Jacob George Predictors of treatment response, baseline and on-treatment

Learning objectives Understand the evolution of HCV therapies over the last decade Be able to define baseline and on-treatment predictors of treatment response following: – Peg-IFN and RBV dual therapy – Triple therapy regimens Understand role of genetic polymorphisms in predicting response Develop an understanding of decision-making in complex patients Understand risks and benefits of HCV therapies

Ms X First seen September yo Caucasian soldier in Australian Army Incidental diagnosis of HCV during medical Born in Australia Smoker: 10 cigarettes/day Alcohol: 30 g/day No medications apart from OCP

Ms X – Past medical history 1970: Jaundice 3 weeks post-transfusion for placenta praevia Tattoos at age 18 Denies IDU; has snorted cocaine Has had body piercing No family history of DM

Ms X – Examinations/Investigations NAD BMI: 18 kg/m 2 Labs: Bili 6 umol/L (0-20) Albumin 40 g/L (38-55) AST 40 U/L (0-40) ALT 41 U/L (0-40) GGT 39 U/L (0-45) FBC Hb 109 g/L ( ) WCC 7.1x10 9 /L (4-11) Platelets294 x10 9 /L ( )

Ms X – Results HBsAg - HBcAb - HCV Ab positive HCV PCR positive Genotype 1a HCV viral load: >850,000 IU/mL

Ms X – Salient features 45 yo female Duration of infection: 31 years Alcohol consumption: Moderate HCV genotype 1a, high vial load What next?

Ms X – Liver biopsy 12 portal tracts Portal activity: 2 Lobular activity:2 Fibrosis stage: 3 Would you treat? Likely response rate?

Omland LH, et al. J Hepatol. 2010;53: Time (years) Cumulative Incidence chronic cleared Liver-related deathsNon–Liver-related deaths Time (years) Cumulative Incidence chronic cleared Standard of care & mortality

307 patients with F3/F4 treated with peg-IFN/RBV: 103 (33%) achieved SVR Cardosa et al. J Hepatol 2010;52: Treatment of HCV prevents complications SVR (n=103) No SVR (n=204) p<0.001 (a) Hepatocellular carcinoma SVR (n=103) No SVR (n=204) p<0.001 (b) Hepatic decompensation Cardosa et al. J Hepatol 2010;52:

Predictors of treatment response Genotype 2 or 3 (not 1, 4) Lower HCV viral load Milder fibrosis (F0-F1 vs F3-4) Lower body weight/insulin resistance Younger Adherence to treatment Female

IDEAL: Importance of adherence peg-IFN 2b 1.5/RBV peg-IFN 2b 1.0/RBV peg-IFN 2a /RBV 80/80/80* 70% (319/456) 74% (327/442) 61% (324/528) Non 80/80/80 16% (87/563) 10% (59/574) 20% (99/507) Data on File, Schering-Plough Corporation. *80% peg-IFN/ 80% ribavirin/ 80% duration. *McHutchison JG, et al. Gastroenterology. 2002;123:1061–1069.

Ms X Shocked by Dx; not keen to start treatment Concerns re. working in army May 2001: Agreed to therapy IFN: 3 miu tiw/RBV (1 g/day) Hb 9.9 at week 5; RBV reduced to 600 mg/day, increased to 800 mg/day Hb stable at 10.2 Week 24: PCR-positive – treatment ceased Nov 2001: What next?

Ms X – Enrolled in EPIC retreatment study Started Rx 28 Jan 2003 Baseline VL: 14,098,837 IU/mL (7.2 log) Peg-IFN 100 ug/mL weekly RBV 400 mg BD Coped with treatment Week 12: HCV RNA: 4,011,628 IU/mL (6.6 log) Patient decided to stop Rx

Ms X – Disappeared from follow up Returned for review in April 2011 Wanting permission to travel overseas with army Examination NAD BMI: 19 kg/m 2

Ms X – Investigations Labs: Bili 10 umol/L (0-20) Albumin 33 g/L (38-55) AST 105 U/L (0-40) ALT 109 U/L(0-40) GGT 214 U/L(0-45) FBC Hb 133 g/L ( ) WCC 4.7x10 9 /L (4-11) Platelets 122 x10 9 /L ( ) AFP 52 IU/ml HCV genotype1a VL 2.77 x10 6 IU/mL

Ms X – What next? CT: No tumour Fibroscan: 15.6 kPa (IQR 1.7) IL28B: rs : CT (N Responder) rs : TT (Responder) IL28B R Rate: 54%

Fischer et al. Hepatology 2012 * * Role of rs and

Ms X – Questions Would you treat? Triple therapy? Wait for 4/5 drug regimen? IFN-free regimen? What are the risks of treatment?

HCV treatment has improved in Asian patients but response rates are still suboptimal in GT1 Yu ML & Chuang WL. J Gastoenterol Hepatol 2009;24: Alfa, peg-interferon alfa; IFN, interferon alfa MU, million units; RBV, ribavirin SVR (%) HCV genotype 1/4 HCV genotype 2/  50  IFN 3MU 24 wks IFN 6MU 24 wks IFN/RBV 24 wks Alfa/RBV 24 wks Alfa/RBV 48 wks ASIAGLOBAL

Ms X Commenced triple therapy Week 2: Hb 10.8, platelets 98, N 2.5 Week 4: Hb 10, platelets 153, N 2.4 HCV VL 1.54E5 IU/mL (17-fold, 5.18 log) Commenced on BOC Week 6: Hb 9.4, Platelets 101, N 1.3

IL28B is a strong baseline predictor of IFN response at end of lead-in (≥1 log decline at TW 4) RESPOND-2 (effect)Odds Ratio (95% CI)p-value IL28B genotype: CC vs. Non-CC4.5 (1.5 – 13.7)0.007 Previous response: relapser vs nonresponder 3.2 (1.6 – 6.4)<0.001 BOC/PR48 vs PR480.2 (0.05 – 0.7)0.01 BOC/RGT vs PR (0.4 – 0.5)0.004 SPRINT-2 (effect)Odds Ratio (95% CI)p-value IL28B genotype: CC vs. Non-CC15.8 (6.3 – 39.8)<0.001 Baseline HCV-RNA: ≤400,000 vs >400, (1.3 – 14.6)0.02 Steatosis 0 vs >02.6 (1.6 – 0.7) Race (non-black vs black)2.1 (1.2 – 3.7)0.007 Gender (female vs male)1.7 (1.1 – 2.6)0.03 BMI: ≤25 kg/m 2 vs >30 kg/m (0.2 to 0.7)0.001

Ms X Week 8: HCV PCR negative, Hb 8.7, platelets 97, N 1.0 Week 10: Hb 8.4, WCC 2.9, platelets 73 N 1.3 RBV reduced to 600 mg Coping with treatment What next?

Multiple stepwise logistic regression model of predictors of SVR including treatment Week 4 response RESPOND-2 (effect)Odds Ratio (95% CI)p-value BOC/PR48 vs PR (4.6 to 28.0)<.0001 BOC/RGT vs PR487.9 (3.3 to 18.9)<.0001 Previous response: relapser vs nonresponder2.2 (1.2 to 4.3)0.01 Log decline in HCV-RNA at TW 4 (continuous variable) 1.8 (1.3 to 2.4)<.0001 BMI: ≤25 kg/m 2 vs >30 kg/m (1.4 to 8.2)0.01 SPRINT-2 (effect)Odds Ratio (95% CI)p-value BOC/PR48 vs PR487.0 (4.1, 12.0)< BOC/RGT vs PR486.0 (3.5, 10.2)< Baseline HCV-RNA: ≤400,000 vs. >400,000 IU/mL5.8 (1.9, 17.5)0.002 Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.0)< Genotype: 1b/others vs 1a2.3 (1.5, 3.6)< BMI: kg/m 2 vs. >30 kg/m (1.4, 3.9)0.002 BMI: ≤25 kg/m 2 vs. >30 kg/m (1.1, 3.3)0.02 Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table.

Ms X Rash on face, cough Husband asked her to see GP ‘Going well’; “I’ll be OK’ Admitted to hospital Week 11 Septic shock All medications ceased

Safety of telaprevir or boceprevir in combination with peg-interferon alfa/ribavirin, in cirrhotic non responders. First results of the French Early Access Program (ANRS CO20-CUPIC) C Hézode 1, C Dorival 2, F Zoulim 3, T Poynard 4, P Mathurin 5, S Pol 6, D Larrey 7, P Cacoub 4, V de Ledinghen 8, M Bourlière 9, PH Bernard 10, G Riachi 11, Y Barthe 2, H Fontaine 6, F Carrat 2, JP Bronowicki 12 for the CUPIC study group (ANRS CO 20) Hôpital Henri Mondor, Créteil 1, UMR-S 707, Paris 2, INSERM U871, Lyon 3, Hôpital de la Pitié-Salpêtrière, Paris 4, Hôpital Claude Huriez, Lille 5, Hôpital Cochin, Paris 6, Hôpital Saint-Eloi, Montpellier 7, Hôpital Haut-Lévèque, Pessac 8, Fondation Hôpital Saint Joseph, Marseille 9, Hôpital Saint André, Bordeaux 10, Hôpital Charles Nicolle, Rouen 11, Hôpital de Brabois, Nancy 12, France

29 French Early Access Program ATU The Temporary Authorisation for Use (ATU) is an Early Access Program for medicinal products which have undergone full clinical development and are waiting for marketing authorisation by the French Health Products Safety Agency (Afssaps) CUPIC Compassionate Use of Protease Inhibitors in viral C Cirrhosis National multicentre observatory in the setting of the ATU Promoter: ANRS Aim: To prospectively collect clinical data and biological specimen

30 Treatment regimen Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up Weeks 72 SVR assessment BOC + Peg-IFN α-2b + RBV Follow-up Peg-IFN + RBV BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day Interim analysis

31 Patients, n (% patients with at least one event)Telaprevir n=296 Serious adverse events (SAEs)*144 (48.6%) Premature discontinuation Due to SAEs 77 (26.0%) 43 (14.5%) Death Septicaemia, septic shock, pneumopathy, oesophageal varices bleeding, encephalopathy, lung carcinoma 6 (2.0%) Infection (Grade 3/4)26 (8.8%) Asthenia (Grade 3/4)14 (4.7%) Rash Grade 3 Grade 4 (SCAR) 20 (6.8%) 2 (0.7%) Pruritus (Grade 3/4)11 (3.7%) Hepatic decompensation (Grade 3/4)13 (4.4%) *407 SAEs in 144 patients; SCAR: severe cutaneous adverse reaction Telaprevir: preliminary safety findings

32 Patients, n (% patients with at least one event)Boceprevir n=159 Serious adverse events (SAEs)*61 (38.4%) Premature discontinuation Due to SAE 38 (23.9%) 12 (7.4%) Death Bronchopulmonary infection, sepsis2 (1.3%) Infection (Grade 3/4)4 (2.5%) Asthenia (Grade 3/4)9 (5.7%) Rash Grade 3 Grade 4 (SCAR) 0000 Pruritus (Grade 3/4)1 (0.6%) Hepatic decompensation (Grade 3/4)7 (4.4%) *158 SAEs in 61 patients; SCAR: severe cutaneous adverse reaction Boceprevir: preliminary safety findings

33 The safety profile of DAAs among compensated cirrhotic patients treated in the CUPIC cohort was poor, but associated with high rates of on-treatment virologic response – Compatible with the use in real-life practice We observed a high rate of SAEs (38.4 to 48.6%) compared to phase III trials results (9 to 14%) and high rate of discontinuation due to SAEs (7.4 to 14.5%) Based on preliminary results of the CUPIC cohort, patients with cirrhosis should be treated cautiously and should be carefully monitored, especially because of a high incidence of anaemia with poor response to EPO SVR rates in a real-world setting are awaited in this population Preliminary conclusions

Summary Baseline and on-treatment predictors of response can aid therapeutic decision making IL28B SNPs are useful in predicting response in CHC Triple therapies have significantly improved cure rates for genotype 1 CHC, but should be used with caution in those with advanced liver disease