Current Antiviral Treatment of HCV cirrhosis

Transcription

1 Current Antiviral Treatment of HCV cirrhosis Hugo R. Rosen, M.D. Waterman Endowed Chair in Liver Research Division Head, Gastroenterology & Hepatology Professor of Medicine and Immunology University of Colorado Health Sciences NIH Hepatitis C Research Center National Jewish Integrated Program in Immunology

2 I have nothing to disclose Support from: NIDDK, NIAID HCV Center Grant and VA Merit Review

3 HCV Cirrhosis Case 55 yo VA patient, genotype 1a Cirrhosis by imaging Prior PEG/Riba, stopped b/c moved; relapsed EGD with variceal eradication (primary prophylaxis); egd 10/12 no varices Labs: Hgb 16, plts 98, Bili 1.1, alb 3.6, VL 1.9 million Would you treat?

4 Triple Therapy for HCV Cirrhotics Pros Prevent decompensation prioritize these patients Decrease risk of HCC Treated patients with advanced fibrosis: No SVR annual liverrelated mortality, 2.7% SVR annual LRM, 0.5% Prevent recurrence post liver transplant Cons Cause decompensation Need to have the talk : is the patient a transplant candidate? 6% rate of hepatic decompensation or death Serious adverse events are more frequent and require close monitoring

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7 SVR% SVR in patients with advanced fibrosis/cirrhosis based on 4 wks >1 log HCV RNA drop <1 log HCV RNA drop SPRINT-2 (naïve), RESPOND-2 (previously treated) Bruno, J Hep 2013

8 Safety: Similar for cirrhotics and non-cirrhotics (surprising) Serious AEs in 16% cirrhotics vs. 11% non-cirrhotics

9 SVR in patients with advanced fibrosis/cirrhosis based on 4 wks Patients failing to achieve 1 log decline by week 4 in lead-in period have low chance of achieving SVR by adding BOC NPV 94% Prediction is uncertain because of small numbers

10 4 week lead-in for TPV-based therapy (REALIZE subanalysis, n = 240) No apparent benefit of assessing response after P/R lead-in in prior relapsers and partial responders In prior null responders, on-treatment response to 4 week lead-in might be clinically useful (PR4T12PR32) < 1 log drop 15% SVR > 1 log drop 54% SVR Only 7 patients were cirrhotic nonresponders with LI decline Foster GR, J Hep 2013

11 Prioritizing cirrhotics for Treatment with Triple therapy >3 fold more deaths are prevented when treating only patients with advanced fibrosis. Aliment Pharm Ther 2012; 36: 670-9

12 HCV cirrhosis triple therapy in real-life setting CUPIC cohort 674 genotype 1 patients with cirrhosis in 55 sites, interim analysis of 455 patients with at least 16 weeks of Tx Relapsers ~45%, Partial responders ~50%, Null responders ~5% Received 48 weeks of treatment Choice of PI was left to the physician (TPV 296, BOC 159)

13 CUPIC cohort Most patients were Child Pugh A 15% had esophageal varices 26% of BOC and 34% of TPV had exclusion criteria for phase III trials

14 CUPIC Efficacy Data with telaprevir regimen

15 Efficacy data with Boceprevir regimen Week 16 BOC vs. week 12 TPV: 61% vs. 71%

16 Safety Findings

17 Safety Findings

18 Hematological Disorders

19 Summary-I In these difficult-to-treat patients, triple therapy associated with good on-treatment response (>70% 16 wks) Longterm outcome data Influence of early and significant RBV reduction on SVR? Consider timing of live donation Serious side adverse events frequent With BOC, consider 4 wk rule Risk of decompensation patients with platelets < 100K, albumin < 3.4, those with history of decompensation

20 Back to the Case... Started Peg2a, Riba 600 bid, TPV 750 q8 on Dec 14 th Wk 4 VL undetectable, Alb 3.2, T bili 2.0 (direct nl) Wk 6 rash on trunk, back, legs, arms (grade 3); stopped TPV; given antihistamines, topical steroids; plan short f/u for possible oral steroids

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22 Case cont d Wk 7 worsening rash, chills, now on face/scalp (grade 4); no oral /genital; systemic steroids; stopped Peg/Riba; develops small volume ascites and LE edema Wk 8: rash better but increased ascites and LE edema; Doppler u/s negative; SBP-, Alb 3.1; start diuretics, taper steroids Wk 9: Prednisone restarted for increased redness hands, arms, legs; Hbg 12; scheduled for EGD b/c decompensation, no GI bleeding Wk 11: massive hematemesis Good Sam hospital, expired within 12 hrs.

23 Summary-II So, treat cirrhotics now or wait for sofosbuvir?

24 NEUTRINO Results (Treatment Naïve Patients) Single group Sofosbuvir + peg-ifn + ribavirin for 12 weeks in genotype 1, 4, 5, and 6 IL-28B Cirrhosis* Race SVR CC 97.9% Non-CC 87.1% No 92.3% Yes 79.6% Non-AA 90.8% AA 87.0% Lawitz, NEJM April

25 NEUTRINO Results Single group Sofosbuvir + peg-ifn + ribavirin for 12 weeks in genotype 1, 4, 5, and 6

26 FISSION Subgroup Analysis Treatment Naïve Patients RCT of SOF + RBV for 12 weeks versus peg-ifn + RBV for 24 weeks in genotype 2 & 3 Race Genotype Cirrhosis IL-28B SVR Rates SOF + RBV pifn + RBV Black 75% (9/12) 40% (2/5) Non-Black 66.8% 67.2% % 77.6% % 62.5% No 72.1% 74.1% Yes 46.9% 38.0% CC 69.8% 77.4% Non-CC 66.2% 58.1% Lawitz, NEJM April

27 Liver MD Team Greg Everson Igal Kam Jay Burton Lisa Forman Michael Wachs Tom Bak Michael Zimmerman Scott Biggins Kiran Bambha Acknowlegments PAs: Sara Tise Lynette Driscoll Lindsay Pratt-Bak Jill Jakovich Hepatology Nurses Barbara Rosa Cathy Ray Tracy Steinberg and Coordinators Research: Jennifer DeSanto

28 Questions? Man Starts Lactating Spontaneously