Update on hepatitis C: treatment and care and future directions

Update on hepatitis C: treatment and care and future directions Professor Greg Dore Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales; St Vincent s Hospital, Darlinghurst

Hepatitis C update Liver disease progression Staging of liver disease Current therapeutic issues Future directions in therapy

Hepatitis C natural history Determinants of liver disease progression Prior evidence ALT level Alcohol intake Age at infection Co-infection (HIV or HBV) Gender Stage of fibrosis New evidence Obesity/hepatic steatosis Smoking Cannabis No/limited evidence HCV genotype HCV viral load

Hepatitis C liver disease staging Methods Clinical examination Serum transaminases (ALT, AST) Poor correlation with fibrosis Normal in 25% (of whom 30-35% progress to significant fibrosis) Surrogate markers Albumin, prothrombin time, bilirubin Liver biopsy (current gold standard)

Hepatitis C liver disease staging Viral - HBV and HCV Cause Immune - Autoimmune, PBC, PSC Toxic - Alcohol Metabolic - Nonalcoholic fatty liver disease (NAFLD) Genetic - Haemochromatosis Stage - fibrosis F1 F2 F3 F4 cirrhosis

Hepatitis C liver disease staging

Hepatitis C liver disease staging Alternative methods Biochemical surrogate markers APRI (AST/platelet ratio) FIB-4 (age, AST, platelet, bilirubin) Fibrotest Hepascore Transient Elastography (Fibroscan)

Hepatitis C liver disease staging: fibroscan

Hepatitis C liver disease staging: fibroscan 2.5 cm Explored volume 1 cm 4 cm

Hepatitis C liver disease staging: fibroscan Range 2.5 kpa 75 kpa Depth (mm) 20 25 30 35 40 45 50 55 60 65 70 75 80 0 10 20 30 40 50 60 70 80 Depth (mm) 20 25 30 35 40 45 50 55 60 65 70 75 80 0 10 20 30 40 50 60 70 80 Depth (mm) 20 25 30 35 40 45 50 55 60 65 70 75 80 0 10 20 30 40 50 60 70 80 Time (ms) Time (ms) Time (ms) V S = 1.1 m/s V S = 1.6 m/s V S = 3.0 m/s E ~ 3 kpa E ~ 8 kpa E ~ 27 kpa F0 F1 F2 F3 F4 Multiple measurements : success rate should be at least 60% IQR should not be >30% of median value

Hepatitis C liver disease staging: fibroscan

Hepatitis C liver disease staging: fibroscan 711 subjects 95 with cirrhosis 27.5 37.5 49.1 53.7 62.7 kpa No varices (2/3) No Child-Pugh B or C No past history ascites No hepatocellular carcinoma No past history variceal bleeding >90% NPV for above complications Foucher et al 2006

Hepatitis C treatment Sustained Virological Response? PEG-IFN+RBV 24-48 weeks IFN-α2b+RBV 48 weeks 61%-65% PEG-IFN 48 weeks 41% IFN-α2b 48 weeks 25%-29% IFN-α2b 24 weeks 15%-22% 8%-12% 15 years

Hepatitis C treatment HCV treatment through HSD: 2003 2008 Removal of mandatory liver biopsy NCHECR 2009

Hepatitis C treatment Issues Positive Curative potential (50 80%) Improving response rates and clinical experience Government-subsidized Some expansion of access removal of liver biopsy Negative Toxicity: flu-like symptoms, depression, anaemia, lethargy Requirement for contraception during and 6 months following Tertiary hospital focused

Hepatitis C treatment HCV treatment response definitions NR Relapse Viral load RVR EVR ETR SVR 0 4 12 24-48 24 post-rx Treatment weeks

Hepatitis C treatment SVR in RVR HCV genotype 1: PEG-IFN2a/RBV 100 90 80 % 70 60 50 40 30 20 10 0 RVR non-rvr 800 mg x 24 wks 1000/1200 mg x 24 wks 800 mg x 48 wks 1000 / 1200 mg x 48 wks Jensen et al Hepatology 2006 RVR = < 50 IU/ml at week 4; 20%

Hepatitis C treatment Time to respond and SVR: genotype 1 100 Null 20% Week 4 15% Partial 15% Week 12 35% Week 24 15% Ferrenci et al. J Hepatology 2005 SVR (%) 80 60 40 20 0 91 66 45 4 12 24 Week HCV RNA (-)

Hepatitis C treatment Factors associated with poorer SVR HCV genotype 1 HCV viral load (genotype 1) Severe fibrosis cirrhosis High body weight Insulin resistance Age > 40 years African American ethnicity HIV coinfection < 80% adherence (RBV > PEG-IFN)

Hepatitis C treatment SVR rates by fibrosis stage: CHARIOT study (genotype 1) Peg IFN alfa 2a 180 g/wk +RBV Peg IFN alfa 2a 360 g/wk + RBV 100 Virological response (%) 80 60 40 20 0 68% 71% 58% 62% 50% 51% 29% 33% 17/25 20/28 60/104 66/107 57/113 62/121 15/51 15/46 1/16 2/14 69/129 65/117 F0 F1 F2 F3 F4 N/A Metavir Stage of Fibrosis 6% 14% 53% 56% Cheng et al. EASL 2009

Hepatitis C treatment Relapse rates by fibrosis stage: CHARIOT study (genotype 1) Peg IFN alfa 2a 180 g/wk +RBV Peg IFN alfa 2a 360 g/wk + RBV 100 80 Relapse rate (%) 60 40 34 41 60 56 20 10 19 15 15 15 19 0 F0 F1 F2 F3 F4 Fibrosis score by METAVIR Cheng et al. EASL 2009

Hepatitis C treatment Re-treatment considerations Factors associated with non-response: - Unable to alter: genotype, HCV viral load, disease stage - Some ability to alter: obesity, alcohol intake, adherence Prior virological response best predictor of future response: - Relapsers > Non-responders (<2 log) > Null responders (<0.5 log) Some indications: - prior therapy with IFN monotherapy or IFN/RBV - PEG-IFN/RBV genotype 2/3 relapsers (if treated for 24 weeks) - heavy alcohol intake or poor adherence Staging of liver disease: - crucial to determine ongoing management strategy - stronger consideration for re-treatment if F3/4 - HCC screening if F4

Hepatitis C treatment REPEAT study: genotype 1 NR to PEG-IFN-2b/RBV Peg IFN alfa 2a 180 g/wk +RBV Peg IFN alfa 2a 360 g/wk + RBV 100 80 SVR (%) 60 40 20 9% 7% 14% 16% 0 N=313 N=156 48 week duration N=156 N=317 72 weeks duration Jensen DM et al. AIM 2009

Hepatitis C treatment HCV enzymes are targets for new therapies C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 Protease domain NS3 Helicase domain NS3 Bifunctional protease / helicase NS5B RNA-dependent RNA polymerase

Hepatitis C treatment Preclinical Phase I Phase II Phase III Protease inhibitors BILN 2061 VX-950 (Telaprevir) X (mitochondrial-cardiac toxicity) SCH-503034 (Boceprevir) BI 201335 MK-7009 TMC 435350 ITMN 191 Polymerase inhibitors HCV-796 R1626 NM-283 (Valopcitibine) X (hepatotoxicity) X (haematological toxicity) X (git toxicity) R7128 PF 00868554 GS-9190

PROVE 1: Telaprevir Study design: Phase II, genotype 1, treatment naive PR48 (control) (n=80) Placebo + Peg-IFN + RBV Peg-IFN + RBV Follow-up T12/PR12 (n=20) TVR + Peg-IFN + RBV Follow-up T12/PR24 (n=80) TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up T12/PR48 (n=80) TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up Weeks 0 12 24 36 48 60 72 Dosing: Peg-IFN = Peg-IFN alfa-2a 180 µg/week, RBV = RBV 1,000 or 1,200 mg/day, TVR = TVR 750 mg q8h McHutchison EASL 2008

PROVE 1 Early virological responses Week 4 (RVR) Week 12 (HCV RNA undetectable) 100 Subjects with undetectable HCV RNA (%) 80 60 40 20 11 45 59 71 81 68 81 80 0 8/75 PR48 34/75 10/17 12/17 T12/PR12 64/79 54/79 T12/PR24 64/79 63/79 T12/PR48 McHutchison EASL 2008

PROVE 1 Sustained virological response 100 SVR rate (%) 80 60 40 41 35 61* 67* 20 0 31/75 PR48 6/17 T12/PR12 48/79 T12/PR24 53/79 T12/PR48 McHutchison EASL 2008

PROVE 3: Telaprevir Study design: Phase II, PEG-IFN/RBV NRs or relapsers A (n=114) PEG/RBV B (n=113) C (n=115) D (n=111) PEG/RBV TPV PEG/RBV TPV PEG TPV Week 0 24 48 72

PROVE-3 Sustained virological response SVR % 100 90 80 70 60 50 51% 52% 40 30 20 10 14% 23% 0 PEG/RBV48 T24/P24 T12/PR24 T24/PR48 Manns et al EASL 2009

PROVE-3 Sustained virological response SVR % 100 90 80 70 60 50 40 30 20 10 0 PEG/RBV48 T24/P24 T12/PR24 T24/PR48 NR Relapsers Manns et al EASL 2009

Polymerase Inhibitor (R7128): phase II Week 4 RVR (Gen 2/3, Rx experienced) RVR % 100 90 80 70 60 50 40 30 20 10 0 60% PEG/RBV 90% PEG/RBV/R7128 (1500bd) Gane et al AASLD 2008

Hepatitis C treatment Dosing regimens for STAT-C agents Phase Dosing Protease inhibitors Telaprevir III 750 mg q 8 hrly (1250 mg q 12 hrly phase II) Boceprevir III 800 mg tds MK 7009 II 300 600 mg bd BI 2100335 II 120 240 mg daily TMC 435350 II 25 200 mg daily Polymerase inhibitors R7128 II 500 1500 mg bd PF 00868554 II 200 500 mg bd

Hepatitis C update Conclusions Lifestyle factors important to potentially modify: alcohol, diet, smoking Liver disease staging crucial for treatment-decision making HCV genotype 1 response rates remain sub-optimal, particularly in context of advanced disease, high HCV viral load, HIV coinfection Many people should defer to await new therapies, particularly those with genotype 1 (esp high VL) and early liver disease Initial protease inhibitors will have significant additional toxicity, but 2 nd generation should be much more tolerable