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Treatment-experienced HCV genotype 1 patients Bill Sievert Sally Bell.

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2 Treatment-experienced HCV genotype 1 patients Bill Sievert Sally Bell

3 Learning objectives Review definitions of treatment failure and characterisation of previous treatment episodes Understand the impact of interferon sensitivity on DAA treatment outcomes Review treatment outcomes in non-cirrhotic and cirrhotic patients Understand the impact of viral resistance Review futility rules in DAA regimens

4 Ms CM 45-year-old woman with HCV genotype 1 referred for assessment in 2003 Prior IDU Current medications: milk thistle, glutamine, vitamins C/E, ‘liver detox’ and ‘liver gourd’ tablets No EtOH Past history – migraines Family history – eczema, alcoholism

5 Ms CM US – cholelithiasis, normal spleen and liver Liver biopsy – Metavir F3, steatohepatitis

6 Ms CM – 2004 Peg-IFN 2a 180 µg + RBV 1000 mg x 48 weeks On-treatment adverse events – Depression, treated with sertraline – Diarrhoea, treated with loperamide

7 Ms CM – 2004 Virological outcomes – Pre-treatment5.60 log IU/mL – Week log IU/mL – Week 24<2.78 log IU/mL – Week 34not detected – End of treatment (Wk 48)not detected – Follow-up Wk 12detected How would you characterise her virological response?

8 Definitions What’s in a name? Relapse Undetectable HCV RNA at the end of treatment but detectable HCV RNA during follow-up Partial responder ≥2 log 10 decline in HCV RNA at week 12 but detectable at week 24 during therapy Null responder <2 log 10 decline in HCV RNA at week 12

9 Challenges in categorising previous treatment response Lack of detailed records Lack of patient evaluation at key time points on previous therapy Differentiation of previous partial response vs null response – May be unable to characterise decline in HCV RNA levels at key times

10 Ms CM – 2008 Liver tests – Bilirubin6 µmol/L – ALT39 U/L – Albumin39 g/L – Hb158 g/L – Platelets244 X 10 9 /L – INR0.9 Liver biopsy – F 3/4 Genotype 1a What would you advise her to do now?

11 Boceprevir and Telaprevir Telaprevir – ADVANCE: Treatment-naïve patients – ILLUMINATE: Response-guided therapy (treatment naïve) – REALIZE: Treatment-experienced patients (relapse, null and partial response) Boceprevir – SPRINT-2: Treatment naïve patients – RESPOND-2: Treatment-experienced patients (relapse and partial response) Potent inhibitors of HCV NS3/4A protease Both tested in combination with standard-of-care peg-IFN alfa/RBV in phase III studies in chronic HCV genotype 1 infection

12 Week 4Week 48 PR + Placebo Follow-up PR lead-in PR + Boceprevir PR lead-in Week 36Week 72 TW 8 HCV-RNA Undetectable TW 8 HCV-RNA Detectable TW 12 Undetectable PR + placebo Follow-up RESPOND – BOC in relapse + partial responders Control 48 P/R (n=80) BOC RGT (n=162) Boceprevir dose: 800 mg tds PR + Boceprevir PR lead-in Follow-up BOC/ PR48 (n=161) HCV-RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 IU/mL) at week 12 were considered treatment failures. Week 12 futility New Engl J Med 2011;364:

13 PR PR + TVR REALIZE: TVR in HCV relapse, partial response and null responders PR PR + TVR n=132 n=264 n=266 PR Week 12Week 16Week 48Week 72Week 4 Lead-in Follow-Up N Engl J Med. 2011;364:

14 Boceprevir and telaprevir improve SVR rates in naïve and experienced patients SOC, standard of care SVR, sustained virologic response 1. Poordad F, et al. NEJM 2011;364: ; 2. Jacobson IM, et al. NEJM 2011;364: Bacon BR, et al. NEJM 2011;364: ; 4. Zeuzem S, et al. NEJM 2011;364: SVR (%) Treatment-naïve patients 1,2 38–44 Current Standard of Care 63–75 SOC + Protease Inhibitor Δ~ 30% Treatment-experienced patients 3,4 17– SVR (%) 59–66 Current Standard of Care SOC + Protease Inhibitor Δ~ 40%

15 Ms CM – 2008 Enters REALIZE study: TPV 750 mg 8-hourly or placebo + peg-IFN 180 µg/RBV 1200 mg Virological outcomes – Pre-treatment6.23 log IU/mL – Week log IU/mL – Week log IU/mL – Week log IU/mL – FU Week log IU/mL Virological response = ‘non-responder’

16 Ms CM – 2010 Assigned to placebo arm in main study; enters open-label roll-over study: TPV + peg-IFN/RBV Virological outcomes – Pre-treatment6.16 log IU/mL – Week 4not detected – Week 12not detected – Week 24not detected – Week 48not detected – FU Week 24not detected Virological response = SVR = cure

17 Relapser SVR (%) 59%* 83%* 54%* %* 15% 29%* P/R 48 T12/PR 48 24% Non- responder 9% 41%* 5% 33%* T12/PR 48, Lead-in Null responder Partial responder REALIZE: SVR rates according to treatment arm and prior response N Engl J Med. 2011;364:

18 HCV Genotype 1a vs 1b GT nucleotide sequences differ by 30-35% Subtypes differ by 20-25% Genotype 1a less susceptible to NS3 protease, NS5B polymerase, NS5a inhibitors than 1b – Pre-existing mutations more frequent in 1a than 1b – 1a requires only one mutation; 1b requires two (1a has lower genetic barrier to resistance) – Higher rate of virological failure with genotype 1a Kuntzen, et al. Hepatology 2008;48:1769. Gao, et al. Nature 2010;465:96.

19 REALIZE (telaprevir): SVR by HCV subtype and prior response to peg-IFN/RBV 123/140 n/N= 6/3110/34119/14227/401/103/1626/5522/591/201/1724/88 1a1b HCV subtype 1a SVR (%) Zeuzem S, et al. J Hepatol 2011;54(Suppl 1):S3. Prior relapsers Prior partial responders Prior null responders Pbo/PR 48 Pooled T12/PR 48 19

20 REALIZE (telaprevir): SVR rates by IL28B genotype and prior response to peg-IFN/RBV Pol S, et al. J Hepatol 2011;54(Suppl 1):S6. Prior relapsers SVR (%) Prior partial responders Prior null responders Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) CCCT TT CCCT TT CCCT TT 4/12 51/58 6/30100/1173/1029/341/55/82/1033/570/510/144/101/1827/921/1510/32 n/N= n/a 20

21 Response-guided therapy – Telaprevir Non-cirrhotic treatment-experienced patients RGT for previous relapse Full 48 weeks for partial or null response

22 Response-guided therapy – Boceprevir Non-cirrhotic treatment-experienced patients RGT for previous relapse and partial response Full 48 weeks for null responders

23 Mr AB 46-year-old man Office manager HCV diagnosed during insurance examination HCV genotype 1b Blood transfusion at birth (Rh- mother); ‘blood brother’ ritual at age 8 years

24 Mr AB – 2000 Bilirubin17 µmol/L ALT254 U/L Albumin43 g/L Hb177 g/L Platelets252 x 10 9 /L INR1.0

25 Mr AB – 2000 Standard IFN 3 MU tiw + RBV 1200 mg/day (December 2000 – August 2001) Virological outcomes – Pre-treatment9.51 MEq/mL * – Week 12detected – Week 24detected – Week 36detected (ceases Rx) Virological response = ‘non-responder’ * Mega equivalents/mL; Chiron bDNA assay

26 Mr AB – 2003 EPIC 3 study* – peg-IFN 1.5µg/kg/wk + RBV 1200 mg/day x 12 wk If response  complete 48 wk, if not, maintenance peg-IFN or observation Virological outcomes – Pre-treatment5.61 log IU/mL – Week log IU/mL Virological response = null responder Randomised to observation arm (36 months) *Gastroenterology 2009;136(5):

27 Mr AB Poor response to IFN-based regimens in two prior treatment episodes Will IFN responsiveness have an impact on DAA treatment?

28 Concept of lead-in phase Identify interferon-responsive patients Decrease risk of resistance to direct-acting agents Avoid costs and side-effects of direct-acting agents PEG IFN + RBV PEG IFN + RBV + direct acting agent PEG IFN + RBV 4 weeks RVR No RVR

29 SVR by Week 4 PR lead-in response Poorly responsive to IFN <1 log 10 viral load decline at treatment week 4 Responsive to IFN ≥1 log 10 viral load decline at treatment week SVR (%) PR 48 BOC RGT BOC/PR 48

30 Predictive value of response to lead-in in treatment-experienced patients

31 Mr AB Liver biopsy: Feb 2003Metavir F2 Dec 2006Metavir F3 Dec 2008Metavir F3 “moderate fatty change” “at least incomplete cirrhosis” What is the significance of cirrhosis in DAA treatment regimens?

32 REALIZE: SVR by baseline fibrosis stage and previous response N Engl J Med 2011;364: Cirrhosis in combination with prior null response has low SVR

33 Interim analysis of Compassionate Use of Protease Inhibitors in Viral C Cirrhosis (CUPIC) National, multicentre, prospective, observational study of French early-access program Inclusion criteria: – Genotype 1 HCV with compensated cirrhosis (Child-Pugh A) – Previous relapse or partial response to peg-IFN/RBV Patients with null response theoretically excluded (<2 log 10 decrease in HCV RNA at Week 12), although some mistakenly included Primary endpoint: SVR Hezode C, et al. EASL 2012

34 Treatment regimen peg-IFN α-2a + RBV TVR + peg-IFN α-2a + RBV Follow-up Weeks 72 SVR assessment BOC + peg-IFN α-2b + RBVFollow-up peg-IFN + RBV 36 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

35 Telaprevir: Preliminary efficacy data Week 4 Week 8 Week 12 Week % of patients with undetectable HCV RNA 145/ / / / / / / / /251 Per Protocol ITT

36 Boceprevir: preliminary efficacy data Week 4 Week 8 Week 12 Week 16 % of patients with undetectable HCV RNA /155 55/149 88/144 89/126 2/155 55/ /151 89/ Per Protocol ITT

37 Main findings Telaprevir- and boceprevir-based regimens: high rates of SAEs in real-world setting 6 deaths in telaprevir group: sepsis (n=2), pneumopathy (n=1), bleeding of oesophageal varices (n=1), encephalopathy (n=1), and lung carcinoma (n=1) 2 deaths in boceprevir group: bronchopulmonary infection (n=1) and sepsis (n=1) SAE in 38% (BOC) and 49% (TPV) : – High rates of discontinuation because of AEs (7% to 15%) – Grade 3/4 anaemia common with both regimens and responds poorly to erythropoietin Treat cirrhosis patients cautiously; carefully monitor because of a high incidence of anaemia with poor response to EPO and risk of sepsis Hezode C, et al. EASL 2012

38 Mr AB – 2008 Bilirubin17 µmol/L ALT 232 U/L Albumin38 g/L Hb180 g/L Platelets184 x 10 9 /L INR1.1

39 Mr AB – 2008 Enters REALIZE study: TPV 750 mg 8-hourly or placebo + peg-IFN 180 µg/RBV 1200 mg Widespread rash – Day 3: Mild (Rx promethazine) – Week 4: Rash improving (promethazine, Kerri Oil baths, betamethasone cream) – Week 10: “Patchy discoid rash on legs” – Week 12: “Macular rash both legs, lower back” – Week 20: “Discoid erythematous areas of rash”

40 Adverse events associated with NS3 protease inhibitors in clinical trials Alfa=peg-IFN alfa RBV=ribavirin 1. Victrelis™ (boceprevir) US prescribing information. May Incivek™ (telaprevir) US prescribing information. May Adverse Event (%) * Boceprevir + alfa-2b/RBV (n=1225) Alfa-2b/RBV (n=467) Anaemia5030 Dysgeusia3516 Adverse Event (%) † Telaprevir + alfa-2a/RBV (n=1797) Alfa-2a/RBV (n=493) Rash5634 Pruritus4728 Nausea3928 Anaemia3617 Telaprevir 2 Boceprevir 1 * Events occurring at ≥10% with boceprevir+alfa-2b vs alfa-2b/RBV alone in treatment-naïve patients † Events occurring at ≥10% with telaprevir+alfa-2a/RBV vs alfa/RBV alone in treatment-naïve and -experienced patients

41 Mr AB – 2008 Virological outcomes – Pre-treatment6.95 log IU/mL – Week 4<25 IU/mL – Week 12<25 IU/mL – Week log IU/mL (216 IU/mL) What is happening? – FU Week log IU/mL – FU Week log IU/mL

42 Mr AB Converted a null response to peg-IFN/RBV to a breakthrough response to triple therapy Could antiviral resistance to telaprevir contribute to his non-response?

43 Antiviral resistance Barriers to resistance – Genetic: number of amino acid substitutions needed for mutant to acquire full resistance 1 substitution = low barrier 3+ substitutions = high barrier – In vivo fitness and drug exposure Low Barrier DAA – First-generation protease inhibitors (telaprevir, boceprevir) – NS5A inhibitors – Non-nucleoside polymerase inhibitors High barrier DAA – Nucleoside polymerase inhibitors – Cyclophilin inhibitors – ? Second-generation protease inhibitors J-M Pawlotsky. J Hepatol 2012;56:11

44 REALIZE: TVR-resistant variants associated with virologic failure in the TVR/placebo treatment phase LI T12/PR 48 (n=149) T12/PR 48 (n=136) V36M+R155K A156T/V Combinations Not available Wild-type (no TVR-resistant variants) LI T12/PR 48 (n=113) T12/PR 48 (n=126) V36A/M T54A/S R155I/K/M/T A156S Combinations Number of patients Genotype 1aGenotype 1b Lower-levelHigher-level Analysis used population-based sequencing. On-treatment virologic failure: patients who discontinued due to a virologic stopping rule and/or patients with viral breakthrough De Meyer, et al. J Hepatol 2011;54:S475

45 CONFIDENTIAL. FOR ADVISORY BOARD USE ONLY. Not for further distribution. Viral kinetics in patients meeting the >1000 IU/mL HCV RNA Week 4 stopping rule with telaprevir Jacobson I, et al. EASL Abstract 45 Treatment-naïve patientsTreatment-experienced patients Weeks HCV RNA (IU/mL) Weeks HCV RNA (IU/mL)

46 Futility rules – Boceprevir Treatment-naïve and treatment-experienced Jacobson I, et al Hepatology 2012; Accepted Article, doi: /hep.25865

47 Futility rules – Telaprevir Treatment-naïve and treatment-experienced

48 Mr AB – 2012 What can you offer this patient with: Cirrhosis and persistent ALT elevation? Null response to peg-IFN/RBV Breakthrough/partial response to TPV + peg- IFN/RBV Re-treat with boceprevir? Refer for clinical trial?

49 Simple, all-oral, pan-genotypic regimens? Alfa/Lambda + RBV Improved tolerability Favourable IL28B genotypes DUAL: 1-2 x DAAs (±RBV) IFN ineligible/intolerant Genotype 1b, 2/3 Future treatment options for HCV Alfa, peg-IFN alfa; DAA, direct-acting antiviral; IFN, interferon; Lambda, peg-IFN lambda-1a; RBV, ribavirin QUAD: IFN/RBV + 2 x DAAs Difficult-to-treat Null/non-responders Cirrhotics TRIPLE: IFN/RBV + DAA Shortened duration Improved tolerability

50 Modeling first-line DAAs vs Quad therapy for null responders Treat F3/4 with DAA now vs quad therapy in 5 yrs Assumptions: – SVR TPR 42% F3, 14% F4; Quad 90% SVR – Quad rescue AFTER TPR –> PI resistance 80%: SVR reduced by 70% Ewan et al # 991 EASL 2012

51 Using DAAs in treatment-experienced patients Assess prior response, histology, subtype – Relapsers likely to do well on either DAA, even if cirrhotic – Null or partial responders who are cirrhotic, G1a are likely to do poorly SVR low, resistance high 1a >1b (-> need 2 DAAs) Risk of sepsis and SAE significant: Check CP score, MELD Consider trials using quad therapy – Null or partial responders, non cirrhotic, G1b DAAs (SVR 40-55%), trials (new trials 80-90%) or wait

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