Management of CHC G1 patients who are relapsers or non-responders to Peg IFN and RBV therapy: Wait or Triple Therapy?

Transcription

1 Management of CHC G1 patients who are relapsers or non-responders to Peg IFN and RBV therapy: Wait or Triple Therapy? Prof. Teerha Piratvisuth NKC Institute of Gastroenterology and Hepatology Prince of Songkla University Thailand

2 Good SVR rates in Asia are likely due to the high prevalence of the favorable IL28B CC genotype Thomas DL, et al. Nature 2009; 461:

3 SVR (%) 100 Sustained Viral Response (SVR) HCV 1 treated with PegIFN/Ribavirin Caucasian vs Asian West: HCV 1 East: HCV 1 Fried et al Hadzyannis et al Manns et al IDEAL Yu et al, China Liu et al, Taiwan Kuboki et al, Japan Yu et al, Taiwan Lee et al, Taiwan Liu et al, Taiwan Adapted from Yu ML, Chuang WL. J Gastroenterol Hepatol 2009;24:336-45

4 Predictors of treatment response Host factors Race Age Gender IL28B genotype Body Mass Index (BMI) Insulin resistance/steatosis Alcohol abuse Modifiable vs nonmodifiable Treatment failure Virus Genotype Viral load On-treatment viral response Disease factors Co-infection Advanced fibrosis Treatment Adherence and tolerance Type of regimen Dose Duration Adapted from Pol & Bourliere, Antiviral Therapy 11:

5 Patients with undetectable HCV RNA (%) SVR rate of 50% achieved in relapsers re-treated for 72 weeks with PegIFN alfa-2a/rbv n= 29/ /107 98/ Treatment week 85/ (EOT) 54/ (SVR) Kaiser S, et al. Hepatology 2008; 48 (4, Suppl); 1140A

6 SVR (%) REPEAT: PegIFN/Ribaviin re-treatment in HCV genotype 1 non-responders 20 p=0.006, Odds ratio 2.0 (95% CI ) 16% 14% 10 7% 9% 0 52/317 11/156 22/156 27/ /180 µg 72 weeks 360/180 µg 48 weeks 180 µg 72 weeks 180 µg 48 weeks Assessed by Cochran-Mantel-Haenszel test stratified by region, HCV genotype and histological stage Non-responder patients previously treated with pegylated interferon alfa-2b plus ribavirin Jensen D, et al. 58th AASLD 2007; Abstract LB4

7 Regional approval status for BOC and TLV Japan: TLV approved 2011 Veitnam BOC approved 2013 Singapore; Malaysia BOC approved 2012 Australia: TLV approved 2012 BOC approved 2011 New Zealand: TLV approved 2012 BOC approved 2012 BOC = boceprevir; TLV = telaprevir

8 Sustained virologic response rates (%) REALIZE: Phase 3 Trial in Tx-Experienced HCV-1 Infected Patients P/R/T (simultaneous) P/R/T (lead-in) PR (n=354) (n=124) (n=184) Peginterferon alfa 180 μg qw Ribavirin mg/day Telaprevir750 mg q8h Zeuzem et al., NEJM 2011

9 SVR (%) REALIZE: SVR by Baseline Fibrosis Stage and Prior Response Prior relapsers Prior partial responders Prior null responders 100 Pooled T12/PR PR n/n = 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/15 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis

10 SVR, % BOC/PR Triple Therapy Significantly Increased SVR Rates vs PR Alone in Previous Treatment Failures Previous Relapsers Previous Nonresponders /51 72/105 77/103 2/29 23/57 30/58 7 PR48 BOC RGT BOC PR48 PR = peginterferon alfa and ribavirin; RGT = response-guided therapy; SVR = sustained virologic response. Bacon BR et al. N Engl J Med. 2011;364:

11 SVR (%) Subjects who failed previous therapy: Boceprevir plus PR achieved > 89% SVR rates in subjects with undetectable viral load at treatment week 8 and treatment week 12 44% (71/162) of subjects in the BOC RGT group and 45% (73/161) of subjects in the BOC PR48 group were early responders, with undetectable HCV-RNA at Treatment Week 8 (early responders) and Treatment Week 12 22% (35/162) of subjects in the BOC RGT group and 25% (40/161) of subjects in the BOC PR48 group were late responders, with detectable HCV-RNA at Treatment Week 8 but subsequently undetectable at Treatment Week Undetectable HCV- RNA at Treatment Week 8 and Treatment Week /71 28/35 71/73 29/40 BOC RGT BOC PR48 Detectable HCV-RNA at Treatment Week 8, but subsequently undetectable HCV-RNA at Treatment Week 12

12 SVR, % Longer duration of combination therapy with Boceprevir was associated with higher SVR in previous treatment failures with cirrhosis Previous With Cirrhosis Previous Without Cirrhosis /10 6/17 17/22 16/66 85/132 85/128 PR48 BOC RGT BOC PR48 Bacon BR et al. N Engl J Med. 2011;364:

13 CUPIC: Treatment regimen Fontaine H. etal. EASL 2013.

14 Virological response in the CUPIC trial (ITT) French early access program for cirrhotic previous PR non-responders Fontainse H. etal. EASL 2013

15 SVR 12 SVR 12 Virological response in the CUPIC trial (ITT) TELAPREVIR BOCEPREVIR 53% 29% 51% 11% Fontainse H. etal. EASL 2013

16 Safety findings in CUPIC up to week 60 Risk of death or severe complication increased in patients with Platelete < 100,000 /mm3 and Albumin < 35 g/l Fontaine H. etal. EASL 2013

17 Sustained virologic response rates (%) CUPIC : SVR according to on-treatment virological response Undetectable W4 > 3 logs decline W8 < 3 logs decline W8 Fontainse H. etal. EASL 2013

18 Protocol for BNPP study global study Eligibility Age>18y Previous treatment failure Compensated advanced fibrosis or cirrhosis Genotype 1 No contraindications for Peginterferon/ribavirin Able to give consent Exclusions Previous boceprevir or PI therapy Decompensated liver disease Organ transplant Co-infection: HIV, HBV Prohibited medications Substance abuse Severe medical illness Peg-IFN + RBV BOC: 800 mg/8h; Peg-IFNα-2b: BOC + Peg-IFN 1.5 µg/kg/week; α-2b + RBV RBV: 800 to 1400 mg/dayfollow-up Weeks SVR12 72 SVR24

19 Treatment response (%) Treatment Response (%) SVR 12 (%) Treatment response according to type of prior treatment failure BNPP Asian Cohort, n=70/79 (completed FU) Thailand, Singapore, Malaysia (provisional data) BNPP CUPIC,n= 190 (boceprevir) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 96% 78% ETR SVR 50% 48% 25% 38% Relapser (%) Partial Responder (%) Null Responder (%) Relapsers Overall SVR = 63% Overall SVR = 41% ETR SVR Partial responders ETRSVR Null responders % 43/85 32/80 Relapsers 40% Partial responders 11% 1/9 Null responders Piratvisuth, APASL Liver Week 2013 (updated) Fontainse H. etal. EASL 2013

20 Serious Adverse Events Type n/n BNPP Asia CUPIC All SAEs 16/ % 51% Death % Sepsis 3/79 3.8% 4.2% Decompensation 2/79 2.5% 4.7% Blood transfusions 11/ % 13.7% Piratvisuth, APASL Liver Week 2013 Fontaine, EASL 2013

21 SAE (16/79 = 20.3%) Hospitalization Sepsis Blood transfusion Decompensation Severe abd pain Number of patients yes yes 1 yes yes yes 1 yes yes yes yes 1 yes yes 1 yes yes yes 1 yes yes 1 yes 2 yes yes 1 yes 6 yes 1

22 SVR (%) Null Responder AVIATOR Study: ABT-450/r, ABT-267, ABT-333 +/- RBV in Null Responders Wk 0 Wk 8 Wk 12 Wk ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV SVR 12 SVR A B C Kowdley K. EASL Poorded F. Gastroenterology 2010;139:

23 Management of CHC genotype 1 with PegIFN/RBV treatment failure Identify and correct modifiable response predictors Stage of liver disease Type of previous treatment response

24 F 0-2 Fibrosis Relapsers Partial responders Nullresponders BOC or TLV PR triple therapy BOC or TLV PR triple therapy Wait for new therapy or triple therapy SVR 75-85% SVR 72 % SVR 40 %

25 F 3-4 Fibrosis Relapsers Partial responders Nullresponders BOC or TLV PR triple therapy Triple therapy or wait Wait new therapy or Triple therapy SVR 75-84% SVR 34 % SVR 14 % Cirrhotic patients with thrombocytopenia and hypoalbuminemia wait for new therapy

26 Thank you