1 / 33

Optimal therapy in genotype 2 and 3 patients

This article discusses the optimal treatment options for patients infected with Hepatitis C virus (HCV) genotype 2 or 3, including the use of pegylated interferon and ribavirin, as well as the importance of viral load monitoring. The article also explores different treatment durations and their impact on sustained virological response rates.

maryrock
Download Presentation

Optimal therapy in genotype 2 and 3 patients

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Optimal therapy in genotype 2 and 3 patients Antonio Craxì Liver & GI Unit, Di.Bi.M.I.S., University of Palermo, Italy craxanto@unipa.it

  2. Treatment for patients infected with HCV genotype 2 or 3: the current SOC No liver biopsy or serological markers of disease severity Pegylated interferon + ribavirin 0.8 g per day x 24 weeks HCV RNA detection at end of treatment and 24 weeks later End-of-treatment virological response Sustained virological response

  3. Optimising treatment based on genotype: 48 weeks for G1, 24 weeks for G2/3 PEG IFN alfa2a 180 g plus Ribavirin 24-LD 100 24-SD 84% 81% 80% 79% 48-LD 80 48-SD 60 52% SVR (%) 42% 41% 40 29% 20 96 144 99 153 n= 101 118 250 271 0 Genotype 1 Genotype 2/3 LD = RBV 800 mg/day SD = RBV 1000/1200 mg/day Hadziyannis S, et al. Ann Intern Med 2004; 140: 346

  4. HCV RNA kinetics during antiviral treatment: importance of HCV genotype 0 –1 –2 Mean decline in HCV RNA (log10 copies/mL) –3 –4 Genotype 2 Genotype 1 –5 0 4 10 2 6 8 12 14 Days Neumann A et al. J Infect Dis 2000; 182: 28

  5. Pooled analysis of genotype 2 and 3 patients treated with antivirals for 24 weeks 0 1/64 1/16 1/4 1 4 16 64 1.489 (1.233/1.798) Better Genotype 2 Better Genotype 3 HCV G2: SVR 74% (782/1050) irrespective of viral load HCV G3: • LVL: SVR 75% (405/737) • HVL: SVR 58% (298/500) Andriulli, APT 2008, 28:397

  6. Response rates in genotype 2/3 patients(pooled analysis of Fried, Hadzyiannis, Shiffman) * Not including RVR; ** not including RVR or cEVR Fried MW, et al. J Hepatol 2008; 48 (Suppl 2); Abstract 7

  7. The Good, the Bad and the Ugly The Good • March 2006: • Female, 38 yrs, HCV known since 1999 (surgery 1977) • No alcohol, BW 61 kg, BMI 22 • ALT 3  8 unl • HCV G2, HCV RNA 6.5 x 106 IU/ml • Fibroscan 4.3 KPa, no liver biopsy • April to October 2006: • PEG IFN -2a 180 g/wk + RBV 800 mg, ITT 24 weeks • Excellent tolerance and adherence • RVR at 4 weeks, EVR at 12, ETR at 24 • March 2007: • SVR confirmed YES Overtreatment? NO

  8. The Good, the Bad and the Ugly The Bad • May 2007: • Male, 46 yrs, HCV known since 2004 (no risk factors) • Alcohol 50 gm/day up to 2004, BW 86 kg, BMI 29 • ALT 2 4 unl • HCV G2, HCV RNA 4.3 x 106 IU/ml • Fibroscan 8.1 KPa, biopsy: stage 3 grade 2 Metavir • July 2007: • Starts PEG IFN -2b 1.5 g/Kg/wk + RBV 1200 mg, ITT 24 weeks • Modest tolerability, adherence >80/80/80 • No RVR at 4 weeks, EVR at 12 • October 2007: • Patient decides to stop at 15 weeks, while HCV RNA negative (work problems, tolerability, has heard about short treatments) • December 2007: • HCV RNA positive, ALT flare YES NO Undertreatment (too short)?

  9. The Good, the Bad and the Ugly The Ugly • October 2003: • Male, 39 yrs, HCV known since early ’90s (IVDU in the ’80s) • Alcohol 80 gm/day up to 2003, “stopped?”; BW 102 kg, BMI 34 • ALT 2 5 unl, PLT 104.000/mm3 • HCV G3, HCV RNA 1.8 x 106 IU/ml; HBV and HOV negative • Fibroscan 16.5 KPa, biopsy: stage 4 grade 2 Metavir • F1 esophageal varices • December 2003  May 2004: • Starts PEG IFN -2a 180 g + RBV 800 mg, ITT 24 weeks • Good tolerability, PEG IFN 135 g since week 8 due to cytopenia • No RVR at 4 weeks, EVR at 12, ETR at 24 weeks • October 2004: • HCV RNA positive, ALT flare YES NO Undertreatment (not enough)?

  10. Optimization of treatment for HCV genotype 2 or 3: 2009 Short treatment (12-16 weeks)? HCV genotype 2 or 3 patients - Who needs: Standard treatment (24 weeks)? Extended treatment (48 weeks)?

  11. Shortening Therapy: Study Designs Week 0 Shiffman Gt 2/3 PEG-IFNα-2a 180 µg qwk, RBV 800 mg 16 weeks 24-wk Follow-up n = 732 n = 731 24 weeks 24-wk Follow-up Week 4 Mangia Gt 2/3 PEG-IFNα-2b 1.0 µg/kg qwk, RBV 1000/1200 mg2 n = 133 – 12 weeks 24-wk Follow-up + n = 80 24 weeks 24-wk Follow-up n = 70 24 weeks 24-wk Follow-up • Shiffman ML, et al. N Engl J Med. 2007;357:124-134. • Mangia A, et al. N Engl J Med. 2005;352:2609-2017.

  12. Shorter Treatment Duration? Mangia et al: SVR rates comparableat 12 vs 24 wk (Gt 2/3)* Shiffman et al: Lower SVR ratesat 16 vs 24 wk (Gt 2/3)* Standard duration regimen (24 wk) Standard duration (24 wk) Variable duration (12 or 24 wk) Shorter duration (16 wk) 100 100 P <.001 80 80 P <.001 P = .23 75 82 70 77 60 60 76 66 76 62 62 62 76 SVR, % SVR, % 62 40 40 20 20 (70) (53) (213) (160) (53) (17) (732) (731) (372) (356) (358) (369) 0 0 AnyHCV Gt HCVGt 2 HCVGt 3 AnyHCV Gt HCVGt 2 HCVGt 3 HCVGt 3 * LOD <50 IU/mL Shiffman ML, et al. N Engl J Med. 2007;357:124-134; Mangia A, et al. N Engl J Med. 2005;352:2609-2017.

  13. 35 35 All patients RVR patients 30 30 25 25 20 20 % % 15 15 10 10 5 5 0 0 Shiffman 2007 Mangia 2005 Dalgard 2008 24 wks 12 – 16 wks 0 Relapse rates in Genotype 2 and 3

  14. ACCELERATE Trial: SVR in Patients With and Without an RVR 16 wks SVR 100% 24 wks 80% RVR: 67%(871 / 1291) 60% 40% 20% 82% 90% 0% Patients infected with HCV genotype 2/3(N = 1291) 378/461 370/410 100% 16 wks SVR 24 wks 80% No RVR: 33%(420 / 1291) 60% 40% 20% 27% 49% 0% 55/205 105/215 Shiffman ML, et al. N Engl J Med. 2007;357:124-134.

  15. SVR rate with 16 vs.24 weeks of treatmentin G2/3 patients with an RVR and LVL 16 weeks PEG IFN alfa 2a plus RBV 800 mg/day 24 weeks PEG IFN alfa 2a plus RBV 800 mg/day 95% 100 90% 92% 88% 84% 78% 80 60 SVR (%) 40 20 n=123 n=101 n=43 n=49 n=295 n=260 0 ≤400 000 IU/mL 400–800 000 IU/mL >800 000 IU/mL Standard analysis Shiffman ML, et al. N Engl J Med. 2007;357:124-134.

  16. PEG IFN alfa-2b and RBV for 14 vs 24 weeks in patients with HCV G2 or 3 and rapid virological response Dalgard, Hepatology 2008, 47:35 PEG IFN alfa 2b 1.5 ug/kg, RBV 800-1400 mg

  17. Randomized comparison of 12 or 24 weeks of PEG IFN alfa-2a and RBV in chronic HCV G2/3 infection Relapse SVR NR 100 90 82% 78% 80 70 58% 56% 60 (%) 50 38% 40 31% 30 20 12% 9% 12% 10% 6% 10 5% 0 Genotype 3 (n=139) Genotype 2 (n=55) Genotype 3 (n=137) Genotype 2 (n=49) 12 weeks of treatment 24 weeks of treatment RBV 800 mg Lagging, Hepatology 2008, 47:1837

  18. 0 Meta-analysis of short vs standard therapy in genotypes 2 and 3 patients with RVR 1/64 1/16 1/4 1 4 16 64 1.629 (1.234/2.152) Better Standard Better Short Andriulli, APT 2008, 28:397

  19. 100 80 60 40 20 0 Should Treatment be Intensified in Genotypes 2/3 without RVR ? Retrospective analysis SVR-Rate (%) Relapse Rate (%) 76 67 67 65 26 24 4 13 n=20/30 3/23 n=28/37 n=14/21 n=15/27 n=22/34 n=7/209 n=1/27 PegIFN alfa 2a Riba 800 24 weeks PegIFN alfa 2a Riba 1000-1200 24 weeks Peg IFN alfa 2a Riba 800 48 weeks PegIFN alfa2a Riba 1000-1200 48 weeks 1Fried M et al, N Engl J Med al. 2002 2 Hadziyannis el at. Ann Intern Med 2004 Willems B et al. EASL 2007

  20. Optimization of treatment for HCV genotype 2 or 3: 2009 Cofactors? Short treatment (12-16 weeks)? HCV genotype 2 or 3 patients - Who needs: Standard treatement (24 weeks)? Extended treatment (48 weeks)?

  21. SVR rates in genotype 2/3 patients(pooled analysis of ACCELERATE, Fried, Hadzyiannis) Bruno et al, EASL 2008, poster

  22. Randomized comparison of 12 or 24 weeks of PEG IFN alfa-2a and RBV in chronic HCV G2/3 infection Relapse SVR NR 100 90 83% 80% 80 75% 70 60 45% 45% (%) 50 40 30 14% 20 15% 8% 9% 10% 9% 10 5% 0 ≥ 40 years of age (n=112) < 40 years of age (n=76) ≥ 40 years of age (n=118) < 40 years of age (n=76) 12 weeks of treatment 24 weeks of treatment RBV 800 mg Lagging, Hepatology 2008, 47:1837

  23. RVR and SVR in patients receiving Peg-IFN 2a 135 g + RBV 11 mg/Kg for 24 Weeks Weiland O et al J Viral Hep 2008;15:641-645

  24. Ribavirin dosage and SVR in G2/3 patients Hadziyannis:Ann Intern Med. 2004;140:346-355. Willems et al: J Hepatol, 2006 Volume 46, S1, p S6

  25. p = 0.02 p = 0.12 SVR in G2/3 patients according to schedule and to RBV concentration at 4 weeks 12 weeks 24 weeks Christensen et al, EASL 2008

  26. WIN-R: impact of weight-based RBV dosing on SVR in G2/3 patients Jacobson IM, et al. Hepatology. 2007;46:971-981.

  27. A RCT of RBV 400 mg vs 800 mg/day in combination with PEG IFN -2a Ferenci P et al Hepatology 2008;47:1816-1823

  28. Response-guided treatment for HCV GT 2/3 RVR: a meta-analysis *Irrespective of RBV regimen. †Irrespective of duration of shorter treatment. Di Martino V, et al. AASLD 2008. Abstract 213.

  29. Determinants of relapse after 12 weeks of therapy in 496 patients with HCV G2 or G3 with RVR EOT: 96%: SVR: 82%, Relapse: 14% *independently associated with SVR PEG IFN alfa 2b 1.5 ug/kg, RBV 800-1200 mg Mangia, Hepatology 2009, in press

  30. Re-treatment of 43 relapsers after short therapy with standard (24 wks) treatment duration Mangia et al, J Hepatol 2008; 48 (Suppl 2): S6

  31. Albinterferon -IFN Naïve, Gt 2/3 (Achieve 2/3): SVR Rates 100 80 60 40 20 0 PEG IFN 2a 180 µg wk N=312 alb-IFN 900 µg q2wk N=310 alb-IFN 1200 µg q2wk N=311 P= ns 84.8 79.8 80 SVR Rate, % All Pts (933) ITT analysis; q2wk, every 2 weeks; ribavirin 800 mg flat dose; G2/3 n=420/513 HGS press release, December 8, 2008

  32. R7128 in HCV G 2/3 nonresponders R7128: nucleoside analogue HCV polymerase inhibitor Individual Patient HCV RNA Values Over Time 8 GT 2 R7128 + PegIFN/RBV GT 3 R7128 + PegIFN/RBV 7 GT 2 placebo + PegIFN/RBV 6 GT 3 placebo + PegIFN/RBV 5 4 HCV RNA (log10 IU/mL) HCV GT 2/3 patients with previous treatment failure (N = 25) 3 2 1 R7128 treatment period 0 0 1 2 3 4 5 6 7 8 Weeks • No virologic breakthrough reported • Adverse events similar to previous reports Gane E, et al. AASLD 2008. Abstract LB10.

  33. The G2/G3 RGT algorithm: 2009 on… Week 4 Week 12 Week 24 - - - + + ≥2log - + + <2log - + + + STAT-C ? LVL 16 weeks G2/3 STOP HVL 24 weeks 24 weeks 48 weeks? • Short therapy not to be chosen if F3/F4 fibrosis is present • Age >40 associated to reduced SVR

More Related