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Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin Paul Y Kwo, MD Professor of Medicine Medical Director,

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Presentation on theme: "Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin Paul Y Kwo, MD Professor of Medicine Medical Director,"— Presentation transcript:

1 Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin Paul Y Kwo, MD Professor of Medicine Medical Director, Liver Transplantation Gastroenterology/Hepatology Division Indiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN 46202-5121 phone 317-274-3090 fax317-274-3106 pkwo@iupui.edu

2 Factors Predictive of Response to IFN/RBV based therapy 1995-2000 Genotype 2/3 No advanced fibrosis Low viral load Younger age <40 years Female Weight 2007-2011 Lack of steatosis/insulin resistance Adherence Rapid viral response (RVR) Ribavirin dosage Race/ethnicity IL-28B Anemia McHutchison JG, et al. N Engl J Med. 2009;361(6):580-593. Manns MP, et al. Lancet. 2001;358(9286):958-965. Patton HM, et al. J Hepatol. 2004;40(3):484-490. Poynard T, et al. Lancet. 1998;352(9138):1426-1432. 2011-present Race/ethnicity low viral load absence of cirrhosis statin use IIL-28B Genotype 1a/1b On treatment viral response  Lead-in  eRVR

3 Pre-treatment predictors of response Telaprevir based therapy 3

4 Significantly Higher SVR rates in Telaprevir- Treated Patients Compared to Peg IFN/Ribavirin Alone SVR 75 44 P<0.0001 271/363158/361n/N = Percent of patients with SVR 0 10 20 30 40 50 60 70 80 90 100 T12PRPR Jacobson IM, et al. NEJM 2011

5 100% 0 % 50% Race 75 62 (16/26) 46 25 (7/28) Patients Achieving SVR (%) 75% 25% White Black Jacobson NEJM 2011 ADVANCE Study: Influence of race on SVR with PegIFN/RBV ±Telaprevir Race White Black PR+TVR PR

6 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 83 70 Age 52 Patients Achieving SVR (%) 75% 25% < 45 ≥ 45<65 ADVANCE Study: Role of Age on SVR with PegIFN/RBV ±Telaprevir Age 38 PR+TVR PR < 45 ≥ 45<65

7 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 78 74 HCV RNA 70 Patients Achieving SVR (%) 75% 25% < 800,000 ≥ 800,000 ADVANCE Study: Role of viral level on SVR with PegIFN/RBV ±Telaprevir HCV RNA < 800,000 ≥ 800,000 36 PR+TVR PR

8 Role of HCV Genotype  Evidence that 1a more difficult to treat than 1b with PR Genotype 1a associated with lower SVR than genotypes 1b, 4a, and 4d when treated with PR for 48 weeks in 537 patients Genotype 1a associated with lower SVR in 115 patients receiving PR for 48 weeks than 1b  Initial HCV subgenomic replicons derived from genotype 1b virus 8 Journal of Medical Virology 81:2029–2035 (2009) Journal of Medical Virology 83:437–444 (2011) Science, 2000

9 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% Genotype 79 71 48 41 Patients Achieving SVR (%) 75% 25% 1b 1a ADVANCE Study: Influence HCV Genotype on SVR with PegIFN/RBV ±Telaprevir Genotype 1b 1a PR+TVR PR

10 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 81 75 Fibrosis F0-F1 F2 F3 F4 62 46 33 (7/21) 48 Patients Achieving SVR (%) 75% 25% ADVANCE Study: Influence of hepatic fibrosis on SVR with PegIFN/RBV ±Telaprevir 62 (13/21) 33 PR+TVR PR Fibrosis F0-F1 F2 F3 F4

11 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 90 71 IL-28B CC CT TT 73 Patients Achieving SVR (%) 75% 25% ADVANCE Study: Role of IL28B on SVR with PegIFN/RBV ±Telaprevir PR+TVR PR 64 25 23 42% (454 of 1088) of patients available for IL28B analysis; all patients were white TVR increased SVR rates across IL28B genotypes, but CC still did better IL-28B CC CT TT

12 On treatment response predicts SVR with Telaprevir based therapy 12

13 ADVANCE/ILLUMINATE: Anemia and Ribavirin dose reduction did not predict SVR in Telaprevir arms AnemiaNo Anemia RBV Dose Reduction No RBV Dose Reduction 145/ 196 116/ 165 247/ 344 44/ 92 206/ 265 173/ 255 164/ 534 135/ 262 135/ 172 106/ 148 241/ 300 37/ 48 226/ 293 163/ 272 434/ 545 117/ 245 n/N = Anemia :Hgb < 10 g /dl

14 SVR Rates According to Maximum Hemoglobin Decrease from Baseline 0/6244/ 321 42 76 62 47 Patients with SVR (%) T12PR n/N = 76 4243 46 8/19211/ 275 77 25 29 0 PR 53/86 135/ 178 1/435/ 74 4/1442/ 92 27/6545/ 105 ≤ 1> 1-2> 2-3> 3-4> 4-5> 5 g/dL

15 Achieving extended RVR Associated with SVR 189/21228/29130/33282/151 89 97 54 39 eRVR+ eRVR- n/N = Percent of patients with SVR 0 10 20 30 40 50 60 70 80 90 100 (All patients received 48 weeks regimen) (TVR patients received a 24 weeks regimen) T12PRPR

16 SPRINT 2: SVR* and Relapse Rates p < 0.0001 Non-Black Patients p = 0.044 p =0.004 Black Patients SVR Relapse Rate *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post-treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39%, 66% and 68%, respectively and in Cohort 2 were 21%, 42% and 51%, respectively. 125 311 211 316 213 311 12 52 22 52 29 55 37 162 21 232 18 230 2 14 3 25 6 35

17 Pre-treatment predictors of response Boceprevir based therapy 17

18 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 68 53 (29/55) 67 42 (22/52) Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Race on SVR with PegIFN/RBV ±Boceprevir PR+BOC PR+ BOC RGT PR 40 23 (12/52) Race White Black Race

19 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 69 65 73 64 Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Age on SVR with PegIFN/RBV ±Boceprevir PR+BOC PR+ BOC RGT PR 52 34 Age 40 40 40 Age

20 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 85 63 76 61 Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Viral Level on SVR with PegIFN/RBV ±Boceprevir PR+BOCPR+ BOC RGT PR 64 33 HCV RNA < 800,000 ≥ 800,000 HCV RNA < 800,000 ≥ 800,000 HCV RNA < 800,000 ≥ 800,000

21 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% Genotype 70 63 66 59 Patients Achieving SVR (%) 75% 25% 1b 1a SPRINT 2 : Influence of HCV Genotype on SVR with PegIFN/RBV ±Boceprevir Genotype 1b 1a PR+BOC PR+ BOC RGT Genotype 1b 1a PR 40 35

22 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 67 52 (22/42) 67 41 14/34) Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Fibrosis on SVR with PegIFN/RBV ±Boceprevir PR+BOC PR+ BOC RGT PR 38 (9/34) Fibrosis F0-F2 F3-F4 Fibrosis F0-F2 F3-F4 Fibrosis F0-F2 F3-F4

23 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 67 42 (10/24) 66 31 (5/16) Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Cirrhosis SVR with PegIFN/RBV ±Boceprevir PR+BOC PR+ BOC RGT PR 37 46 (6/13) No Cirrhosis Cirrhosis

24 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011; 100% 0 % 50% 86 (6/7) 66 67 (6/9) 63 Patients Achieving SVR (%) 75% 25% SPRINT 2 : Influence of Statin use on SVR with PegIFN/RBV ±Boceprevir PR+BOC PR+ BOC RGT PR 100 (3/3) 37 Statin user non-statin user

25 Why would statin use be associated with SVR?  HCV forms lipoviral particles which represent the primary form of HCV within the circulation  LDL receptor is thought to play a role in the receptor binding and endocytosis of the virus  Antiviral effects of statins have been shown with HIV-1 respiratory syncytial virus, and HCV  Higher SVR rates with PR reported for those taking statins  Statins reduce/delay resistance in combination with HCV protease inhibitors Significant Drug-Drug interactions occur with TVR/BOC w and certain statins 25 Pandya Gastro 2011 Hepatology. 2009 Jul;50(1):6-16.

26 SPRINT-2: SVR by IL28B Polymorphism % SVR 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 *~90% eligible for short duration therapy * 62% of individuals (653/1048) had consented to IL28 pharmacogenomic studies

27 On treatment response predicts SVR with Boceprevir based therapy 27

28 SVR by Week 4 PR Lead-In Response Non-Black PatientsBlack Patients ≥1 log 10 HCV RNA decline from baseline <1 log 10 HCV RNA decline from baseline SVR (%) 121 234 187 228 178 218 12 26 16 24 22 36 3 62 21 73 31 79 6 24 5 16 0 21

29 IL28B is no longer an important predictor of SVR when Lead-in Response is considered SPRINT-2 (effect)Odds Ratio (95% CI)p-value BOC/PR48 vs PR487.0 (4.1, 12.0)< 0.0001 BOC/RGT vs PR486.0 (3.5, 10.2)< 0.0001 Baseline HCV-RNA: ≤400,000 vs. >400,000 IU/mL5.8 (1.9, 17.5)0.002 Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.0)< 0.0001 Genotype: 1b/others vs 1a2.3 (1.5, 3.6)< 0.001 BMI: 25-30 kg/m 2 vs. >30 kg/m 2 2.3 (1.4, 3.9)0.002 BMI: ≤25 kg/m 2 vs. >30 kg/m 2 1.9 (1.1, 3.3)0.02 Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table.

30 Anemia on treatment was identified as a significant factor for attaining SVR (P<0.001) SVR by Absence/Presence of Anemia Sulkowski M, et al. EASL 2011, Abst. 476. SVR (%) Hb ≥10g/dL Hb <10g/dL Hb ≥10g/dL Hb <10g/dL PR48 BOC/PR SPRINT-2 77 246 80 109 212 363 263 362

31 Summary: Addition of TVR or BOC to Peg IFN/RBV improves SVR rates across all treatment groups  Black race, high baseline HCV RNA, genotype 1a, age, cirrhosis all with lower SVR rates  Anemia, statin use predicts SVR with BOC  IL-28B CC: High likelihood of 24-28 weeks of therapy CT/TT : marked improvement with TVR/BOC addition  On treatment response remains strongest predictor of SVR Response to 4 week lead –in Achieving eRVR 31

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