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Hepatitis C coinfection update 2014

Hepatitis C coinfection update 2014. Andrea L. Cox, MDPhD Associate Professor Viral Hepatitis Center. Disclosures. Nothing to disclose. Outline- what is new in HCV?. Importance of HCV. Evaluation of HCV and the need for Rx New therapies- summary of the landscape in 2014 and beyond

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Hepatitis C coinfection update 2014

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  1. Hepatitis C coinfection update 2014 Andrea L. Cox, MDPhD Associate Professor Viral Hepatitis Center

  2. Disclosures • Nothing to disclose.

  3. Outline- what is new in HCV? • Importance of HCV. • Evaluation of HCV and the need for Rx • New therapies- summary of the landscape in 2014 and beyond • Need for and prospects for a prophylactic HCV vaccine

  4. Hepatitis C: A Global Perspective 170-200 Million Carriers Worldwide Far East Asia 60 M Eastern Europe 10 M Western Europe 5 M US 3-4 M South East Asia 30-35 M Americas 12-15 M Africa 30-40 M Australia 0.2 M World Health Organization, 1999.

  5. HCV is a significant problem • Leading cause of ESLD, HCC in US and many other countries • HCV kills 10,000-15,000 annually

  6. Hepatitis C mortality is rising. Mortality Rates of HBV, HCV and HIV: United States, 1999-2007 1 HIV HCV HBV • Adapted from Ly KN, et al. Ann Intern Med. 2012;156:271-278.

  7. Natural History of HCV Infection Exposure (Acute phase) 75% 25% HIV Chronic Resolved 80% 20% Cirrhosis Stable 25% 75% Slowly Progressive HCC Transplant Death Alter MJ, Semin Liver Dis, 1995. Management of Hepatitis C, NIH Consensus Statement, 1997.

  8. Prevalence of HIV/HCV Coinfection • Johns Hopkins HIV clinic • Urban setting • Prospective, longitudinal database • HCV-coinfection clinic established in 1997 • 1742 HIV-infected patients screened for HCV infection (1997-2000) • HCV+: 798 patients HIV/HCV Coinfection Prevalence by Risk Factor 84.1% Prevalence of Antibody HCV+ (%) 45.1% 14.3% 9.8% IDU Hetero- Homo- Entire sexual sexual Cohort sex sex Sulkowski MS, et al. Hepatology. 2000;32. Abstract 204.

  9. Liver Disease is the Second Leading Cause of Death in HIV-Infected Patients (1999-2004) Of 23,441 HIV infected, 1246 Deaths Percent of deaths Weber R, et al. Arch Intern Med. 2006;166:1632-1641.

  10. HIV coinfection is associated with accelerated liver disease progression Cirrhosis (%) 0 5 10 15 20 25 30 Years Thein H-H et al. AIDS. 2008;22:1979-1991.Thein H-H et al. Hepatology. 2008;48:418-431.

  11. HCV cure is associated with survival in HIV/HCV coinfected patients Limketkai et al. JAMA. July 25, 2012,308(4):370-378

  12. Mortality increase can be stopped… Mortality Rates of HBV, HCV and HIV: United States, 1999-2007 1 Declines in mortality similar to those seen with HIV and HBV will be facilitated by a commitment to detect and link infected persons to care and successful treatment and a prophylactic vaccine. • Adapted from Ly KN, et al. Ann Intern Med. 2012;156:271-278.

  13. Effective HCV treatment is rarely achieved– HIV/HCV Baltimore (Population based cascade) HIV/HCV coinfected patients attending the Johns Hopkins HIV clinic 1999-2003 Mehta SH et al, AIDS, 2006

  14. HCV treatment cascade is not unique – HCV Veterans, USA (Population based)

  15. Why aren’t people with HIV treated for their HCV? Knowing when to treat is hard • Staging has required biopsy • Deciding when to refer is a challenge

  16. Why aren’t people with HIV treated for their HCV? Knowing when to treat is hard Therapy is suboptimal Many side effects Low rate of efficacy • Staging by biopsy • Deciding when to refer is a challenge

  17. How to stage Accepted staging methods • Liver biopsy • Blood markers • Fibroscan

  18. How to stage Accepted staging methods Not for staging Viral load HCV genotype Ultrasound CT scan or MRI • Liver biopsy • Blood markers • Fibroscan

  19. Stages of Fibrosis in Chronic Hepatitis Periportal Portal 1 2 3 4 Septal Cirrhosis

  20. Experience/tradition Other forms of liver disease (steatosis) Informs treatment and HCC screening Predicts ESLD (HIV neg) Liver Biopsy is an Imperfect Method to Stage Liver Fibrosis Pro-Biopsy

  21. Experience/tradition Other forms of liver disease (steatosis) Informs treatment and HCC screening Predicts ESLD (HIV neg) 1/3000 risk of major complication $1500-2,000 USD Limited availability Limited repeatability Limited validity Liver Biopsy is an Imperfect Method to Stage Liver Fibrosis Pro-Biopsy Anti-Biopsy

  22. Samplingerror of liverbiopsy Fibrosis area: 65% Fibrosis area: 15% Courtesy of M. Pinzani, Florence

  23. Fibrotest1: α2-macroglobulin, apolipoprotein A1, GGT, haptoglobin, total bilirubin SHASTA2: hyaluronic acid, albumin, AST Fib-43: age, AST, platelet count, ALT Forns4: platelet count, GGT, age, cholesterol APRI5: AST, platelet count Serum Markers of Liver Fibrosis in HIV/HCV Coinfected Persons 1Myers AIDS 2003; 2Kelleher JAIDS 2005; 3Sterling Hepatology 2006; 4Forns Hepatology 2002; 5Wai Hepatology 2003

  24. Validity of Noninvasive Methods of Detecting Significant* Liver Fibrosis *Metavir 2-4, MHAI 3-6 (except FIB 4 Metavir 3-4) 1Myers AIDS 2003; 2Kellener J Hepatol 2005; 3Sterling Hepatology 2006- MHAI 0-3 vs. 4-6; 4Maciás Gut 2007

  25. TRANSIENT ELASTOGRAPHY • Measures elasticity using sound waves • Stiffness determined by • Degree of Fibrosis • Degree of Inflammation • Degree of Steatosis • Approved in the US in 2013 J Gastrointestin Liver Dis. 2008 Jun;17(2):155-163 J Gastrointestin Liver Dis. 2008 Jun;17(2):155-163

  26. Validity of Fibroscan Versus Liver Biopsy

  27. Validity of Fibroscan Versus Liver Biopsy

  28. Why aren’t people with HIV treated for their HCV? Knowing when to treat is hard Therapy is suboptimal Many side effects Low rate of efficacy • Staging by biopsy • Deciding when to refer is a challenge

  29. Interferon adversely impacts nearly every body system Sulkowski MS et al. Nature Reviews Gastroenterol Hepatol 2011;8:212–223

  30. HIV/HCV coinfected patients have more comorbid medical and psychiatric conditions that may complicate HCV care Butt A. Alimentary Pharmacology & Therapeutics Volume 24, Issue 4, Pages 585-591. 2006

  31. HIV/HCV coinfected patients have more comorbid medical and psychiatric conditions that may complicate HCV care Butt A. Alimentary Pharmacology & Therapeutics Volume 24, Issue 4, Pages 585-591. 2006

  32. HIV/HCV coinfected patients have more comorbid medical and psychiatric conditions that may complicate HCV care Butt A. Alimentary Pharmacology & Therapeutics Volume 24, Issue 4, Pages 585-591. 2006

  33. Multiple HCV Proteins Can Serve as Targets for DAAs Structural Proteins Nonstructural (NS) Proteins Phospho/RNA binding protein Serine protease/RNA helicase RNA-dependent RNA polymerase Nonnucleoside and nucleoside inhibitors NS5A antagonists PIs (boceprevir/telaprevir) NS3 NS5A NS5B HCV proteins with approved DAAs or DAAs in development Cytosol ER membrane CORE p7 NS2 NS4A NS4B ER lumen E1 E2 Adapted from Moradpour et al. Nat Rev Microbiol. 2007;5:453-463.

  34. 2013: DAA Regimens in Phase 3 Trials *Genotype 2 or 3; †Genotype 1b only

  35. Standard of Care for Treatment of chronic HCV Infection – December 2013

  36. FISSION Study: Treatment Naïve, Genotype 2 or 3 Patients 0 12 24 Week 36 SOF + RBV*, n=256 SVR12 Peg-IFN + RBV* (SOC), n=243 SVR12 *RBV dose 1000-1200 mg/day for SOF + RBV and 800 mg/day for Peg-IFN + RBV Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 5.

  37. FISSION: SVR12 by Genotype and Cirrhosis SVR12 (Percentage) 58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No cirrhosis Cirrhosis No cirrhosis Cirrhosis GT 2 GT 3 Error bars represent 95% confidence intervals. Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 5.

  38. FISSION: Adverse Events *p-value from 2-sided Fisher exact test.

  39. Significantly less anemia vs. PR No neutropenia Fission: SOF +RBV Adverse Events

  40. NEUTRINO Study: Design 0 12 Week 24 • Open label • SOF 400 mg QD + Peg-IFN-alfa-2a 180 µg/week + RBV 1,000‒1,200 mg/day for 12 weeks (no response-guided therapy) • Treatment-naïve, genotype 1, 4, 5, and 6 HCV-infected patients • 20% of patients with cirrhosis SVR12 SOF + PegIFN + RBV, n=327 Lawitz E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1411.

  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 Error bars represent 95% confidence intervals. Lawitz E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1411.

  42. QUEST-1/2: Trial Design for GT1, Treatment-Naïve Patients Response Guided Treatment • RGT in simeprevir arm: if HCV RNA <25 IU/mL at week 4 and undetectable at Week 12, complete treatment at Week 24 Post-Therapy Follow-Up Post-Therapy Follow-Up Placebo + PR SMV 150 mgQD+PR PR PR PR PR Post-Therapy Follow-Up N=264 N=130 Weeks 0 24 12 48 72 PR, peginterferon a-2a 180 µg/wk + ribavirin 1,000-1,200mg/day; QD, once daily.. Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1425.

  43. QUEST-1 and QUEST-2: Simeprevir (PI) + PegIFN + RBV in Treatment-Naive GT1 • 85%-91% qualified for shortened therapy 211/264 65/130 208/257 67/134 n/N = Manns M, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1413. Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 1425.

  44. Preliminary SVR rates in HIV/HCV coinfected patients treated with Simprevir + PegINF/RBV /PR SVR4 SVR12 • Data presented for patients with SVR data available at the time of the interim analysis • RGT-eligible patients: non-cirrhotic treatment-naïve and non-cirrhotic relapse patients Overall Patients (%) 30/35 10/13 21/25 6/8 9/10 4/5 Dieterich DT et al. CROI 2013 *Including only non-cirrhotic patients

  45. Dosing with ARV’s • Sofosbuvir is not metabolized via CYP3A/4 (renal) – minimal interactions with antiretrovirals • No change in dose of SOF or ARV’s with FTC, TDF, EFV, RAL, DRV/r, or RPV • Not recommended with TPV/r • Simeprevir can be dosed with ARV’s: • dose unchanged of SIM or ARV’s with RPV, RAL, MVC, or NRTI’s. • Avoid coadministration with NNRTI’s except RPV, ritonavir, HIV-1 PIs, or cobicistat-based regimens.

  46. LONESTAR: Sofosubuvir + Ledipasvir (Fixed Dose Tablet) Gilead Reports Interim Data from Phase 2 LONESTAR Study. http://www.gilead.com/news/press-releases/2013/5/gilead-reports-interim-data-from-phase-2-lonestar-study. Accessed August 16, 2013.

  47. AVIATOR: SVR12Rates by HCV Subtype 100 98 90 88 86 82 Percentage of patients achieving SVR12 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 RBV 8 weeks 12 weeks 12 weeks Treatment-naϊve patients Null Responders

  48. AVIATOR: Adverse Events in the 8- and 12-week Arms • No study drug-related serious adverse events • One SAE (arthralgia) in a 24-week treatment arm was possibly related • 2/448 patients discontinued treatment due to AEs attributed to study drug by the investigator: • Cholestatic hepatitis in a patient with gallstones • Multiple events (aphthousstomatitis, diarrhea, burning sensation, headache, generalized pruritus) in a second patient Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-1.

  49. Standard of Care for Treatment of chronic HCV Infection – December 2014?

  50. HCV- Do we need a vaccine? • Therapies dramatically better but…

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