How to Optimize Treatment of non G1 Patients Luncheons PHC Paris January 31, 2012 How to Optimize Treatment of non G1 Patients Alessandra Mangia S. Giovanni Rotondo ITALY

March 14, 2011 49 years old man, BMI: 28 HCV diagnosed in 1998 - previous iv drug and alcohol user - genotype 3, HCVRNA:410.000 IU/ml - liver biopsy: stage 2/3 fibrosis (Metavir) Combination treatment with standard IFN and RBV offered declined Presents in 2011 to be treated with Peg-IFN/RBV new liver biospy offered  declined

Pt understanding of treatment Double combination treatment with Peg-IFN and RBV 800 mg Duration24 weeks SVR rate75%

Counseling What is the response rate with Peg-IFN/RBV? Is treatment recommended now? Can the patient wait? How long? Would a liver biospy guide the treatment making decision process? How do we prepare this patient in light of comorbidities? Is there any way to increase the response rate? What might be the response rate with the coming treatment regimens?

What to do in this pts? Treat now Wait for next therapeutical options Perfom fibrosis evaluation

Which is the likelihood of SVR with the current SOC? SVR is achieved in 65-82% of pts infected with HCV 2 and 3 treated with Peg-IFN alpha plus Ribavirin at approved doses EASL Clinical practice guidelines. J Hepatol 2011

PROPHESYS STUDY: Virological response over time in HCV 2 and 3 patients 92 91 wk4 wk 12 EOT SVR APASL 2012

Metanalisi di Jordan feld Duarte-Rojo A et al J Hepatol 2011

Possible negative predictors

Cirrhosis reduces the response rate Bruno S, Hepatology 2010

Peg-IFN α2a plus RBV in HCV pts with advanced fibrosis and cirrhosis on treatment virologic response N=629 N=189 S.Bruno, Hepatology 2010

Predictors of relapse in 67/476 EOT HCV 2/3 pts with RVR receiving 12 wks of Peg/RBV OR; 95% CI Age >45 years 0.004 - BMI >30 kg / m2 0.0001 2.5; 1.49 – 4.20* Platelet counts <140.000 m3 1.7; 1.03 – 2.70* Peg INF α2b (1.5 μg/kg) + RBV (800-1200 mg) EOT: 96%; SVR: 82%, Relapse: 14% Mangia et al, Hepatology 2009 *independently associated

Which is the expected tx duration in this pt? 1. 12 2. 24 3. 48

Even if RVR+ve... treat for 24 weeks

Which is the most appropriate RBV dose ? AASLD guidelines advise 24 wks course of Peg-IFN and fixed doses of RBV(800 mg) European guidelines recommend 15 mg/kg in HCV 2 and 3 patients with unfavourable baseline predictors

Response rates in GT2 and GT3 100 94 90 84 81 85 82 79 80 80 EOT SVR 60 REL Patients (%) 40 20 11 10 6 4 24 Weeks- LD 24 Weeks- SD 48 Weeks- LD 48 Weeks- SD Hadziyannis S, et al. Ann Intern Med. 2004;140:346-355. 17

SVR rates according to RBV dosage in 673 pts with HCV G2 and 3 wk – 4 R n = 473 wk – 4 NR n = 200 % % 269/356 19/22 110/169 23/30 mg/kg mg/kg Mangia et al EASL 2009

RG Peg-IFN plus RBV tx duration in chronic HCV: meta-analyses of RCT and implications for the future Flat RBV or 12-14 wks course Flat RBV WB-RBV or 16 wks course Di Martino V et al Hepatology 2011

Is it possible to increase SVR extending tx duration?

Sustained Virologic Response Variable Duration Standard Duration Mangia et al, AASLD 2009

Does IL28B matter?

IL28B is associated with increased SVR in non-RVR pts treated for 24 wks Virological response on treatment in HCV G2-3 patients on the basis of IL-28B type. Mangia A Gastroenterology 2010

IL28B in HCV G3 Pts number SVR SVR if RVR+ve RVR-ve Scherzer TM CC CT 71 53 57 (80%) 14 CC 27 (38%) 19 (70%) 18/25 (72%) 1/2 (50%) CT 39 (54%) 31 (79%) 26/29 (89%) 5/10 (50%) TT 5 (7%) 3 (60%) 3/3 (100%) 0/2 Moghaddam 281 226 201 (71%) 81 129 (46%) 99 (77%) 87/108 (81%) 22/22 (100%) 105 (81%) 77/80 (96%) 28/49 (57%) 23 (8%) 22 (96%) 13/13 (100%) 9/10 (90%)

IL 28B: clinical implications in G2 and G3 RVR (+) No role for IL28B 24 wks If IL28B CC RVR (-) 48 wks? DAA? If unfavourable IL28B

What if the patients is tx experienced?

Re-treatment of relapser pts after an initial short course Study Schedule SVR (%) HCV G1 Berg C, 2006 Pegα2a+ RBV >1000 mg/daily 18/35 (51%) HCV G2/3 Mangia A,2009 RBV 1000-1200 mg/daily 30/43 (70%)

Wait for new therapeutical options?

What else is in our therapeutic armamentarium? Agents directly targeting viral functions (DAAs) NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside Nonnucleoside NS5A inhibitors Other viral targets Alternative interferons Agents targeting host cofactors Cyclophillin antagonists miRNA inhibitors

DAAs as components of new treatment paradigm for hepatitis C PR Prospect of shorter treatment duration for a greater proportion of patients 1 x DAA + PR IFN-based 2 x DAAs + PR Slide 6. DAAs as components of new treatment paradigm for hepatitis C IFN-free? IFN-free? 2009 ~2012 2016 Time DAA = direct-acting antiviral; IFN = interferon; PR = pegylated interferon (Peg-IFN) plus ribavirin (RBV) 31

Is the tx safe? Risk/benefit analysis with comorbidities How do we prepare the patient in light of comorbidities?

Safety profile of HCV therapy Contraindications Decompensated cirrhosis Renal insufficiency Advanced cardiac/pulmonary disease Active depression Severe mental illness Anemia, neutropenia, throbocytopenia Lack of compliance

AEs More Frequent in Experimental Arm vs PR Agent AEs More Frequent in Experimental Arm vs PR Discontinuations due to AEs, % (Wk) Boceprevir[1] Anemia, dysgeusia 14 (48) Telaprevir[2] Rash, anemia, pruritus, nausea 10 (48) ANA598[3] Rash incidence and severity increased with 400-mg dose 2 (12) BI 201335[4] Gastrointestinal events, jaundice, and rash* 5 (12) BMS-790052[5] None reported 8 (12) Danoprevir[6] ALT elevation, neutropenia, nausea diarrhea 4 (12) Filibuvir[7] 0 (4) RG7128[8] TMC435[9] Mild bilirubin increases in first 2 wks of therapy 7 (24) Vaniprevir[10] Vomiting with 600-mg dose 0 (6)

Pros Peg/RBV tx Cons Peg/RBV tx Risk of liver disease progression IFN free tx available not earlier than 2017 Possible additional SAE of future Tx Cons Peg/RBV tx Risk of low response rate IFN and RBV related SAE

Conclusions This pt can be treated now with Peg-IFN and weight based RBV for not less than 24 wks Fibrosis re-evaluation is needed IL28B evaluation useful In case of non response….

Thank you

Biomarkers for significant fibrosis and cirrhosis Adjusted AUROC (n=382) Biomarker Significant fibrosis Cirrhosis Fibrometer 0.86 0.90 Fibrotest 0.84 0.87 Forns’ score 0.81 – APRI 0.80 Hepascore 0.89 FIB4 Fibroscan 0.93 Significant fibrosis: AUROCs range from 0.80 to 0.86 with no significant difference between Fibrometer, Fibrotest, Hepascore and Fibroscan Cirrhosis: AUROCs are higher (range 0.87–0.93) with no significant difference Zarski JP, et al. J Hepatol 2011; in press

RG Peg-IFN plus RBV tx duration in chronic HCV: meta-analyses of RCT and implications for the future Flat RBV Weight-based RBV Di Martino V et al Hepatology 2011

SNP near IL28B predicts SVR with PR p = 1.06 x 10–25 p = 2.06 x 10–3 p = 4.39 x 10–3 p = 1.37 x 10–28 SVR (%) rs 129760 predicts SVR -chromosome 19 -3kb upstream of IL28B -P=1.37 x10-28 across all population groups TT TC CC TT TC CC TT TC CC TT TC CC n=102 n=433 n=336 n=70 n=91 n=30 n=14 n=35 n=26 n=186 n=559 n=392 Caucasian African American Hispanic Combined SVR Non-SVR Ge D, et al. Nature 2009; 461: 399–401

Original study protocol Standard-24 (SD) PegIFN + ribavirin for 24 weeks n=68 Variable-12/24 (VD) PegIFN + RBV for 12 or 24 weeks n=200 Week 0 HCV-RNA -ve Treated for 12 weeks n=122 HCV-RNA +ve Treated for 24 weeks n=78 Week 4 Drop out n=2 Drop out n=3 Week 12 Completed n=120 Drop out n=4 Drop out n=1 Completed n=64 Completed n=74 Week 24 * 13 patients did not provide informed consent; genotyping failed in 2 Mangia EASL 2010

. Association of the IL28B genotypes with (A) sustained virologic response, (B) relapse, (C) non-response to (pegylated) interferon-alfa and ribavirin in HCV genotype 2/3 infected patients. Sarrazin C et al. J Hepatol 2010 in press

On-treatment responses in a real-world setting RVR cEVR pEVR 100 80 73 66 60 Patients (%) 40 31 31 27 25 21 17 16 20 11 11 7 G1 (n=3387) G2 (n=740) G3 (n=940) G4 (n=225) Ribavirin prescribed with either PEGASYS or Peg-IFN a-2b in accordance with local label Ferenci P, et al. EASL 2010; poster 256

HCV RNA titre at week 2 G1 (n=887) G2 (n=138) G3 (n=199) G4 (n=45) 100 90 80 70 60 54 Patients (%) 50 47 39 37 40 35 Missing: G1, n=963 (51%); G2, n=140 (49.1%); G3, n=281 (57.7%); G4, n=74 (61.2%) HCVRNA >15 IU/mL not quantifiable: G1, n=38 (2%); G2, n=7 (2.5%); G3, n=7 (1.4%); G4, n=2 (1.7%) 31 33 30 24 21 22 20 20 10 9 10 5 6 7 <15 IU/mL >2-log >1-log to <2-log <1-log (Prophesys) 44 44

Genotypes 2 & 3 treatment duration: ≤ 16 vs 24 wks SVR rates Shiffman, 2007 Yu, 2007 Lagging, 2008 62 %, 94 %, 69% 70 %, 95 %, 78 % ≤ 16 weeks 24 weeks NoRVR Dalgard, 2008 Von Wagner, 2005 81 %, 82 % 91 %, 80 % NoRVR Mangia, 2005 Mecenate, 2008 77 % 76 % noRVR = 64% RVR = 85 % 4 ≤ 16 24 Weeks 45 45 45 45

HCV 2 and 3 pts without RVR Shiffman 2007; Lagging 2008

Genotype 1, high viral load Genotype 1, low viral load Genotypes dictates dose & duration of Tx 800mg x 24 wks 1.0 – 1.2g x 48 wks PegIFN -2a Plus RBV 100 80 60 40 20 16 41 78 51 26 35 53 73 77 61 46 SVR (%) Genotype 1, high viral load Genotype 1, low viral load Genotype 2/3 Hadzyiannis et al, Ann Int Med 2004;140:348-355

Re-treatment of HCV 2 and 3 HALT-C (only 12% of previous IFN/RBV failure) Genotype 1 539 14% 2 31 65% 3 26 54% EPIC C Genotype 2/3 F3 54% . F4 15%

PPV and NPV of RVR in these pts

SVR to PEG IFN+RBV in NRs to IFN+RBV by Genotype 50 37% 40 30 20 % 10 0% Genotype 1 Genotype 2-3 SVR Moucari et al. J Hepatol 2007