A New Era in Hepatitis C Therapy: A Public Health Problem with Solutions Hemant Shah MD MScCH HPTE Clinic and Education Director Francis Family Liver Clinic @ TWH University of Toronto Disclosures • Consulting within the last year: – Boehringer-Ingelheim, Gilead, Idenix, Janssen, Merck, Roche, Vertex Learning Objectives • Analyze the epidemiology of Hepatitis C in Canada • Understand how to evaluate individuals at-risk • Appreciate the evolution of therapy for Hepatitis C • Discuss gaps in Hepatitis C care important to primary and specialty care UNDERSTANDING HCV IN CANADA – THE SCOPE OF THE PROBLEM Hepatitis C in Canada • Widely quoted as: – 0.8% of the population – 79% of those infected know they have it • Based on mathematical modeling by PHAC “Modeling the Incidence and Prevalence of Hepatitis C Infection and its Sequelae in Canada, 2007” http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/pdf/model07-eng.pdf PHAC Results – Prevalence by Risk Group Exposure Category Total Pop in Canada IDU 84,361 Ex-IDU 183,839 Hemophilia 2,162 Transfused 3,325,746 Other 27,624,347 TOTAL 31,220,455 HCV number (rate) 52,512 (62.2%) 87,452 (47.6%) 861 (39.8%) 25,905 (0.78%) 75,790 (0.27%) 242,521 (0.78%) Rate of Diagnosed Patients TOTAL = 192,225 (79% of cases) Canadian Community Health Survey (2012) • Individuals living in private households (i.e. EXCLUDED aboriginals, institutionalized, homeless) • HCV: 0.5% prevalence • HCV: 70% did not know of diagnosis PHAC Results – Prevalence by Risk Group Exposure Category Total Pop in Canada IDU 84,361 Ex-IDU 183,839 Hemophilia 2,162 Transfused 3,325,746 Other 27,624,347 TOTAL 31,220,455 HCV number (rate) 52,512 (62.2%) 87,452 (47.6%) 861 (39.8%) 25,905 (0.78%) 75,790 (0.27%) 242,521 (0.78%) PHAC Results – Prevalence by Risk Group Exposure Category Total Pop in Canada IDU 84,361 Ex-IDU 183,839 Hemophilia 2,162 Transfused 3,325,746 Other 27,624,347 TOTAL 31,220,455 HCV number (rate) 52,512 (62.2%) 87,452 (47.6%) 861 (39.8%) 25,905 (0.78%) 138,121 (0.5%) 304,852 (0.97%) Additional 62,331 Cases Hepatitis C has the Highest Impact of all Infections in Ontario Advanced Liver Disease Increasing Disease State Decompensated cirrhosis HCC Liver-related deaths Estimated Peak Cases 3,380 2,220 1,880 Peak Year 2031 2035 2034 Increase (2013 to 2035) 80% 205% 160% Proportion of HCV with Advanced Disease Increasing 2013 (8.7%) 2035 (23%) Myers et al. Can J Gastro Hep. 2013 TESTING AND ASSESSING THE PERSON AT RISK FOR HCV Who should be screened? Risk Factors • Anyone with abnormal ALT/AST levels • Injection drug use – Annual screen if ongoing use? – Shared inhalational equipment? • • • • • High risk sexual behaviour History of incarceration Blood products or organs prior to 1992 Children born to mothers with HCV From an endemic country Best Practice Document for Ontario Public Health, modified Who should be screened? Risk Factors vs Age-Based • Anyone with abnormal ALT/AST levels • Injection drug use – Annual screen if ongoing use? – Shared inhalational equipment? • • • • • High risk sexual behaviour History of incarceration Blood products or organs prior to 1992 Children born to mothers with HCV From an endemic country • Baby Boomer Cohort (DOB 1945-1975) Best Practice Document for Ontario Public Health, modified HCV tests • Antibody based (2-steps) – Immune recognition of exposure, Not protective • Step 1 negative: NOT exposed • Step 1 positive, step 2 negative: Inconclusive • Step 1 positive, step 2 positive: Exposed • PCR based (HCV RNA) – Genotype (6 major types) – Viral load • Not Detected • Detected but <LLQ • Positive and Quantifiable Screening Algorithm for Hepatitis C Immunocompetent patient at risk of having Hepatitis C Anti-HCV Antibody Negative Positive NOT INFECTED Confirm with HCV RNA (Quantitative) HCV RNA Negative Repeat HCV RNA PCR in 6-12 months to confirm NOT INFECTED HCV RNA Positive Obtain Genotype and refer to l’Actuel Assessment of the HCV+ individual • How active is the hepatitis C? – How quickly is the liver being damaged • How much damage has been done? – How much liver fibrosis • F0-1: minimal • F2: moderate (current threshold for treatment) • F3-4: advanced • Look for extrahepatic disease – Vasculitis • Insurance Status Hep C: Long Asymptomatic Phase Cirrhosis INR Platelets Bilirubin Albumin Symptoms Imaging, Biopsy Approximate Percentage of Patients With Cirrhosis Annual Risk of Progression to Cirrhosis is Low Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis 100 80 Bridging (F3) Portal (F2) None 60 40 20 0 0 5 10 Time (Years) Yano M, et al. Hepatology. 1996;23:1334-1340. 15 20 Survival Excellent Even With Cirrhosis Compensated Survival Probability 100 After first major complication Patients (%) 80 60 40 20 0 0 12 24 36 48 60 72 Mos 84 Patients at Risk 384 376 342 288 236 165 126 79 65 39 21 11 7 4 4 3 Fattovich G, et al. Gastroenterology 1997 Feb;112(2): 463-472. 96 108 120 52 3 39 2 25 1 Fibrosis Assessment Toolkit Non-Invasive • Blood Tests: – – – – – AST:ALT (>1.5) Platelet (<150) APRI (AST:Platelet Ratio) Fibrotest NAFLD Fibrosis Score • Imaging: – Ultrasound/CT/MRI – Fibroscan Invasive • Biopsy – Fibrosis Score APRI • Cirrhosis – Platelets fall – AST > ALT (alcohol) AST/ULN x 100 Platelet count • Limitations – Must be calculated! – <0.5 is good – High is bad • >1.5 L Castera et al. Gastroenterology 2005;128:343 Fibrotest • • • • • • • Age Gender GGT Bilirubin α2-Macroglobulin Haptoglobin Apo-Lipoprotein A1 L Castera et al. Gastroenterology 2005;128:343 Fibroscan • Elastography – Stiffness of the liver • • • • <6: normal 10-14: F3 >14: cirrhosis Up to 75 – Degree of cirrhosis? Tips for Cirrhotic Patients • Compensated – Avoid EtOH, Minimize salt intake, Elective procedures usually ok – Ultrasound q6 months for HCC screen (AFP not recommended – Upper endoscopy q1-2 yrs for variceal surveillance • Decompensated – Elective procedures not ok – Minimize/Eliminate all psychotropic drugs – Monitor MELD score Hepatitis C is a Systemic Disease Haematological • Mixed cryoglobulinemia • Aplastic anaemia • Thrombocytopenia • Non-Hodgkin’s b-cell lymphoma Dermatological • Porphyria cutanea tarda • Lichen planus • Cutaneous necrotising vasculitis Renal • Glomerulonephritis • Nephrotic syndrome Endocrine • Anti-thyroid antibodies • Diabetes mellitus Salivary • Sialadenitis Ocular • Corneal ulcer • Uveitis Vascular • Necrotising vasculitis • Polyarteritis nodosa • Pulmonary fibrosis Neuromuscular • Weakness/myalgia • Peripheral neuropathy • Arthritis/arthralgia Autoimmune Phenomena • CREST syndrome • Granuloma • Autoantibodies Hadziyannis. J Eur Acad Dermatol Venereol. 1998. TREATMENTS FOR HCV: A RAPIDLY CHANGING LANDSCAPE Goal of treatment = SVR (Cure) Treatment 7 Null Response HCV RNA (log10 IU/mL) 6 5 Partial Response 4 3 Relapse 2 1 0 Undetectable RVR -8 -4 -2 0 4 EVR 8 12 ETR 16 20 24 32 Wks After Start of Therapy 40 48 52 60 SVR 72 Why Treat HCV? Long-term follow-up of patients with F3/F4 post-treatment Overall Mortality, % 30 10-yearoccurence occurrence 10-year SVR: 8.9 % (95% CI 3.3-14.5) SVR: 8.9% (95%CI Non-SVR: CI 20.2-28.4) non-SVR: 27.4% 26.0%((5% (95%CI 20.2-28.4) 20 Non-SVR p<0.001 10 SVR 0 0 1 2 3 4 5 6 7 8 9 10 Follow-up time, years SVR Reduces ALL-CAUSE Mortality Van de Meer et al JAMA 2012 The Good News 100% 80% Peginterferon Ribavirin Standard Interferon 2001 1998 60% 1995 40% 2002 1991 DAA 2010 75% 55% 42% 39% IFN/R 12 mo PegIFN 12 mo 34% 16% 20% 6% 0% IFN 6 mo IFN 12 mo IFN/R 6 mo PegIFN/R P/R/DAA 6-12 mo 12 mo Therapeutic Options for HCV Immune-Boosters “Non-Specific” Direct Acting Antivirals “Specific” • Peg-Interferon-alpha (2A or 2B) • Protease Inhibitors – Immune modulation and antiviral properties – Pegasys (2A): fixed dose of 180mcg/week – Pegetron (2B): weight-based dosing • Ribavirin – Purine analogue, exact mechanism unknown – Boceprevir/Telaprevir (1st gen) – Simeprevir • Nucleos(t)ide Analogue: – Sofosbuvir Simeprevir Faldaprevir Boceprevir Telaprevir ABT-450/r Sofosbuvir ABT-333 Daclatasvir Ledipasvir ABT-267 Therapy Decision: What Factors Matter? Patient • Need • Motivation Treatment • Efficacy • Safety/Tolerability • (HIV doesn’t matter!) System • Cost • Capacity Out with the Old…In With the New SMV=1/d BOC = 12/d TVR = 6/d SOF=1/d New Therapy Scorecard Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible Simeprevir Therapy Scorecard (G1 and G4) Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible ✔ ✔ ✔✔ - SVR of ~85% in Well-Selected Patients n/N = 224/ 264 235/ 257 203/ 224 202/ 235 8-15% did not meet RGT  SVR 21-32% Jacobson I, et al. EASL 2013. Abst. 1425. Manns M, et al. EASL 2013. Abst. 1413. Sofosbuvir Therapy Scorecard (G1, 4, 5, 6) Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible ✔✔ ✔✔ ✔✔ ✔ Patients with HCV RNA <LLOQ (%) NEUTRINO Study: Virologic Response by Cirrhosis Status 249/273 50/54 Week 2 269/271 52/54 Week 4 On treatment 267/267 53/53 Week 12 252/273 43/54 Week 12 Post-treatment Lawitz E, et al. EASL 2013. Abst. 1411. AASLD/IDSA Guidelines (USA) IFN ineligible is defined as one or more of the following: Intolerance to IFN, Autoimmune hepatitis and other autoimmune disorders, Hypersensitivity to PEG or any of its components, Decompensated hepatic disease, History of depression or clinical features consistent with depression, A baseline neutrophil count below 1500/μL, a baseline platelet count below 90,000/μL or baseline hemoglobin below 10 g/dL, A history of preexisting cardiac disease SOF + SIM Therapy Scorecard Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible ✔✔✔ ✔✔ ✔✔✔ X COSMOS: Nuc (Sofosbuvir) + PI (Simeprevir) +/- RBV SVR12 Relapse Cohort 1: F0-2 NULL 12 wks SVR12 (%) 100 80 Non-virologic failure Cohort 2: F3-4 NULL/NAIVE 24 wks 12 wks 24 wks 4 96 7 93 4 17 79 7 93 7 93 7 93 7 93 100 26/27 13/14 19/24 14/15 25/27 13/14 28/30 16/16 S/S/R S/S S/S/R S/S S/S/R S/S S/S/R S/S 60 40 20 0 F0-2   F3-4 No breakthrough on therapy – 6 relapses Caveats: small n, no Phase 3 trial  not approved Jacosbson AASLD 2013 LB-3 Lawitz EASL 2014 Abst 165 Sofosbuvir Therapy Scorecard (G2/3) Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible G2 ✔✔ ✔✔ ✔✔ X G3 ✔ ✔✔ XX FUSION: (Treatment Failures) SVR12 by HCV Genotype/Cirrhosis SOF + RBV 16 weeks SVR12 (Percentage) SOF + RBV 12 weeks 25/26 23/23 6/10 No cirrhosis 7/9 Cirrhosis GT 2 14/38 25/40 5/26 No cirrhosis 14/23 Cirrhosis GT 3 Improved SVR with 16 week duration of Sofosbuvir + Ribavirin VALENCE G3 Results 100 85 94 92 87 60 80 SVR12 (%) Overall Noncirrhotic Cirrhotic 60 40 20 0 212/25 212/250 0 Overall 86/92 12/13 87/100 27/45 Naïve, Experienced, Experienced, Naïve, Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic 24 week duration superior to 16 weeks though not head-to-head The Good(er) News 100% 80% Peginterferon Ribavirin Standard Interferon 2001 1998 60% 1995 40% 2002 1991 DAA DAA 2010 2014/5 >90% 75% 55% 42% 39% IFN/R 12 mo PegIFN 12 mo 34% 16% 20% 6% 0% IFN 6 mo IFN 12 mo IFN/R 6 mo PegIFN/R P/R/DAA 6-12 mo 12 mo DAA <3 mo We MUST Increase Treatment…  ~10% ↓ 34% ↓  68% ↓ * * Assumes 30% dx & up to 25% rx’d in 2010. Outcomes at 2020. Davis et al Gastroenterology 2010 Summary • HCV therapy for all nearly here • Funding decisions expected soon • Need to find infected persons and get them into the cycle of care! The Future of HCV Therapy?? Thank You! Merci! HCV AMAZINGOVIR/EXPENSOVIR/CUROVIR