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Genotype 1 HCV in 2016: Clinical Decision Making in a Time of Plenty

Stay updated with the latest recommendations and regimens for managing HCV Genotype 1 in 2016. Learn about new regimens, recommended treatment options, and important factors to consider in clinical decision-making.

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Genotype 1 HCV in 2016: Clinical Decision Making in a Time of Plenty

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  1. Genotype 1 HCV in 2016: Clinical Decision Making in a Time of Plenty Ira M. Jacobson, MDChair, Department of MedicineMount Sinai Beth IsraelSenior Faculty and Vice-Chair,Department of MedicineIcahn School of Medicine at Mount SinaiNew York, New York Supported by educational grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, and ViiV Healthcare.

  2. About These Slides • Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients • When using our slides, please retain the source attribution: • These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details Slide credit: clinicaloptions.com

  3. Disclosures Ira. M. Jacobson, MD, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; has served on speaker bureaus for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Janssen; and has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen, Merck, and Trek.

  4. New Regimens and Data for Genotype 1 HCV Infection AASLD Guidance Updated February 24, 2016 • AASLD guidance stratifies regimens as “recommended” and “alternative” Slide credit: clinicaloptions.com AASLD/IDSA. HCV guidelines. April 2016.

  5. AASLD: Recommended and AlternativeRegimens for GT1 Without Cirrhosis Nucleotide No nucleotide Slide credit: clinicaloptions.com RecommendedAlternative †If NS5A RAVs present. AASLD/IDSA. HCV guidelines. April 2016.

  6. AASLD: Recommended and Alternative Regimens for GT1 With Compensated Cirrhosis Nucleotide No nucleotide Slide credit: clinicaloptions.com *Not with Q80K. †If NS5A RAVs present. RecommendedAlternative AASLD/IDSA. HCV guidelines. April 2016.

  7. Grazoprevir/Elbasvir: Approved Jan 2016 • Genotype 1a, with/without compensated cirrhosis, treatment naive or treatment experienced • Without NS5A RAVs: GZR/EBR, 12 wks • With NS5A RAVs: GZR/EBR + RBV, 16 wks* • RAVs at positions 28, 30, 31, 93 • Genotype 1b, with/without compensated cirrhosis, treatment naive or treatment experienced • GZR/EBR, 12 wks • RAV testing not indicated Slide credit: clinicaloptions.com *Listed as “alternative” regimen. AASLD/IDSA. HCV guidelines. April 2016.

  8. C-EDGE TN: 12 Wks of GZR/EBR in Genotype 1, 4, or 6 100 • Good safety and tolerability profile • No drug-related serious AEs; 2 deaths unrelated to drug • No concurrent ALT/bilirubin increase • Lower SVR12 rates in pts with BL NS5A RAVs (2/9, 22%); associated with > 5-fold loss of EBR susceptibility • Virologic failure only if baseline HCV RNA > 800,000 IU/mL 99 97 95 100 94 92 80 80 60 SVR12 (%) 40 299/ 316 231/ 246 68/ 70 144/ 157 129/ 131 18/ 18 8/ 10 20 n/N = 0 All Pts 3 1 9 1 0 1 0 0 0 0 0 2 Non-VF Breakthrough Relapse Noncirrhotics Cirrhotics GT1a GT1b GT4 GT6 Slide credit: clinicaloptions.com Zeuzem S, et al. Ann Intern Med. 2015;163:1-13.

  9. C-EDGE TE: 12 or 16 Wks of GZR/EBR ± RBV in Treatment-Experienced GT1, 4, or 6 • Virologic failures driven by RAVs • Analysis from AASLD 2015 shows that presence of baseline NS5A RAVs by population sequencing or next-generation sequencing (with 10% to 20% cutoff) is predictive of failure 97 94 92 92 100 12 wks 80 16 wks SVR12 (%, 95% CI) 60 97/ 105 98/ 104 97/ 105 103/ 106 40 n/N = 20 No RBV + RBV No RBV + RBV 0 Breakthrough Rebound Relapse LTFU/early d/c 0 0 6 2 0060 1241 0003 *ITT population. Slide credit: clinicaloptions.com Kwo P, et al. EASL 2015. Abstract P0886. Jacobson I, et al. AASLD 2015. Abstract LB22.

  10. C-EDGE TE: Efficacy of 12 Wks of GZR/EBR ± RBV by Baseline RAVs • Should baseline RAV testing be done with this regimen? • The NS5A RAVs that matter are in the 28, 30, 31, and 93 positions Slide credit: clinicaloptions.com Kwo P, et al. EASL 2015. Abstract P0886.

  11. C-SURFER: Grazoprevir/Elbasvir in Pts With GT1 HCV and Stage 4/5 CKD • 76% on dialysis • 34% with diabetes • 52% GT1a, 48% GT1b • 6% cirrhosis TreatmentWk 12 Follow-upWk 4 Follow-upWk 16 SVR12* Randomized period GT1 HCV–infected pts with stage 4/5 CKD(n = 224) Grazoprevir/Elbasvir(n = 111) 99% Open-label period Placebo(n = 113) Grazoprevir/Elbasvir(n = 113) 98% Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11) in which pts were treated as in the randomized grazoprevir/elbasvir study group. *Modified full analysis set population. Slide credit: clinicaloptions.com Roth D, et al. Lancet. 2015;386:1537-1545 Roth D, et al. Kidney Week 2015. Abstract SA-PO1100.

  12. Daclatasvir + Sofosbuvir • Genotype 1a or 1b, treatment naive or experienced, without cirrhosis • DCV + SOF, 12 wks • Genotype 1a or 1b, treatment naive or experienced, with compensated cirrhosis • DCV + SOF ± RBV, 24 wks* *Listed as “alternative” regimen Slide credit: clinicaloptions.com AASLD/IDSA. HCV guidelines. April 2016.

  13. DCV + SOF ± RBV for 24 Wks in GT1 Pts With Advanced Liver Disease SVR12 by Genotype 100 98 98 98 97 97 100 96 96 91 92 90 89 80 60 SVR12 (%) 40 20 Slide credit: clinicaloptions.com 0 All GT1 GT1a GT1b As observed DCV + SOF DCV + SOF + RBV mITT DCV + SOF DCV + SOF + RBV Welzel T, et al. EASL 2016. Abstract SAT-275.

  14. Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir • Genotype 1a, treatment naive or experienced • No cirrhosis: OBV/PTV/RTV + DSV + RBV, 12 wks • With compensated cirrhosis: OBV/PTV/RTV + DSV + RBV, 24wks* • RAV testing not indicated • Genotype 1b, with/without compensated cirrhosis, treatment naive or experienced • OBV/PTV/RTV + DSV, 12 wks • RAV testing not indicated Slide credit: clinicaloptions.com *Listed as “alternative” regimen. AASLD/IDSA. HCV guidelines. April 2016.

  15. TURQUOISE III: 12 Wks of OBV/PTV/RTV + DSV Without RBV in Cirrhotic GT1b Pts Virologic Response 100 100 100 100 100 80 60 Pts (%) 40 20 n/N = 60/60 60/60 60/60 60/60 0 RVR EOTR SVR4 SVR12 Slide credit: clinicaloptions.com AASLD guidance now recommends OBV/PTV/RTV + DSV 12 wks withoutRBV for GT1b cirrhotics Still need 24 wks + RBV for GT1a cirrhotics, naive or experienced Poordad F, et al. AASLD 2015. Abstract 1051. AASLD/IDSA. HCV Guidance. April 2016.

  16. Real-World Efficacy of OBV/PTV/RTV ± DSV ± RBV: German HCV Registry Cohort • Efficacy population (complete follow-up): n = 543; safety population (initiated treatment): n = 1017 • GT1: 88%; GT4: 12%; cirrhosis: 22% (CTP B/C: 7%); tx experienced: 59% 100 100 96 95 93 96 96 97 96 97 98 100 80 *Includes 13 pts with mixed or unknown GT1 subgenotype infection, all of whom achieved SVR. 60 SVR24 (%) 40 20 365/378 108/113 246/ 254 51/ 51 121/ 127 26/ 28 93/ 97 2/ 2 200/208 268/ 274 46/ 48 Slide credit: clinicaloptions.com n/N = 0 GT1Total* GT1Total* (peg)IFN ± RBV GT4 GT1a GT1b GT1a GT1b GT4 Naive TVR/BOC + pegIFN + RBV Without Cirrhosis With Cirrhosis Hinrichsen H, et al. EASL 2016. Abstract GS07.

  17. Real-World Efficacy of OBV/PTV/RTV ± DSV ± RBV: Israeli Cohort • Efficacy population (complete follow-up): n = 432; safety population (initiated treatment): n = 661 • GT1: 100%; cirrhosis: 62% (CTP A/B: 98.5%/1.5%); tx exp’d: 62% • Post LT: n = 22 • SVR12 mITT/overall: 82%/86%; 4 discontinued due to serious AEs, one of which achieved SVR 99 99 100 80 No cirrhosis Cirrhosis Pts With Undetectable HCV RNA (%) 60 40 20 161/163 251/ 253 *Excludes pts who did not achieve SVR12 for reasons other than virologic failure. Slide credit: clinicaloptions.com 161/ 163 251/ 253 n/N = 0 SVR12 (mITT*) Zuckerman E, et al. EASL 2016. Abstract PS004.

  18. Real-World Safety of OBV/PTV/RTV ± DSV ± RBV: German and Israeli Cohorts • Most common AEs across both cohorts[1,2]: fatigue, pruritus, headache, insomnia, nausea, diarrhea (Israeli), anemia (German) • Serious AE: 2.1% to 3.8% • D/c for AE: 1.5% to 3.0% • 3 deaths deemed unrelated to HCV therapy: stroke, MI, multiple organ failure • In Israeli cohort, 20 pts discontinued for AEs[2] • Serious AE: n = 12 • Decompensation: n = 8 • In Israeli cohort, several factors identified as significant predictors of hepatic decompensation[2] Slide credit: clinicaloptions.com 1. Hinrichsen H, et al. EASL 2016. Abstract GS07. 2. Zuckerman E, et al. EASL 2016. Abstract PS004.

  19. Ledipasvir/Sofosbuvir for GT1 Tx-Naive Noncirrhotics With HCV RNA < 6 M IU/mL: Are 8 wks sufficient? Or are 12 wks better? • Established by retrospective analysis of ION-3 • Many clinicians were initially uncomfortable • What do “real-world” data show? Slide credit: clinicaloptions.com

  20. 8 vs 12 Wks of LDV/SOF in Pts With GT1 HCV: HCV-TARGET and TRIO Network • Treatment-naive, noncirrhotic pts with GT1 HCV • HCV RNA < 6 M IU/mL in HCV-TARGET HCV-TARGET[1] TRIO Network[2] 97 97 95 96 100 100 80 80 60 60 SVR12 (%) SVR12 (%) 40 40 Slide credit: clinicaloptions.com 20 20 127/131 187/192 251/263 604/632 n/N = 0 0 8 Wks 8 Wks 8 Wks 12 Wks 1. Terrault N, et al. AASLD 2015. Abstract 94. 2. Curry M, et al. AASLD 2015. Abstract 1046.

  21. 8 Wks of LDV/SOF in Pts With GT1 HCV: German Real-World Single-Center Study • Pts noncirrhotic (100%) and primarily treatment naive (97%), GT1 (98%), and HCV RNA < 6 M IU/mL (96%) 99 100 80 60 SVR12 (%) 40 Slide credit: clinicaloptions.com 20 127/128 n/N = 0 8 Wks Buggisch P et al, EASL 2016. Abstract SAT-242.

  22. LDV/SOF: SVR12 by Treatment Regimen and Duration in Pts Without Cirrhosis • Pooled data from multiple trials, HCV RNA < 6 M IU/mL in 8-wk arm With RAVs No RAVs 99 99 99 98 100 80 60 SVR12 (%) 40 Slide credit: clinicaloptions.com 20 30/32 107/108 187/189 504/509 n/N = 0 8 Wks 12 Wks Zeuzem S, et al. AASLD 2015. Abstract 91.

  23. PPIs and Ledipasvir:Does Acid Suppression Matter?

  24. HCV-TARGET: Effect of PPI Use? • Pts treated according to local standards of care at 44 academic/17 community medical centers in North America/Europe • Virologic outcome known for 1074 pts SVR12 According to Baseline PPI Use PPI: No PPI: Yes 98 98 93 93 100 80 60 SVR12 (%) 40 Slide credit: clinicaloptions.com 20 122/ 124 28/ 30 456/ 464 151/ 163 n/N = 0 8-Wk LDV/SOF 12-Wk LDV/SOF Terrault N, et al. AASLD 2015. Abstract 94.

  25. TRIO Network: No Effect of PPI Use? • Real-world data from 2034 pts with GT1 HCV receiving LDV/SOF • A per protocol analysis (n = 1979) showed no effect of PPIs on SVR SVR12 According to Baseline PPI Use 100 100 99 98 98 97 97 80 PPI: No PPI: Yes 60 SVR12 (%) Slide credit: clinicaloptions.com 40 20 230/234 41/ 41 1024/1045 287/297 243/246 113/116 n/N = 0 12 Wks 24 Wks 8 Wks Afdhal N, et al. EASL 2016. Abstract LBP519.

  26. TRIO Network: Predictors of Response to LDV/SOF by PPI Usage • Per protocol analysis (n = 1979) 97% n = 454 PPI drug Dexlansoprazole (n = 10) Esomeprazole (n = 48) Lansoprazole (n = 26) P = .799 Omeprazole (n = 288) “Caution with use of high dose PPIs with LDV/SOF” Pantoprazole (n = 77) Rabeprazole (n = 5) PPI dose Low (n = 282) P = .965 High (n = 172) Slide credit: clinicaloptions.com PPI frequency Once daily (n = 420) P = .030 Twice daily (n = 34) 80% 90% 100% Afdhal N, et al. EASL 2016. Abstract LBP519.

  27. New Regimens

  28. ASTRAL-1: VEL/SOF FDC for 12 Wks in GT1/2/4/5/6 With and Without Cirrhosis • Velpatasvir (GS-5816): pangenotypic HCV NS5A inhibitor • GT3 pts evaluated in separate study • 19% cirrhosis, 32% treatment experienced 99 99 98 100 75 SVR12* (%) 50 Slide credit: clinicaloptions.com 25 618/624 117/118 206/210 n/N = 0 Overall GT1a GT1b *HCV RNA < 15 IU/mL Feld JJ, et al. AASLD 2015. Abstract LB-2.

  29. ASTRAL-4: VEL/SOF FDC for HCV in Pts With Decompensated Liver Disease • Treatment-naive or treatment-experienced pts with GT1-6 HCV infection and CTP B cirrhosis (N = 267) • 55% treatment experienced; 95% MELD < 15; 75% to 83% ascites; 58% to 66% encephalopathy • GT1: 78%; GT3: 15%, GT2/4/6: 8% Wk 0 Wk 12 Wk 24 Wk 36 SVR12 VEL/SOF* n = 90 Slide credit: clinicaloptions.com SVR12 VEL/SOF* + RBV n = 87 SVR12 VEL/SOF* n = 90 *100 mg/400mg Charlton MR, et al. AASLD 2015. Abstract LB-13.

  30. ASTRAL-4: VEL/SOF FDC for HCV in Pts With Decompensated Liver Disease SOF/VEL 12 wks SOF/VEL + RBV 12 wks SOF/VEL 24 wks • RBV arm: Hb < 10 mg/dL, 23%; Hb < 8.5 mg/dL, 7% • RBV decreased in 37% and d/c in 17% • D/c due to AE: 3% (n = 9) • Death due to AE: 3% (n = 9) • Fatigue (29%); nausea (23%); HA (22%); anemia (13%; 31% in RBV arm) • AE more frequent with RBV 94 96 92 100 88 86 83 80 60 SVR12 (%) 40 20 75/90 82/87 77/90 60/68 65/68 65/71 n/N = 0 Overall Genotype 1 Breakthrough, n Relapse, n LTFU, n Death, n - 11 1 3 1 2 - 2 1 7 3 2 - 5 1 2 - 1 - 2 - 3 3 - Slide credit: clinicaloptions.com Charlton MR, et al. AASLD 2015. Abstract LB-13

  31. ASTRAL-5: VEL/SOF FDC for 12 Wks in Pts Coinfected With HCV and HIV-1 SVR12 N = 106 VEL/SOF Wk 0 12 24 100 100 95 95 100 92 92 80 2 relapse 1 LTFU 1 withdrewconsent 60 1 LTFU SVR12 (%) 40 Slide credit: clinicaloptions.com 20 99/104 62/65 11/12 11/11 11/12 4/4 n/N = 0 Total GT1a GT1b GT2 GT3 GT4 Wyles D, et al. EASL 2016. Abstract PS104.

  32. VEL/SOF + GS-9857 for 6 or 8 Wks in Treatment-Naive Pts With GT1-6 HCV Genotype 1 Genotypes 1-6 No Cirrhosis Cirrhosis • 8 wks of VEL/SOF + GS9857 highly effective including pts with RAVs and cirrhosis • Single tablet QD in phase III • 6 wks had high relapse • No benefit of RBV with 8 wks • Will the triplet be used as primary first-line treatment or as salvage treatment for persons who fail current DAAs? 96 100 94 100 100 81 79 71 80 80 60 60 SVR (%) SVR (%) 40 40 20 20 53/67 95/99 25/35 36/36 31/33 25/31 n/N = 0 0 No RBV6 Wks No RBV 8 Wks No RBV6 Wks No RBV8 Wks No RBV8 Wks RBV8 Wks Slide credit: clinicaloptions.com Gane EJ, et al. EASL 2016. Abstract SAT-138.

  33. VEL/SOF + GS-9857 for 12 Wks in Treatment-Experienced GT1-6 HCV • 1 pt relapsed at posttreatment Wk 8 99 100 100 80 60 SVR12 (%) 40 20 n/N = 127/128 63/63 0 Slide credit: clinicaloptions.com Overall GT1 Lawitz E, et al. EASL 2016. Abstract PS008.

  34. SURVEYOR-I/II: ABT-493 + ABT-530 for 8 or 12 Wks in Pts With GT1 or 2 HCV • Open-label, treatment naive or pegIFN/RBV experienced SVR12 in Pts With GT1 HCV 8 wks 12 wks 100 97 96 100 100 80 80 60 60 SVR12 (%) SVR12 (%) 40 40 Slide credit: clinicaloptions.com 20 20 n/N = 33/34 33/33 26/27 0 0 ITT mITT Cirrhosis[2] No Cirrhosis[1] 1. Poordad F, et al. EASL 2016. Abstract SAT-157.2. Gane EJ, et al. EASL 2016. Abstract SAT-135.

  35. C-CREST 1 and 2: MK-3682/GZR/MK-8408 for 8 Wks in Tx-Naive Noncirrhotic Pts • GT1, 2, or 3 without cirrhosis (N = 240) • In GT1 arm, no impact of baseline NS5A, NS3, or NS5B RAVs on SVR12 100 100 87 80 60 40 MK-3682 (300 mg) + GZR + MK-8408 MK-3682 (450 mg) + GZR + MK-8408 20 n/N = 24/24 20/23 0 Genotype 1 Slide credit: clinicaloptions.com Gane EJ, et al. EASL 2016. Abstract 139.

  36. Conclusions • 5 highly effective regimens approved for GT1 HCV • Newest is GZR/EBR, which requires RAV testing in GT1a • Need for extended therapy and/or RBV in cirrhotics depending on regimen, GT1 subtype, and prior treatment status • Real-world data reflect efficacy in clinical trials • Data support 8 wks of LDV/SOF in GT1 treatment-naive noncirrhotics with HCV RNA < 6 M IU/mL • High-dose PPIs should be avoided with LDV (same likely to be the case with VEL based on clinical trial designs) Slide credit: clinicaloptions.com

  37. New Regimens in Development • Promising regimens • VEL/SOF (likely to be approved in June 2016) • Second-generation 2-drug regimen of ABT-493/ABT-530 • Triplet regimens of PI/NS5A/Nuc • New regimens may offer 8-week option for noncirrhotics • High SVR rates in DAA failures Slide credit: clinicaloptions.com

  38. Go Online for More CCO Coverage of HIV! Multimedia modules featuring video of expert faculty discussions of controversies and challenging cases Downloadable slidesets for your own study or presentations clinicaloptions.com/hcv

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