 0.00 0.00 Emergency ward 147.00 0.00 0.00 0.76 1.00 0.57 0.39 1.00 0.1 Lab Tests Creatinine 1.30 1.69 2.000 4.00 4.14 4.71 4.57 8.33 5.0 Glycemia 1.20 1.69 2.000 3.86 4.00 4.71 4.57 8.33 5.0 HbA1c 7.30 0.42 0.313 0.47 0.47 0.24 0.38 3.33 1.7 Hemogram 6.40 1.88 2.125 3.86 4.00 5.00 4.86 8.33 5.0 Ionogram 1.60 1.26 1.638 4.00 4.14 4.71 4.57 8.33 5.0 C-reactive protein (CRP) 4.50 0.75 0.388 2.30 2.44 1.86 2.14 8.33 3.3 Lipids 8.20 1.19 1.025 1.71 1.86 0.79 1.07 2.67 3.3 Prostate-specific antigen (PSA) 7.90 0.55 0.550 0.44 0.59 0.61 0.61 1.33 1.3 Uric acid 1.40 0.38 0.625 0.86 1.14 1.14 1.00 5.33 2.7 Urine 2.90 0.38 0.500 2.21 2.36 0.71 0.86 8.33 5.0 Uroculture 21.30 0.00 0.000 0.53 1.46 0.21 0.50 3.33 2.0 5

Urea 1.30 1.13 1.625 3.57 3.14 3.57 3.43 8.33 5.0 γ-gt 1.60 1.59 2.000 3.71 3.86 4.14 4.00 8.33 5.0 Liver transaminases - AST 1.40 1.81 2.125 3.71 3.86 5.00 4.86 8.33 5.0 Liver transaminases - ALT 1.40 1.81 2.125 3.71 3.86 4.14 4.00 8.33 5.0 Alkaline phosphatase 1.50 1.44 1.875 3.43 3.57 4.14 4.00 8.33 5.0 Bilirubin (total and direct) 1.90 1.69 2.000 3.86 4.00 5.00 4.86 8.33 5.0 Bilirubin (other test) 1.70 0.50 0.750 1.57 1.14 1.43 1.29 0.00 0.0 Proteins (total) 1.70 1.13 1.500 2.29 2.86 2.29 2.14 6.33 1.7 Albumine 4.80 1.25 1.500 3.71 4.00 4.14 4.00 8.33 3.7 Amylase 1.90 0.38 0.625 1.14 1.14 1.57 0.86 1.33 2.0 anti-hcv 18.70 0.05 0.125 0.14 0.14 0.14 0.14 0.00 0.0 Anti-HCV (confirmation) 102.90 0.01 0.066 0.01 0.01 0.01 0.01 0.02 0.0 HCV - viral load 66.80 0.12 0.450 0.59 0.86 0.43 0.43 2.33 2.0 HCV - genotype 148.20 0.05 0.069 0.04 0.01 0.15 0.15 0.02 0.0 HCV - RNA qualitative 171.70 0.00 0.063 0.00 0.00 0.29 0.29 0.00 0.0 AgHbs 15.00 0.06 0.250 0.43 0.43 0.43 0.43 0.67 0.7 Anti-HBs 15.60 0.08 0.250 0.43 0.43 0.43 0.43 0.67 0.7 Anti-HBc total 16.00 0.08 0.250 0.43 0.43 0.43 0.43 0.67 0.7 Anti-HIV1 18.70 0.08 0.256 0.43 0.43 0.43 0.71 0.67 0.7 Anti-HIV2 18.70 0.06 0.256 0.43 0.43 0.43 0.71 0.67 0.7 Free triiodothyronine (T3) 4.50 0.38 0.400 0.29 0.43 0.29 0.57 1.33 1.0 Free thyroxine (T4) 4.50 0.38 0.400 0.29 0.43 0.29 0.57 1.33 1.3 Anti-nuclear antibodies (ANAs) 13.70 0.51 0.406 0.15 0.15 0.15 0.15 0.35 0.4 Anti-smooth muscle antibodies (ASMA) 13.70 0.51 0.406 0.15 0.15 0.01 0.01 0.35 0.4 Thyroid-stimulating hormone (TSH) 5.00 0.51 0.425 0.31 0.46 0.30 0.30 0.67 0.7 Alpha-Fetal Protein 7.80 1.04 1.750 1.71 1.71 2.43 2.29 1.67 1.7 Anti-Sm (identification) 13.00 0.51 0.256 0.15 0.15 0.15 0.15 0.35 0.4 Prothrombin time 4.70 1.28 1.875 3.57 3.71 3.57 3.43 7.67 5.3 Activated partial thromboplastin time (APTT) 4.60 0.38 0.500 1.14 1.43 0.86 1.29 3.00 1.7 Hemoculture 13.60 0.00 0.00 0.28 0.28 0.00 0.00 0.00 0.00 Urine sodium 1.30 0.00 0.00 0.00 1.21 0.00 0.00 0.00 0.00 Exams Liver biopsy (percutaneously) 79.00 0.10 0.069 0.00 0.00 0.16 0.00 1.17 0.7 Liver biopsy (transvenously) 65.00 0.03 0.031 0.01 0.00 0.00 0.00 0.00 0.0 Abdominal ultrasound 28.80 1.15 2.000 2.29 2.29 2.00 2.00 1.33 1.5 6

Abdominal CT 22.30 0.30 0.550 0.91 0.79 1.93 1.79 2.33 1.3 Ophthalmoscopy 19.50 0.00 0.000 0.00 0.14 0.00 0.00 0.00 0.1 ECG (12-lead) 7.40 0.15 0.150 0.57 0.44 0.14 0.43 0.00 0.4 Abdominal magnetic resonance 133.50 0.01 0.238 0.60 0.61 0.93 1.07 1.40 0.4 Ecodoppler (spleno-portal axis) 33.10 0.16 0.563 1.20 1.49 0.96 1.24 3.67 2.3 Paracentesis 20.50 0.00 0.000 1.14 1.57 0.86 1.14 0.00 0.0 Renal ultrasound 28.80 0.00 0.000 0.16 0.17 0.14 0.29 0.00 0.7 Endoscopy 38.10 0.27 0.563 1.06 1.29 0.73 0.83 0.07 0.0 FibroScan 31.70 0.07 0.525 0.29 0.00 0.14 0.29 0.00 0.0 Thorax x-ray 81.00 0.00 0.250 0.59 0.59 0.37 0.51 0.00 0.3 Colonoscopy 54.00 0.00 0.000 0.03 0.00 0.03 0.06 0.00 0.0 Relevant Medications Various drugs, 0.00 359.50 438.14 443.36 9,561.37 8,752.86 4,787.78 4,787.78 Hepatic fibrosis stage was based on Metavir fibrosis scoring system: F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = portal fibrosis with numerous septa without cirrhosis; and F4 = compensated cirrhosis. DC1 = decompensated cirrhosis, first year; DC2 = decompensated cirrhosis, subsequent years; HCC1= hepatocellular carcinoma, first year; HCC2= hepatocellular carcinoma, subsequent years. 7

Table 4. Unit cost for hospitalizations F0-F3 F4 DC1 DC2 HCC1 HCC2 LT1 LT2 Hospital Admission, - - 3,051.86 3,051.86 3,696.69 3,696.69 103,103.2 - Hospital Readmission, - - - - - - 4,613.98 4,613.98 Hepatic fibrosis stage was based on Metavir fibrosis scoring system: F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = portal fibrosis with numerous septa without cirrhosis; and F4 = compensated cirrhosis. DC1 = decompensated cirrhosis, first year; DC2 = decompensated cirrhosis, subsequent years; HCC1= hepatocellular carcinoma, first year; HCC2= hepatocellular carcinoma, subsequent years. Table 5. Mean cost by item and health state (per year) Cost Items, F0-F3 F4 DC1 DC2 HCC1 HCC2 LT1 LT2 Hospitalization 0 0 6,104 6,758 9,242 8,450 104,180 923 Consultations 380 413 1,059 1,197 1,253 1,127 1,890 1,025 Laboratory tests 131 197 284 332 337 356 722 516 Exams 69 187 337 354 355 402 493 307 Relevant Medication a 0 360 438 443 9,561 8,753 4,788 4,788 Total 580 1,156 8,222 9,085 20,749 19,088 112,073 7,558 Hepatic fibrosis stage was based on Metavir fibrosis scoring system: F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = portal fibrosis with numerous septa without cirrhosis; and F4 = compensated cirrhosis. DC1 = decompensated cirrhosis, first year; DC2 = decompensated cirrhosis, subsequent years; HCC1= hepatocellular carcinoma, first year; HCC2= hepatocellular carcinoma, subsequent years. a Excludes HCV medication. 8