Hepatitis C: Management of Treatment Naïve Patients with First Line Protease Inhibitors

Transcription

1 Hepatitis C: Management of Treatment Naïve Patients with First Line Protease Inhibitors Eric Lawitz, MD, AGAF, CPI The Texas Liver Institute Clinical Professor of Medicine University of Texas Health Science Center San Antonio, Texas

2 To Treat or Not to Treat 35-year-old mother of 3 young children Transmission date and mechanism unknown No previous treatment Transaminases normal for 3 years No extrahepatic symptoms, no other relevant diseases

3 The Patient with Mild Disease No alcohol, no psychiatric history Physical examination normal Body mass index 31.5 kg/m 2 IL-28b genotype CC HCV genotype 1b Viral load 210,00 IU/L Liver biopsy stage F1 Hemoglobin 13.5 g/dl Motivated to be treated

4 The Patient with Mild Disease Questions patient asks: Can I take any currently approved PI twice per day instead of 3 times per day? Should I evaluate my interferon responsiveness with 4 weeks of PEG/RBV before starting a PI? What is my optimal duration of therapy? How early can nonresponse be predicted?

5 OPTIMIZE: Study Design Phase III, randomized, open-label, international, non-inferiority study examining telaprevir bid vs q8h, when administered with PR (N=740) Treatment-naïve patients with genotype 1 HCV Stratified by fibrosis stage and IL-28B genotype RGT based on response at Week 4 (RVR) T12(bid)/ PR n=369 TVR + PR PR PR Follow-up Follow-up T12(q8h)/ PR n=371 TVR + PR PR PR Follow-up Follow-up Weeks Buti M, et al. Poster presented at AASLD 2012:LB8

6 OPTIMIZE: Telaprevir BID was Non-Inferior to Q8H in Terms of SVR All patients received TVR/PEG/RBV Difference 1.5% (95% CI: 4.9%, 12.0%) 274/369 T12(BID)/PR 270/371 T12(Q8H)/PR Buti M, et al. Poster presented at AASLD 2012:LB8

7 OPTIMIZE: SVR12 by Cirrhosis Status All patients received TVR/PEG/RBV No cirrhosis Cirrhosis 491/ / / / / 54 24/ 49 All patients TVR bid TVR q8h All patients TVR bid TVR q8h Horsmans Y, et al. EASL 2013; Abstract 826

8 12 WEEK RESULTS: A PEEK INTO THE NEAR FUTURE

9 NEUTRINO: Sofosbuvir/IFN/RBV x 12 Weeks: SVR Independent of Baseline Factors 249/273 50/54 269/271 52/54 267/267 53/53 252/273 43/54 Week 2 Week 4 Week 12 Week 12 On treatment Post-treatment Lawitz E, et al. EASL 2013, Amsterdam, #1411; Lawitz E et al NEJM April 2013

10 OPTIMIZE: Adverse Events Preferred term,* n (%) T12(BID)/ PR N=369 T12(Q8H) /PR N=371 Any adverse event 360 (98) 367 (99) Serious adverse event 28 (8) 35 (9) Response by Metavir fibrosis stage /cirrhosis TVR Q8H n=371 TVR BID n=369 All patients N=740 Death* 0 1 (<1%) Any Grade 3 adverse event 156 (42) 139 (38) Grade 3 anemia SSC 95 (26) 70 (19) Hb <8.5 g/dl, n/n (%) F0 2 26/250 (10) 35/256 (14) 61/506 (12) F3/4 16/108 (15) 30/100 (30) 47/208 (22) Cirrhosis 4/49 (8) 15/54 (28) 19/103 (18) Grade 3 rash SSC 18 (5) 22 (6) Any Grade 4 adverse event Any adverse event leading to permanent discontinuation of telaprevir 23 (6) 24 (7) 57 (15) 69 (19) Without cirrhosis 38/309 (12) 50/302 (17) 88/611 (14) Horsmans Y, et al. EASL 2013, Amsterdam, #826; Buti M, et al. Poster presented at AASLD 2012:LB8

11 The Patient with Mild Disease Sophisticated patient wants to know Can I take any currently approved PI twice per day instead of 3 times per day? Should I evaluate my interferon responsiveness with 4 weeks of PEG/RBV before starting a PI? What is my optimal duration of therapy? How early can nonresponse be predicted?

12 Boceprevir: SVR and Lead-In Response 100 PR48 BOC RGT 80 BOC/PR SVR (%) /62 Poorly Responsive to PR <1-log 10 decrease in viral load at treatment Week Responsive to PR 1-log 10 decrease in viral load at treatment Week 4 Poordad F, et al. N Engl J Med 2011;364(13):

13 The Patient with Mild Disease Sophisticated patient wants to know Can I take any currently approved PI twice per day instead of 3 times per day? Should I lead in with PEG/RBV before starting a PI? What is my optimal duration of therapy? How early can nonresponse be predicted?

14 CONCISE Interim Analysis: High SVR rates for 12-week Total TVR Combination Therapy in IL28B CC Treatment-Naives and Prior Relapsers With G1 Chronic Hepatitis C 80 (33%) Not randomized Variable T12/PR12 n=106 Hemoglobin, n (%) <10 g/dl <8.5 g/dl N=239 T/PR T12/PR12 89% (93/104) SVR4 87% (74/85) SVR12 54 (51) 14 (13) 159 (67%) RVR Randomized T12/PR24 n=52 23 (44) 8 (15) 52 T12/PR24 100% (38/38) SVR4 97% (29/30) SVR12 Summary of hemoglobin levels during the 12-week TVR treatment phase Nelson DR, et al. EASL 2013, Amsterdam, #881 Patients with SVR (%) Safety population N= (47) 36 (15) Sustained virologic response at Weeks 4 and 12 for randomized patients treated with T12/PR12 and T12/PR T12/PR12 87 T12/PR /104 38/38 74/85 29/30 SVR4 SVR12

15 The Patient with Mild Disease Questions patient asks: Can I take any currently approved PI twice per day instead of 3 times per day? Should I evaluate my interferon responsiveness with 4 weeks of PEG/RBV before starting PI? What is my optimal duration of therapy? How early can nonresponse be predicted?

16 Correlation of Early Detection of HCV NS3-Resistance and Virologic Failure in Patients Treated With Triple Therapy Including TVR or BOC Aim: To investigate the clinical relevance of early genotypic resistance test in G1 patients with advanced disease treated with triple therapy by population and ultra-deep sequencing 2 weeks HCV RNA values >100 IU/mL are associated with virologic breakthrough Log HCV RNA (IU/mL) Log HCV RNA (IU/mL) Log HCV RNA (IU/mL) Baseline Cento V, et al. EASL 2013, Amsterdam, #63 24 Time (weeks) patients with TND HCV RNA values at Week 2: 0 failures 18 patients with <100 IU/mL HCV RNA at Week 2: 1 failure 15 patients with >100 IU/mL HCV RNA at Week 2: 8 failures p=0.001 TND, target not detected

17 Correlation of Early Detection of HCV NS3-Resistance and Virologic Failure in Patients Treated With Triple Therapy Including TVR or BOC Virologic failure to TVR with the appearance of V36M + R155K in a patient infected with G1a showing at 48h minor resistance variants ID_13 HCV G1a Age: 43 Sex: M Null responder to SOC IL28: CT 7 TVR + PegIFN-2α + RBV PegIFN-2α + RBV No treatment Log HCV RNA (IU/mL) GRT Day 0 NS3=protease: None GRT 48h NS3=protease: None By UDPS: V36A 2.3%, R155K 4.3% Mutational load: V36A=182 IU/mL R155K=301 IU/mL PI interruption GRT 30 weeks NS3=protease: V36M, R155K GRT 18 weeks NS3=protease: V36M, R155K 1 Day 0 Day 2 Wk 2 Wk 4 Wk 8 Wk 12 Wk 16 Wk 18 Wk 24 Wk 30 LLOQ (15 IU/mL) LLOD (10 IU/mL) Cento V, et al. EASL 2013, Amsterdam, #63

18 Summary First generation protease inhibitors are a significant advance in hepatitis C therapy Evaluate baseline predictors of IFN-responsiveness Although newer therapies are on the horizon, IFNresponsive patients can achieve high rates of SVR today The longer a patient remains viremic while on therapy, the more likely virologic failure will occur New therapies are on the horizon thus discussions with patients about risks, benefits and alternatives are important