A New Era in Hepatitis C Therapy: A Public Health Problem with Solutions

Transcription

1 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 TWH University of Toronto

2 Disclosures Consulting within the last year: Boehringer-Ingelheim, Gilead, Idenix, Janssen, Merck, Roche, Vertex

3 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

4 UNDERSTANDING HCV IN CANADA THE SCOPE OF THE PROBLEM

5 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,

6 PHAC Results Prevalence by Risk Group Exposure Category Total Pop in HCV number (rate) Canada IDU 84,361 52,512 (62.2%) Ex-IDU 183,839 87,452 (47.6%) Hemophilia 2, (39.8%) Transfused 3,325,746 25,905 (0.78%) Other 27,624,347 75,790 (0.27%) TOTAL 31,220, ,521 (0.78%)

7 Rate of Diagnosed Patients TOTAL = 192,225 (79% of cases)

8 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

9 PHAC Results Prevalence by Risk Group Exposure Category Total Pop in HCV number (rate) Canada IDU 84,361 52,512 (62.2%) Ex-IDU 183,839 87,452 (47.6%) Hemophilia 2, (39.8%) Transfused 3,325,746 25,905 (0.78%) Other 27,624,347 75,790 (0.27%) TOTAL 31,220, ,521 (0.78%)

10 PHAC Results Prevalence by Risk Group Exposure Category Total Pop in HCV number (rate) Canada IDU 84,361 52,512 (62.2%) Ex-IDU 183,839 87,452 (47.6%) Hemophilia 2, (39.8%) Transfused 3,325,746 25,905 (0.78%) Other 27,624, ,121 (0.5%) TOTAL 31,220, ,852 (0.97%) Additional 62,331 Cases

11 Hepatitis C has the Highest Impact of all Infections in Ontario

12 Advanced Liver Disease Increasing Disease State Estimated Peak Increase Peak Year Cases (2013 to 2035) Decompensated cirrhosis 3, % HCC 2, % Liver-related deaths 1, %

13 Proportion of HCV with Advanced Disease Increasing 2013 (8.7%) 2035 (23%) Myers et al. Can J Gastro Hep. 2013

14 TESTING AND ASSESSING THE PERSON AT RISK FOR HCV

15 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

16 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 ) Best Practice Document for Ontario Public Health, modified

17 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

18 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 HCV RNA Positive Repeat HCV RNA PCR in 6-12 months to confirm NOT INFECTED Obtain Genotype and refer to l Actuel

19 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

20 Hep C: Long Asymptomatic Phase Cirrhosis INR Bilirubin Platelets Albumin Imaging, Biopsy Symptoms

21 Annual Risk of Progression to Cirrhosis is Low Approximate Percentage of Patients With Cirrhosis Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis Time (Years) Bridging (F3) Portal (F2) None Yano M, et al. Hepatology. 1996;23:

22 Survival Excellent Even With Cirrhosis Patients (%) Survival Probability Compensated After first major complication Mos Patients at Risk Fattovich G, et al. Gastroenterology 1997 Feb;112(2):

23 Fibrosis Assessment Toolkit Non-Invasive Blood Tests: AST:ALT (>1.5) Platelet (<150) APRI (AST:Platelet Ratio) Fibrotest NAFLD Fibrosis Score Invasive Biopsy Fibrosis Score Imaging: Ultrasound/CT/MRI Fibroscan

24 APRI Cirrhosis Platelets fall AST > ALT (alcohol) Limitations Must be calculated! <0.5 is good High is bad >1.5 AST/ULN x 100 Platelet count L Castera et al. Gastroenterology 2005;128:343

25 Fibrotest Age Gender GGT Bilirubin α2-macroglobulin Haptoglobin Apo-Lipoprotein A1 L Castera et al. Gastroenterology 2005;128:343

26 Fibroscan Elastography Stiffness of the liver <6: normal 10-14: F3 >14: cirrhosis Up to 75 Degree of cirrhosis?

27 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

28 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

29 TREATMENTS FOR HCV: A RAPIDLY CHANGING LANDSCAPE

30 Goal of treatment = SVR (Cure) HCV RNA (log 10 IU/mL) Treatment Null Response Partial Response Relapse Undetectable RVR EVR ETR SVR Wks After Start of Therapy

31 Why Treat HCV? Long-term follow-up of patients with F3/F4 post-treatment Overall Mortality, % year occurence occurrence SVR: 8.9% % (95%CI ) Non-SVR: non-svr: 27.4% 26.0% ((5% (95%CI ) 20 Non-SVR p< SVR Follow-up time, years SVR Reduces ALL-CAUSE Mortality Van de Meer et al JAMA 2012

32 The Good News 100% 80% 60% 40% Standard Interferon Ribavirin Peginterferon % 42% 39% 34% DAA % 20% 6% 16% 0% IFN IFN IFN/R IFN/R PegIFN PegIFN/R 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo P/R/DAA 6-12 mo

33 Therapeutic Options for HCV Immune-Boosters Non-Specific Peg-Interferon-alpha (2A or 2B) Immune modulation and antiviral properties Pegasys (2A): fixed dose of 180mcg/week Pegetron (2B): weight-based dosing Ribavirin Purine analogue, exact mechanism unknown Direct Acting Antivirals Specific Protease Inhibitors Boceprevir/Telaprevir (1 st gen) Simeprevir Nucleos(t)ide Analogue: Sofosbuvir

34 Simeprevir Faldaprevir Boceprevir Telaprevir ABT-450/r Sofosbuvir ABT-333 Daclatasvir Ledipasvir ABT-267

35 Therapy Decision: What Factors Matter? Patient Need Motivation Treatment Efficacy Safety/Tolerability (HIV doesn t matter!) System Cost Capacity

36 Out with the Old In With the New SMV=1/d SOF=1/d BOC = 12/d TVR = 6/d

37 New Therapy Scorecard Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible

38 Simeprevir Therapy Scorecard (G1 and G4) Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible -

39 SVR of ~85% in Well-Selected Patients n/n = 224/ / / / % did not meet RGT SVR 21-32% Jacobson I, et al. EASL Abst Manns M, et al. EASL Abst

40 Sofosbuvir Therapy Scorecard (G1, 4, 5, 6) Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible

41 NEUTRINO Study: Virologic Response by Cirrhosis Status Patients with HCV RNA <LLOQ (%) 249/273 50/54 269/271 52/54 267/267 53/53 252/273 43/54 Week 2 Week 4 Week 12 Week 12 On treatment Post-treatment Lawitz E, et al. EASL Abst

42 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

43 SOF + SIM Therapy Scorecard Higher SVR (cure rate) Shorter treatment Better tolerated Cheaper and more accessible X

44 COSMOS: Nuc (Sofosbuvir) + PI (Simeprevir) +/- RBV SVR12 Relapse Non-virologic failure Cohort 1: F0-2 NULL Cohort 2: F3-4 NULL/NAIVE SVR12 (%) S/S/R 12 wks 26/27 13/14 S/S F wks /24 S/S/R /15 S/S 12 wks /27 13/14 S/S/R S/S No breakthrough on therapy 6 relapses Caveats: small n, no Phase 3 trial not approved F wks /30 S/S/R 16/16 S/S Jacosbson AASLD 2013 LB-3 Lawitz EASL 2014 Abst 165

45 Sofosbuvir Therapy Scorecard (G2/3) G2 Higher SVR (cure rate) - G3 Shorter treatment Better tolerated Cheaper and more X XX accessible

46 FUSION: (Treatment Failures) SVR12 by HCV Genotype/Cirrhosis SOF + RBV 12 weeks SOF + RBV 16 weeks SVR12 (Percentage) 25/26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis No cirrhosis Cirrhosis GT 2 GT 3 Improved SVR with 16 week duration of Sofosbuvir + Ribavirin

47 VALENCE G3 Results Overall Noncirrhotic SVR12 (%) Cirrhotic /250 86/92 12/13 Overall 0 Naïve, Naïve, Noncirrhotic Cirrhotic 87/100 Experienced, Noncirrhotic 27/45 Experienced, Cirrhotic 24 week duration superior to 16 weeks though not head-to-head

48 The Good(er) News DAA 100% 80% 60% 40% Standard Interferon Ribavirin 34% 1998 Peginterferon % 39% % DAA % 2014/5 >90% 20% 6% 16% 0% IFN IFN IFN/R IFN/R PegIFN PegIFN/R P/R/DAA DAA 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo 6-12 mo <3 mo

49 We MUST Increase Treatment ~10% 34% 68% * * Assumes 30% dx & up to 25% rx d in Outcomes at Davis et al Gastroenterology 2010

50 Summary HCV therapy for all nearly here Funding decisions expected soon Need to find infected persons and get them into the cycle of care!

51 The Future of HCV Therapy??

52 Thank You! Merci! HCV AMAZINGOVIR/EXPENSOVIR/CUROVIR