Clinical Case n. 3 Massimo Puoti AO Ospedale Niguarda Ca Granda Milano, Italy

Clinical Case n. 3 Massimo Puoti AO Ospedale Niguarda Ca Granda Milano, Italy

Disclosures Member of advisory boards &/or speaker in own events &/or investigator in RCT &/or research grants &/or teacher during courses for employees for Janssen, Vertex, MSD, Roche, ViiV, GSK, Abbott, Abbvie, Novartis, BMS, Gilead Sciences, Boehringer Ingelheim, Astellas, Astra Zeneca.

Clinical Case presentation 1: Clinical History Male born on september 1961; non smoker; alcohol < 40 g/d until 1989 then abstinent; married with a 47 years old woman HCV-; 2 sons HCV-; BMI 26 Kg/m 2 Family history of HCV: mother died of HCV cirrhosis at 62yrs.; 1 brother died after LT for decompensated cirrhosis at 40 yrs 1989 Increased aminotrasferases HCVAb+ HCV G1b PLT 90.000/mL 1994 Liver biopsy A2F2 PLT 80.000/mL 1 st cycle of recombinant alpha interferon + RBV 1200 mg/d 1999 HCVRNA late negativization on qualitative assay (< 50 IU/mL) then relapse after treatment withdrawal 2 nd cycle 2001: leukocyte derived alpha interferon + 1200 mg /d RBV + amantadine HCVRNA always positive (no data on quantitative HCVRNA during both treatment cycles). From 2001 to 2010 4 cycles of leukocyte derived interferon alfa duration 1-2 years PLT during treatment 100.000/mL with mild increase above baseline; between interferon courses progressive decrease of PLT count 2004 Fibroscan Stiffness 22.8 IQR 4.2 Succes rate 12%

Clinical case presentation 1: first visit 1 st visit: July 2011 HCVAb+ HCVRNA+ HCV Genotype 1b HBsAg- anti HBc- anti HBs+ (vaccinated) HAVAb IgG + PLT 45.000/mL GGT 54 IU/mL ALT 56 IU/mL AST 44 IU/mL ALP 89 IU/mL INR 1.1 Total Bilirubin 1 mg/dl Albumin 4.6 g/dl Creatinine, urinary stick, blood glucose, triglyceride, cholesterol, transferrin saturation, fibrinogen + alpha 1 antitripsyn in the normal range Anti-LKM, SMA and AMA negative; ANA positive 1/80 homogeneous pattern

Clinical case presentation. Question 1 Summary 50 years old man with chronic hepatitis C and family history of liver disease Fibroscan F4 relapser then non responder to suboptimal anti HCV treatment; ANA reactivity thrombocytopenia; no other comorbidities How to complete diagnostic workup? US & EGDS IL 28 rs12979860 SNP HOMA Vitamin D Review of 1994 histology Haematological consultation A new Fibroscan

Clinical case presentation 3 Review of 1994 histology: Chronic hepatitis C no alpha 1 antitripsin or fibrinogen or copper or iron storage no signs of autoimmune hepatitis IL 28 rs12979860 SNP CT HOMA 5.4 vitamin D normal US no focal lesion irregular margin splenomegaly Fibroscan Stiffnesss 23 KPa IQR 2,1 Success rate 72% EGDS F1 varices no red signs; no congestive gastropathy Haematological consultation: blood tests + BONE MARROW BIOPSY: Diagnosis: Immune Thrombocytopenia

Milan Italy July 2011 Clinical case presentation. Question 2 Telaprevir & Boceprevir still not available; Eltrombopag available and reimbursed for ITP only if PLT < 30.000 EAP for Telaprevir & NPP for Boceprevir planned but still not finalized What to do? Treatment with PEGIFN + RBV off label (PLT < 90.000/mL) Watchful waiting

Clinical case presentation. Question 3 The patient was not treated and started follow up December 2011: 2 liver focal lesion segment IV diameter 2.2 cm and segment II 1,1 cm near gallbladder NMR : HCC Liver function and liver enzymes: stable Two nodules of HCC in a CTP A5 cirrhosis with MELD 7 and portal hypertension (Esophageal varices) ; RFTA or PEI not feasible What to do? TACE + listing for OLT Liver resection What about anti HCV Tx?

Clinical case presentation 4 Consultation with the transplant team: Liver resection then listing for OLT in case of relapse Anti HCV treatment if no HCC lesions at 3 mo. January 2012 laparoscopic Da Vinci robot assisted liver resection II & IV segment + cholecistectomy Histology: two nodules of 2 and 1 cm grade II HCC without microvascular invasion; micronodular cirrhosis with chronic hepatitis April 2012: NMR no HCC relapse. PLT 29.000/mL INR 1.1 Bilirubin 1 mg/dl. AST 76 ALT 90 GGT 65 normal creatinine Not eligible for Telaprevir EAP and Boceprevir NPP planned Eltrombopag then request for Telaprevir NPP

Clinical case presentation 5 Eltrombopag was started at 25 mg/d on may 29 th 2012 PLT >90.000 after 2 weeks Maintenance: Eltrombopag 25 mg 1-3 pills week Telaprevir NPP was requested Telaprevir (still not reimbursed by Italian NHS) Patient started: Telaprevir 750 mg thrice daily + Pegasys 180 mcg weekly + Ribavirin mg 600 bid on June 13th 2012

Clinical case presentation 6 Date 13/6 21/6 28/ 6 5/7 12/7 19/7 26/7 09/08 16/08 06/09 13/09 PLT 165 193 105 56 48 91 114 81 68 59 76 N 1920 1890 174 0 119 0 810 1410 1000 830 940 910 740 Hb 15.6 14.5 12.7 11.3 11.6 11.9 12.4 12.5 12.3 11.1 11.1 ALT 81 97 69 74 77 89 84 96 97 84 125 INR 1.25 1.19 1.18 1.20 1.27 1.23 1.17 1.18 Total Bil 0.92 2.41 2.52 2.04 1.67 1.16 0.96 1.14 1.09 1.27 Alb 4.35 4.31 4.26 4.14 4.16 4.34 4.04 4.15 4.15 4.13 HCVRNA IU/mL Abbot HCVRNA IU/mL Roche Eltrombopag 25 mg 181745 153 <12 <LLD <12 <12 <12 <LLD <LLD <12 <LLD <LLD <LLD <LLD 1/w 1/w 1/w 3/w 3/w 3/w 2/w 2/w 2/w 2/w 3/w

Clinical case presentation 7 During treatment: Mild rash treated with antihistamine + topical steroids Anal discomfort treated with local lidocaine No flu like symptoms; no infections Optimal adherence to treatment On July NMR non HCC lesions On September 6 th 2012 stop Telaprevir

Clinical case presentation Question 4 Date 04/10 PLT 70 N 680 Hb 10.9 ALT 100 INR 1.14 Total Bil 1.4 Alb 4.19 HCVRNA Abbott <12 HCVRNA roche <LLD Eltrombopag 25 mg 2/w N < 750. NMR on October no HCC lesions What to do? Decrease PEGIFN from 180 135 mg/w Add G-CSF Stop anti HCV Tx

Clinical case presentation 8 Date 04/10 19/10 02/11 30/11 13/12 PLT 70 71 62 51 44 N 680 790 780 750 750 Hb 10.9 11.2 11.5 11.4 10.8 ALT 100 107 122 111 110 INR 1.14 1.12 1.18 1.2 Total Bil 1.4 1.5 1.52 1.62 1.26 Alb 4.19 4.11 4.10 4.11 4.31 HCVRNA Abbott IU/mL <12 <LLD <12 <12 175 HCVRNA Roche IU/mL <LLD <LLD 95 Eltrombopag 25 mg 2/w 2/w 2/w 2/w 3/w G-CSF IU 1/w 1/w 1/w 1/w

Clinical case Question 5 HCV cirrhosis recent resection for HCC On eltrombopag for ITP Late breakthrough HCVRNA (24 th week) after P+R+T 12 w + PR 12 w What to do: Stop P+R Continue P+R Continue P+R and add Boceprevir

janu Clinical case presentation 9 Date 04/10 19/10 02/11 30/11 13/12 09/01 PLT 70 71 62 51 44 49 N 680 790 780 750 750 790 Hb 10.9 11.2 11.5 11.4 10.8 11.6 ALT 100 107 122 111 110 110 INR 1.14 1.12 1.18 1.2 1.2 Total Bil 1.4 1.5 1.52 1.62 1.26 1.51 Alb 4.19 4.11 4.10 4.11 4.31 4.23 HCVRNA Abbott <12 <LLD <12 <12 175 2439 HCVRNA roche <LLD <LLD Eltrombopag 25 mg 2/w 2/w 2/w 2/w 3/w 3/w G-CSF IU 1/w 1/w 1/w 1/w 1/w January 2013 NMR no HCC relapse. P & R were withdrawn