Treating HCV Genotype 2 & 3

Transcription

1 Treating HCV Genotype 2 & 3 3rd Workshop on HCV Therapy Advances, Rome Christoph Sarrazin Klinikum der J. W. Goethe-Universität Frankfurt am Main, Germany

2 HCV Genotypes 2 & 3 Laurel and Hardy

3 Geographical distribution and prevalence Genotype 2 and 3 in Europe Canada Norway Germany Sweden Czech Republic Poland Russia UK Hungary France Portugal HCV Prevalence <1% 1-1,9% 2-2,9% >3% unknown Spain Switzerland Italy Greece Israel Romania Turkey Cornberg et al. Liver International 2011; Suppl 2:30-60

4 Geographical distribution and prevalence Genotype 2 and 3 Global Syria Iraq Iran Pakistan China Korea Lebanon Japan Egypt Taiwan Jordan Saudi Arabia India Thailand HCV Prävalenz <1% 1-1,9% 2-2,9% >3% Nicht untersucht Vietnam Australia Sievert et al. Liver International 2011; Suppl 2:61-80

5 Summary distribution and clinical features Genotype 2 and 3 Genotype 2 Approx. 8% of HCV infections globally High prevalence in - Italy - Korea - Japan - Taiwan Genotype 3 Approx. 10% of HCV infections globally High prevalence in - Pakistan - India - Thailand - Europe - Australia HCV associated NHL? Hepatic steatosis Faster fibrosis progression? Ferri et al., Autoimmun Rev 2007; Bochud et al., J Hepatol 2009, Probst et al., J Viral Hepatitis 2011

6 Treatment options Genotype 2 and 3 Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs

7 Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive) PEG-IFN-α plus Ribavirin (24 weeks) SVR (%) Genotype 2 Genotype Dalgard et al. Mangia et al. Shiffman et al. Zeuzem et al. Dalgard et al., Hepatology 2008; Mangia et al., NEJM 2005; Shiffman et al., NEJM 2007; Zeuzem et al., J Hepatol 2004

8 Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive) Meta-Analysis of 8 studies with PEG-IFN-α plus Ribavirin (12-16 versus 24 weeks in RVR patients irresp. of baseline viral load) SVR (%) Genotype 2 Genotype weeks (RVR) 24 weeks (RVR) Andriulli et al., Alim Pharm Ther 2008

9 Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive) Meta-Analysis of 8 studies with PEG-IFN-α plus Ribavirin (non-rvr patients with 24 weeks of treatment) 24 weeks (non-rvr) SVR (%) Genotype 2 Genotype 3 Genotype 2 Genotype 3 Andriulli et al., Alim Pharm Ther 2008

10 Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive) Extension of treatment duration in non-rvr patients? N-Core Study design CHC G2/3 patients on PegIFN alfa- 2a/ RBV RVR: continue treatment outside the study Non-RVR: enrolled in the study n=400 n=235 STOP n=160 PegIFN alfa-2a/ RBV n= week follow-up n=95 n=93 24 week follow-up Entry into study at week 8 if no RVR Randomization of patients without RVR, but with undetectable HCV RNA or 2-log drop in HCV RNA from baseline at week 12

11 Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive) SVR24 (% of patients) ITT (n=188) PP (n=176) SC (n=153) Odds ratio PegIFN 2a/RBV 24 weeks PegIFN 2a/RBV 48 weeks SC population: Significantly higher SVR24 rates with 48 weeks vs. 24 weeks of PegIFN 2a/RBV 95% CI p value CI = confidence interval; ITT = intent-to-treat; PP = per protocol; SC = study completer; SVR24 = sustained virologic response 140 days after end of treatment. Cheinquer H et al. AASLD 2012; #156 (S271A)

12 Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (Relapser/NR) EPIC-3 Study: relapser / non-responder to (PEG)IFN + ribavirin 48 weeks PEG-IFN plus Ribavirin SVR (%) Genotype 2 (n=75) Genotype 3 (n=292) GT2/3 Relapser GT2/3 Non- Responder Poynard et al., Gastroenterology 2009

13 Treatment options Genotype 2 and 3 Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs

14 Telaprevir Genotype 2 Genotype 3 Median HCV RNA decline (log 10 IU/ml) A Genotype 2 0,0-1,0-2,0-3,0-3,65-4,0-5,0-4,83-5,51-6,0-6,0 Baseline Telaprevir monotherapy Time (days) Median HCV RNA decline (log 10 IU/ml) B 0,0-1,0-2,0-3,0-4,0-5,0 Genotype 3-6,0-6,0 Baseline Time (days) -0,54 Telaprevir monotherapy -4,72-4,85 Telaprevir monotherapy Telaprevir plus Peg-IFN/RBV Peg-IFN/RBV Foster et al. Gastroenterology 2011; 141:

15 Boceprevir Antiviral activity of Boceprevir monotherapy in genotype 2/3 Silva et al. J Hepatol 2013

16 Telaprevir and Boceprevir Mean maximum log10 HCV RNA decline during mono-therapies 7-14 days HCV RNA log10 decline ,4 2,1 3,9 1,4 1,7 0,5 0,9 GT 1 GT 2 GT 3 GT 4 GT 5 GT 6 Telaprevr 750mg TID; Reesink et al., Gastro 2006, Foster et al., Gastro 2011, Benhamou et al., EASL 2009 Boceprevir 400mg TID (current dose 800mg TID); Sarrazin et al., Gastroenterology 2007; Silva et al., APASL 2011 no data

17 Telaprevir and Boceprevir Rescue treatment in patients with incomplete virologic response viral load log 10 decline Case: 45 years female 80kg (BMI 26) Genotype 3 F4 (cirrhosis) treatment-naive PEG-2a 180 plus 1200 Riba Treatment week

18 Telaprevir and Boceprevir Rescue treatment in patients with incomplete virologic response Add-on Boceprevir 3x800mg per die viral load log 10 decline Case: 45 years female 80kg (BMI 26) Genotype 3 F-3 fibrosis treatment-naive PEG-2a 180 plus 1200 Riba Treatment week

19 Telaprevir and Boceprevir Rescue treatment in patients with incomplete virologic response HCV Genotype Fibrosis Metavir IL28B* Pre-Tx Status Protease- Inhibitor Viral load PI baseline Virological response 2a 4 CT Relapse Telaprevir 6400 SVR 2a 2 CT Partial-NR Telaprevir Relapse 3a 4 CC Naive Boceprevir SVR 3a 2 CT Naive Boceprevir 320 SVR 3a 4 CT Naive Boceprevir 1120 BT 3a 4 CT Relapse Boceprevir 1250 Relapse 3a 4 CC Naive Boceprevir 125 SVR *rs

20 Treatment options Genotype 2 and 3 Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs

21 Sofosbuvir Monotherapy: antiviral activities EC50 (µm) GT1b con1 GT1a H77 GT2a JFH-1 GT1b/ 2a J6 GT1b/ 2b pt GT1b/ 3a pt SOF Median HCV RNA change from baseline (log IU/mL) Days PSI mg QD In HCV GT2/3 (ELECTRON) PSI mg QD In HCV GT1 (NUCLEAR) 1 Lam et al., AAC 2012; Gane et al., AASLD 2011; Lawitz et al., EASL 2011

22 Sofosbuvir + Riba: IFN-intolerant tx-naive (Positron) No cirrhosis Cirrhosis SVR12 (%) /92 16/17 57/84 3/14 GT 2 GT 3 100% on tx response, no viral break-through, failure = relapse No resistance (deep and phenotypic) Jacobson et al., EASL 2013; #61 and NEJM 2013

23 Sofosbuvir plus Riba vs. PEG/R tx-naive (Fission) SOF + RBV Peg-IFN + RBV SVR12 (%) /59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No cirrhosis Cirrhosis No cirrhosis Cirrhosis GT 2 GT 3 Gane et al., EASL 2013; #5 and NEJM 2013

24 Sofosbuvir plus Ribavirin in tx-experienced (Fusion) SOF + RBV 12 weeks SOF + RBV 16 weeks SVR12 (%) /26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis 0 No cirrhosis Cirrhosis GT 2 GT 3 Gane et al., EASL 2013 and NEJM 2013

25 Sofosbuvir plus Ribavirin 12 vs. 24 wks. (Valence) Genotype 2/3, tx-naive and Non-Responder: Extension of treatment duration in GT3 patients Zeuzem et al., AASLD 2013; 1085

26 Sofosbuvir plus Ribavirin 12 vs. 24 wks. (Valence) Genotyp 2/3, Tx-naive and Non-Responder: Extension of treatment duration in genotype 3 patients Zeuzem et al., AASLD 2013; 1085

27 Sofosbuvir+ PEG + Riba: tx-experienced (Lonestar 2) Genotyp 2/3, Re-treatment (85% BT or Relapse), 50% F4, n=47 Sofosbuvir 400mg QD plus PEG-2a + Riba for 12 weeks 120 SVR12 (%) all no cirrhosis cirrhosis /23 20/24 Genotype 2 Genotype 3 Relapse Lawitz et al., AASLD 2013; LB4

28 Sofosbuvir + Riba +/- PEG: Adverse events Overall safety Hematolog ic abnormalit ies Patients, n (%) SOF + RBV n=207 Placebo n=71 AEs 185 (89) 55 (78) Serious AEs 11 (5) 2 (3) Treatment disc. due to AEs 4 (2) 3 (4) Hemoglobin <10 g/dl 15 (7) 0 Hemoglobin <8.5 g/dl 2 (1) 0 Absolute neutrophil count <750/mm (1) Platelets <50,000/mm (3) Preferred term, n (%) SOF + RBV n=207 Placebo n=71 p-value* Fatigue 91 (44) 17 (24) Nausea 46 (22) 13 (18) Headache 43 (21) 14 (20) 1.00 Insomnia 39 (19) 3 (4) Pruritus 23 (11) 6 (9) Anemia 27 (13) 0 <0.001 Jacobson et al., EASL 2013; #61

29 Simeprevir Genotype 1: -3.8 log decline log -0 log log log Moreno et al., J Hepatol 2012

30 Faldaprevir Potentcy of BI (Faldaprevir), telaprevir, and boceprevir against NS3-NS4A proteins of differnt HCV genotypes White et al., AAC 2010

31 Sofosbuvir: FDA approval Dec. 13

32 Treatment options Genotype 2 and 3 Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs

33 Future drugs NS3 Protease-Inhibitors MK-5172 (activity against genotype 3 at toxic doses only) NS5A-Inhibitors: Daclatasvir (lower activity against GT3 versus GT1) Ledipasvir (in vitro low activity against GT3) ABT-267 (in vitro lower activity against GT3 versus GT1) GS-5816 (improved activity against GT3) Non-nucleoside Polymerase-Inhibitors no clinical data Nucleoside Polymerase-Inhibitors several compounds in phase 1/2 (VX-135, IDX-20963, ACH3422)

34 Summary Different geographical distribution of genotypes (GT) 2 and 3 Countries with high prevalence of GT 2 or 3 (>30%) PEG-Interferon plus ribavirin for weeks in patients with RVR (without cirrhosis, <45 years and BMI <30) PEG-Interferon plus ribavirin for 48 weeks in non- RVR and previous Rel/NR patients? Rescue treatment with Boceprevir / Telaprevir? Sofosbuvir plus Ribavirin for 12 weeks in genotype 2 Sofosbuvir plus Ribavirin for 24 weeks in genotype 3 (Sofosbuvir + Riba + PEG for 12 weeks?) No efficacy / data for Simeprevir and Faldaprevir

35 HCV Genotypes 2 & 3 Laurel and Hardy