Personalizzazione della Cura in Epatologia. Epatite Cronica C: Pazienti con Genotipo 2

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1 Monotematica AISF 213 Personalizzazione della Cura in Epatologia Pisa, Ottobre 213 Epatite Cronica C: Pazienti con Genotipo 2 Maria Grazia Rumi U.O. Epatologia, Ospedale San Giuseppe Università degli Studi di Milano

2 Prototypes of HCV-2 Naive Patients Indicated to P/R treatment Age: 18 ~7 yrs ALT pattern: normal/near normal elevated Viral load: low high IL28B: CC TT Fibrosis stage: F F4

3 Some Good Reasons to Treat HCV-2 Patients HCV-2 associated with slower fibrosis progression (Marabita, Hepatol 211 & Bochud, J Hepatol 29) but also with sudden ALT flares that lead to rapid progression (Rumi, JVH 22 and Gut 25) HCV-2 associated with higher risk of non Hodgkin lymphoma (Hartridge- Lambert, Hepatology 212) High SVR with 24 Weeks of PegIFN plus Rbv (Grassi E, Liver Int 213; 33 Suppl 1:35-4) Cost and affordability of future DAAs still uncertain

4 AISF & EASL Endorsed Treatment Schedules in HCV-2 Patients AISF EASL PegIFNalfa2b 1.5 µg/kg/wk plus w.b. RBV PegIFNalfa2b 1.5 µg/kg/wk plus RBV 8 mg/day PegIFNalfa2a 18 µg/wk plus w.b. RBV PegIFNalfa2a 18 µg/wk plus RBV 8 mg/day 24 weeks 24 weeks Patients with genotypes 2 and 3 with baseline factors suggesting low responsiveness should receive weight-based ribavirin at the dose of 15 mg/kg per day (C2). AISF PG, DLD 21:81-91; EASL CPG, J Hepatol 211,55:245-64

5 Flat Dose Rbv is Sufficient in HCV-2 Patients FD Rbv + PegIFNα2a WBD Rbv + PegIFNα2a FD Rbv + PegIFNα2b WBD Rbv + PegIFNα2b 1 8 9% 85% 5 4 SVR (%) 6 4 SVR (%) % 4% SVR Rate RELAPSE Rate Rizzetto M et al, J Hepatol 25,42: Jacobson IM et al, Hepatology 27,46:

6 Treatment Optimization by Shortened Duration in HCV-2: a Meta-Analysis of RCTs Mangia, 25 Von Wagner, 25 Dalgard, 28 Shiffman, 27 Yu, 27 Combined 1,6 % (95% CI: -,2 % - 5,6%), p=,47 -,2 -,1,1,3,4 Better short duration Risk Difference Better 24 wk Di Martino V et al, Hepatology 211,54:789-8

7 RVR is the Strongest Predictor of Treatment Outcome in HCV-2 Patients RVR No RVR SVR (%) / / 1 151/ / 48 95/ 1 1/ / 858 7/ 157 Shiffman 27 Rumi 27 Yu 27 Marcellin 212 Grassi E, Liver Int 213; 33 Suppl 1:35-4

8 Treatment Optimization by Shortened Duration in HCV-2: a Meta-Analyses of RCTs HCV-2 Mangia, 25 Von Wagner, 25 Dalgard, 28 Shiffman, 27 Yu, 27 Combined 1,6 % (95% CI: -,2 % - 5,6%), p=,47 Better short duration -,2 -,1,1,3,4 Risk Difference Better 24 wk B.L. features associated with relapse after short Tx: Bridging fibrosis/cirrhosis, high BMI, HVL Di Martino V et al, Hepatology 211,54:789-8

9 Response Guided Treatment Duration in HCV-2 & 3 Patients: The AISF & EASL Clinical Practice Guidelines HCV-RNA Week Neg (RVR) Pos Risk factors (fibrosis, IR) Pos <2log drop or positive at week 24 AISF GL: Although the SVR rates obtained by means of 24 weeks Pos treatment >2log drop in but HCV-2 and HCV-3 negative patients thereafter without (DVR) an RVR are comparatively low, none of available data Neg supports (EVR) the use of longer treatment duration. (CII) Stop Tx weeks of therapy* 24 weeks of therapy 48 weeks of therapy EASL CPG, J Hepatol 211,55:245-64

10 Treatment Extension to 48 wks in HCV-2 & 3 without an RVR: the N-CORE Study 24-wk PegIFN/wbRBV 1 48-wk PegIFN/wbRBV SVR (%) ITT (n = 188) PP (n = 176) Study Completer (n = 153) Odds Ratio % CI P Value Cheinquer H et al, AASLD 212: A156

11 Treatment Extension to 48 Weeks in HCV-2 & 3 Patients with Cirrhosis 112 HCV-2 and HCV-3 pts with bridging fibrosis or cirrhosis (Hadziyannis Trial) Percentage of patients LD 24 SD 7 48 LD 48 SD SVR REL Hadziyannis SJ et al, Ann Intern Med 24;14:

12 Efficacy of PegIFN plus Rbv in HCV-2 Patients with or without Cirrhosis Without advanced fibrosis Bridging fibrosis & cirrhosis SVR (%) EOT SVR Marcellin P et al, Hepatology 212, 51(2):388-97

13 Reduced Efficacy of PegIFN / Rbv in HCV-2 Patients with Advanced Liver Disease 1 1 % 8 Cirrhosis with Portal Hypertension Decompensated Cirrhosis Listed for OLT 8 Listed for OLT SVR (%) Negative at OLT Negative post OLT Di Marco 27 Iacobellis 27 Annichiarico 28 Everson 213

14 Prototypes of HCV-2 Experienced Patients: the Difficult-to-Cure HCV-2 Age > 45 yrs Fibrosis stage > F2 BMI > 25 Diabetes / IR Cryoglobulinemia Indicated to P/R retreatment? Relapser / Non responder

15 Re-treatment of HCV-2 Patients 1 HCV2 48 weeks HCV2 & HCV3 24 weeks HCV2 48 weeks HCV2 24 weeks SVR (%) / 31 3/ 43 44/ 75 33/ 46 Shiffman 24 Mangia 29 Poynard 29 Huang 213

16 New Horizons in Antiviral Therapy for HCV-2 Patients Naives FISSION IFN Not an Option POSITRON Trial Prior IFN Tx FUSION Trial SVR (%) 5 5 Cirrhosis 5 Cirrhosis 68 /7 12 wks SOF+Rbv 52 /67 24 wks P/R 11 /19 12 wks SOF+Rbv 16 /17 31 /36 3 /32 12 wks 16 wks SOF+Rbv 6 /1 7 /9 12 wks 16 wks SOF+Rbv Lawitz E et al, NEJM 213 Jacobson IM et al,nejm 213

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18 Rapid Virological Response (RVR) Rates in HCV 2 Patients Studies PegIFN + Rbv HCV 2 RVR % Dalgard Hep 24 Von Wagner Gastro 25 Rumi AntiVirTher 27 Mangia NEJM 25 Shiffman EASL 26 α2b + wb α2a + wb α2b + wb α2b + wb α2a + fd wb= weight based dose Rbv fd= fixed dose Rbv

19 Decline in SVR Rate with Increasing Fibrosis Severity Patients achieving an SVR (%) PROPHESYS Dual therapy F F1 F2 F3 F4 OPTIMIZE Triple therapy 58.5 F3-F4 n/n 37/63 143/ / /495 26/ /28 SVR = sustained virological response (HCV RNA <5 IU/mL) at 24 weeks after end of treatment Ferenci P, et al. APASL 212. Buti M et al, AASLD 212.

20 Identifying HCV-2 & 3 Patients Who Can Receive a 16-wk Abbreviated Course of PegIFNalfa2a and Ribavirin Similar SVR rates 87% vs 88% in patients with at least 2 positive predictors LVL, <4 yrs, <65 Kg and absence of cirrhosis Diago M et al, Hepatology 21 ; 51(6):

21 The Role of IL28B SNPS as Predictors of Treatment Outcome is Limited in HCV-2 & 3 Patients SVR (%) % % ns 74% 72% 77% ns 81% 96% p=.1 87% 73% 7% 4 2 CC CT TT CC CT TT Mangia et al Moghaddam et al 21 CC CT TT Sarrazin et al Gastroenterology 21;139:821-7 Hepatology 211;53(3): J Hepatol. 211;54(3):415-21

22 Efficacy of PegIFNalfa2a plus Rbv in 818 HCV-2 & HCV-3 Patients with or without Cirrhosis Without advanced fibrosis Bridging fibrosis (no cirrhosis) Cirrhosis Response rates (%) EOT SVR Rel Bruno S et al, Hepatology 21, 51(2):388-97

23 Cirrhosis Decreases SVR in HCV-3 Patients Genotype Pts Staging ETR SVR OR for Relapse HCV S -4 S 5,6 9% 1% 8% 7% ( ) HCV S -4 S 5,6 92% 82% 84% 35% ( ) Rumi MG et al Antiviral Ther 27; Aghemo A et al Antiviral Ther 26

24 RVR is The Strongest Predictor of Treatment Outcome in HCV-2 Patients SVR Reference Patients RVR Non-RVR Shiffman % (21/247) 53% (53/1) Rumi 23 83% (151/182) 52% (25/48) Yu 15 95% (95/1) 77% (1/13) Marcellin % (662/858) 45% (7/157) Grassi E, Liver Int 213; 33 Suppl 1:35-4

25 SVR in HCV-2 Patients to an Abbreviated Course weeks 24 weeks Author RVR No-RVR RVR No-RVR 1) Dalgard 2) Mangia 3) von Wagner 4) Dalgard 5) Shiffman 6) Yu 7) Lagging 91% 87% 95% 93% 62% 78% 94% 1% 56% 71% % 57% 41% % 97% 75% 85% 95% 98% 82% 91% 56% 5% 36% 56% 53% 77% 62% 1) Bridging fibrosis/cirrhosis: 71% vs 95% p=.1 4) Non inferiority margin not reached 5) Relapse rate 16 w vs 24 w: 3% vs 15% p<.1 7) 12 weeks overall inferior to 24 weeks; p<.1

26 Reduced Efficacy of PegIFN plus Rbv in HCV-2 Patients with Advanced Liver Disease 1 % Cirrhosis & portal hypertension Decompensated Cirrhosis Cirrhosis awaiting OLT 1 % Cirrhosis pretransplant Negative at OLT SVR Negative post OLT Di Marco 27 Iacobellis 27 Annichiarico 28 Everson 213

27 Response Guided Treatment Duration in HCV-2 & 3 Patients: The AISF & EASL Clinical Practice Guidelines HCV-RNA Week Neg (RVR) Pos Risk factors (fibrosis, IR) Pos <2log drop or positive at week 24 AISF GL: Althoug the SVR rates obtained by means of 24 weeks Pos treatment >2log drop but in HCV-2 and HCV-3 negative thereafter patients without (DVR) an RVR are comparatively low, none of available data Neg supports (EVR) the use of longer treatment duration. (CII) Stop Tx weeks of therapy* 24 weeks of therapy 48 weeks of therapy EASL CPG, J Hepatol 211,55:245-64

28 New Horizons in Antiviral Therapy for HCV-2 Patients POSITRON Trial Interferon intolerant, unwilling Overall SOF Cirrhosis FISSION Trial Naive Overall SOF FUSION Trial Experienced & cirrhosis HCV-2 1% % 97 1% 96 1 SOF-PR 12 Wks SOF-PR 16 Wks 78 6 SVR HCV-2 HCV-2 25/26 23/23 6/1 7/9 F-2 F3,4

29 Reduced Efficacy of PegIFN plus Rbv in HCV-2 Patients with Advanced Liver Disease 1 Cirrhosis with Portal Hypertension Decompensated Cirrhosis Cirrhosis awaiting OLT 1 % Cirrhosis pretransplant 8 8 SVR (%) Negative at OLT Negative post OLT Di Marco 27 Iacobellis 27 Annichiarico 28 Everson 213

30 High SVR with 24 Weeks of PegIFN plus Rbv in HCV-2 Patients Grassi E, Liver Int 213; 33 Suppl 1:35-4