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Individualisation of HCV Therapy

Individualisation of HCV Therapy. Achieving an SVR What is the evidence? Dr Allister J Grant. Achieving an SVR. The ability to achieve SVR is the result of two independent steps: 1. Achieving a virologic response a. Interferon/peginterferon dose b. The presence of ribavirin

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Individualisation of HCV Therapy

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  1. Individualisation of HCV Therapy Achieving an SVR What is the evidence? Dr Allister J Grant

  2. Achieving an SVR The ability to achieve SVR is the result of two independent steps: 1. Achieving a virologic response a. Interferon/peginterferon dose b. The presence of ribavirin 2. Not relapsing a. How fast the patient becomes HCV RNA undetectable b. How long the patient remains on treatment c. Dose of ribavirin

  3. Rx duration Wk 12 PCR “EVR” 48 weeks Neg/2log drop Genotype 1,4-6 Stop Pos 24 weeks Genotype 2,3

  4. 2004 Regimes

  5. Ribavirin 800mg/d (FD) vs 800-1400mg/d PEG IFN 2b G1 48wks G2/3 randomised to 24/48 wks Community based US study 4913 patients G1 significant advantage in WBD of RBV No advantage for G2/3 but….. WIN-R trial Weight based Interferon and Ribavirin TrialAASLD 2005

  6. WIN-R Trial • Analysis of SVR by weight • More dose reductions • No more discontinuations 49% 52% 45% 44% 42% 39% 47% 34% P<0.0001 p=0.11

  7. WIN–R Trial G2 had a higher SVR and lower relapse rate than those with G3 (72% vs. 60% and 6% vs.10% respectively). Investigators concluded that higher weight-based doses of ribavirin appear to be necessary to achieve similar SVR rates in G3 patients

  8. What is the clinical evidence to support the value of EVR as a predictor of SVR?

  9. EVR – Treatment Outcome (All Genotypes) PEG IFN alfa-2a 180 g + ribavirin 1,000–1,200 mg Week 72 Week 12 Start of study No SVR 35% (n=137/390) EVR 86% (n=390/453) SVR 65% (n=253/390) Overall SVR 56% (255/453) Total study population (n=453) SVR 3% (n=2/63) No EVR 14% (n=63/453) No SVR 97% (n=61/63) Fried et al. NEJM 2002

  10. EVR – Treatment Outcome (All Genotypes) PEG IFN alfa-2b 1.5 g/kg + ribavirin 10.6 mg/kg Week 72 Week 12 Start of study No SVR 20% (n=29/143) EVR 76% (n=143/188) SVR 80% (n=114/143 Total study population (n=188) Overall SVR 61% (114/188) SVR 0% (n=0/45) No EVR 24% (n=45/188) No SVR 100% (n=45/45) Davis G, et al. Hepatology 2003

  11. But what about the difficult-to-treat Genotype 1 patients?

  12. EVR – Week 12 in Genotype 1 (Patients HCV RNA negative and patients HCV RNA positive >2 Log at week 12) PEG-IFN α-2a 180 g + ribavirin 1,000-1,200 mg N=298 19% No EVR N=58 81% Achieved EVR N=240 58% Achieve SVR N=139 2% Achieve SVR N=1 PPV=58% NPV=98% Ferenci P et al. J Hepatol 2005;43(3):425-33.

  13. EVR – Week 12 in Genotype 1 (Patients HCV RNA Negative and patients HCV RNA positive >2 Log at week 12) PEG-IFN α-2a 180 g + ribavirin 1,000-1,200 mg N=569 84% Achieved EVR N=477 16% No EVR N=58 58% Achieve SVR N=264 NA% Achieve SVR N=NA PPV=58% NPV=NA Reddy K et al. DDW2005, Abstract # S1540

  14. So are we able to push prediction back further?

  15. Treatment Of Chronic HCVPredicting SVR Over Time PEG-IFN-2a + Ribavirin The later a patient becomes HCV RNA undetectable, regardless of EVR the lower the chance for SVR. HCV RNA + at week 24 P Ferrenci et al. J Hepatology 2005; 43:425-33.

  16. Relapse Rate Relationship to First Time HCV RNA Negativity Data on file Schering-Plough Corp. Adapted Poynard T. et al, Lancet 1998, McHutchison JG, NEJM, 1998, Lindsay K. et al, Hepatology 2001

  17. RAPID VIROLOGIC RESPONSE • Rapid virologic response (RVR) defined as HCV RNA (-) by week 4 • Occurs regardless of the interferon type or if ribavirin utilised or not P Ferrenci et al. J Hepatology 2005; 43:425-33.

  18. RVR- Effect Of Genotype P Ferrenci et al. J Hepatology 2005; 43:425-33. ML Shiffman et al. EASL 2006.

  19. RVR- Frequency P Ferrenci et al. J Hepatology 2005; 43:425-33 ML Shiffman et al. EASL 2006.

  20. Individualisation of Therapy According to HCV Genotype and Viral Load

  21. 89% 85% 81% 74% 50% 71% Manns et al 2001 Zeuzem et al J.Hepatol 2006 • Open multicentre, historical controlled trial to test whether HCV-1 patients with low viral load can be treated with 24 weeks therapy (PEG IFN 2b +Ribavirin 800-1400mg/) • 724 patients screened and 235 enrolled

  22. Virologic response in patients with HCV-1 and HCV RNA < 600,000 IU/mL 89% 80% 75% Patients (%) 50% 37% 25% 17% 8% (47%) (26%) (10%) Time to first negative HCV RNAPEG-IFN a-2b + RBV Zeuzem et al., J Hepatol 2006

  23. Shorter treatment in HCV-2 and HCV-3 ?

  24. Peginterferon alfa-2a 180 µg qw + Ribavirin 1000-1200 mg qd HCV-RNA A N = 71 < 600 IU/mL B N = 153 N = 69 C N = 13  600 IU/mL 0 4 8 12 16 20 24 48 follow-up period weeks v. Wagner, Gastroenterology 2005

  25. End-of-treatment (EOT) and sustained virologic response (SVR)- HCV genotypes 2 and 3 combined - SVR B vs C: P = 0.003 94% 86% 82% 81% 69% Virologic response (%) 39% 67/71 58/71 59/69 56/69 9/13 5/13 (16 weeks) (24 weeks) (24 weeks) v. Wagner et al, Gastroenterology 2005

  26. SHORTENING TREATMENT FOR G2-3RAPID VIROLOGIC RESPONDERS Shortening therapy even in patients with RVR doubles the relapse rate M Von Wagner et al. Gastroenterology. 2005;129:522-527.

  27. Peginterferon alfa-2b 1.0 µg/kg+ Ribavirin 1000-1200 mg qd A N = 70 HCV-RNA B - N = 133 N = 213 C + N = 80 0 4 8 12 16 20 24 48 follow-up period weeks Mangia et al, N Engl J Med 2005

  28. Sustained virologic response (SVR) according to HCV genotype Rx: PEG-IFN alfa-2b 1.0 µg/kg + RBV 1000-1200 mg 87% 77% 76% 76% 72% SVR (%) 41% 40/53 13/17 89/102 24/31 42/58 9/22 (24 weeks) (12 weeks) (24 weeks) Mangia et al, N Engl J Med 2005

  29. HCV Genotypes 2 & 3ACCELERATE TRIAL N=1469 PEGASYS 180 mcg/wk Ribavirn 800 mg/d PEGASYS 180 mcg/wk Ribavirin 800 mg/day 4 16 24 48 0 12 Weeks ML Shiffman et al. EASL 2006.

  30. HCV Genotypes 2 & 3ACCELERATE TRIAL N=1469 * * ML Shiffman et al. EASL 2006.

  31. HCV Genotypes 2 & 3Impact Of Rapid Response Rapid Virologic Response: * * ML Shiffman et al. EASL 2006.

  32. Viral load at baseline Rx duration Wk 4 PCR Wk 12 PCR 48 weeks Neg/2log drop* Stop Pos Pos Neg Low 24 weeks PPV 89% Genotype 1,4-6 48 weeks Neg High PPV75-85% / 46-72% Pos 48 weeks Neg/2log drop* Pos Stop 24G2(48G3) Pos Low 16G2/24G3 Neg Genotype 2,3 PPV 82-90% High 24 weeks Neg Pos 24G2(48G3) Low= <600,000 IUml <3x106 cpm * If 2 log drop then PCR at 24 weeks

  33. HCV Treatment in 2007

  34. SUMMARY OF RECOMMENDATIONS Shorten duration of therapy for Genotype 1 LVL with RVR………………24 weeks instead of 48 Genotype 2 LVL with RVR………………16 weeks instead of 24 Consider lengthening duration of therapy for Genotype 3 who do not have RVR……..48 weeks instead of 24 Do PCR at 4 weeks for everyone If 4 week PCR negative then no need for further PCR till 24 weeks post Rx If 4 week PCR positive then do PCR at 12 weeks. If PCR positive at 12 weeks stop therapy If PCR shows 2 log drop at 12 weeks do PCR at 24 weeks

  35. 48 weeks Pegasys 180 mg QW Ribavirin 800 mg/d 72 weeks EXTENDING TREATMENT DURATION HCV RNA (+) N=165 N=162 96 0 4 72 48 Weeks JM Sanchez-Tapias et al. Gastroenterology 2006; 131: 451-460.

  36. EXTENDING THERAPY Extending the duration of therapy reduced relapse from 47% to 13% P=0.014 JM Sanchez-Tapias et al. Gastroenterology 2006; 131: 451-460. G1 without RVR SVR 28%(48w) vs 44%(72w)

  37. Urgent Treatment Recommended For • Acute HCV • Stable compensated cirrhotics • HCV with cryoglobulinaemia/renal involvement • Occupation where HCV infection is hazardous

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