1. A, B, C’s of Viral Hepatitis Chia C. Wang, MD, MS University of Washington Harborview Medical Center Hepatitis and Liver Clinic

2. Outline Overview of viral hepatitis Hepatitis A Hepatitis B Hepatitis C

3. Viral Hepatitis A virus that has particular tropism for hepatocytes In contrast, viruses such as the yellow fever virus, EBV, CMV cause liver inflammation but cause systemic inflammation as well

4. Viral Hepatitis acutechronicfecal-oral Hepatitis AXX Hepatitis BXX Hepatitis CX*X Hepatitis DXX Hepatitis EXX *symptoms of acute infection are rare

5. Differences in hepatitis A, B, and C How they are transmitted Whether or not they cause chronic infection Treatment Vaccine

6. Hepatitis A– 2003 outbreak In November 2003 there were 555 cases of hepatitis A in a single outbreak 3 deaths All cases had eaten at a Mexican restaurant in Monaca, PA

7. Hepatitis A Outbreak Investigation Cases Mild Salsa 94% Chili Con Queso 15% Controls 39% 3% Hepatitis A is fecal-orally transmitted

8. How are green onions a particularly likely vector for hepatitis A? HARVESTING STORAGE SURFACE DISTRIBUTION

9. Impact of hepatitis A outreatk 555 cases 3 deaths (.5%) Mean age 34 (4-73) Days of work lost average 27 days ~22% hospitalized

10. Take Home Points– Hep A Fecal-orally transmitted Restaurant outbreaks are the most common means of transmission Cooking inactivates virus Incubation period ~ 28 days, duration of illness ~ 4-6 weeks Recovery confers immunity

11. Who should get the hepatitis A vaccine?  People traveling to endemic areas  Injection drug users  Men who have sex with men  People who have clotting factor disorders  People who work with primates  Individuals with chronic liver disease  Children in states with HAV rates more than twice the national average (Arizona, Alaska, Oregon, New Mexico, Utah, Washington, Oklahoma, South Dakota, Idaho, Nevada, California)

14. Worldwide prevalence of hepatitis and HIV

15. Chronic hepatitis Marked by the presence of circulating virus in the bloodstream Liver biopsy usually shows inflammation, which may progress to fibrosis over time May be associated with the development of cirrhosis May be associated with the development of hepatocellular CA

16. Symptoms of chronic hepatitis Fatigue Difficulties with concentration and memory Right-sided abdominal pain Loss of appetite Extra-hepatic  Rashes  Joint pains  Kidney disease Depression

17. Why do we care about chronic hepatitis? Chronic hepatitis Cirrhosis and/or liver cancer 20%

18. Gross pathology of cirrhosis Courtesy of: http://www.meddean.luc.edu/lumen/MedEd/orfpath/cirhosis.html Normal liver Fibrotic liver

19. Outline of hepatitis B talk Natural history Hepatitis B serologies Epidemiology Treatment

20. Spectrum of Disease Acute HBV infection Chronic HBV infection Fulminant hepatic failure HCC Death Fatal progressive liver failure Cirrhosis Decompensated cirrhosis 20% ~2% Resolve

21. Likelihood of developing chronic hepatitis B Patient Type Adult Child Transmission Routes Sexual, Parenteral Vertical, Horizontal 2-10 % 80-90 % Likelihood of developing chronic infection

22. HBV Serologies

23. HBV Markers HBsAg+ Anti-HBc+ Anti-HBs+ HBV Infection present Exposure to HBV Immunity Slide courtesy of Ray Kim, Mayo clinic

24. Surface antigen and antibody 0841216202428323652100 HBsAg anti-HBs Symptoms Titer

25. 0841216202428323652100 Core IgM and IgG antibody Titer IgM Anti-HBc Total anti-HBc

26. 0841216202428323652100 HBeAg Symptoms Titer anti-HBe Envelope antigen and antibody

27. Resolution of Acute hepatitis B 0841216202428323652100 HBsAg Anti-HBs Symptoms Titer IgM Anti-HBc Total anti-HBc HBeAg anti-HBe

28. If you only remember 2 things... Hepatitis B surface antibody (anti-HBs)  Indicates immunity Hepatitis B core antibody (anti-HBc IgG)  Indicates exposure  (but not timing of that exposure)  IgM suggests acute infection So what about the patient who is anti-HBs positive but anti-HBc IgG negative??

29. What does chronic HBV look like? 0841216202428323652100 HBsAg Possible Symptoms Titer HBV DNA HBeAg Anti HBc IgM

30. 132456789102030 Sx Titer Chronic hepatitis B Years Sx HBsAg HBV DNA and ALT

31. 15% <1% 15% <1% 5% HEPATITIS B AROUND THE WORLD

32. Origin of Immigrants to US Statistical Report, INS, 2001 Slide courtesy of Ray Kim 1 2 3 4 5 6 7 8 9 10 19201940196019802000 People (million) EuropeAsiaAmericaAfrica

33. Vaccine licensed HBsAg screening of pregnant women recommended OSHA rule enacted Decline among MSM & HCWs Decline among injecting drug users Infant immunization recommended Sources: 1 NNDSS. Adolescent Immunization recommended 0 2 4 6 8 10 12 14 196719701973197619791982198519881991199419972000 Year Cases per 100,000 Population Historical and Forecasted HBV Prevalence 11 12 13 14 15 2001200220032004200520062007200820092010

34. Transmission of hepatitis B Risk of infection after needlestick exposure  HIV: 1 in 300  HCV: 1 in 30  HBV: 1 in 3 HBV is a DNA virus and is quite stable outside of the body

35. Risk factors for adult-acquired chronic hepatitis B in the U.S. Sexual exposure IDU Household contact Health care and public safety occupational exposure Hemodialysis patients

36. 21 Incident HBV infection in King County in 2005

37. Who should be vaccinated for hepatitis B? All children Household/sexual contacts Health care workers Hemodialysis patients Recipients of blood products International travelers IDU MSM Men and women recently diagnosed with an STD or with multiple sexual partners Prison inmates

39. Hep B antivirals Tenofovir (Viread) ** Entecavir (Baraclude) ** Telbivudine (Tyzeka) Lamivudine (Epivir HBV) Adefovir (Hepsera) Pegylated interferon alfa 2a (Pegasys)

40. What to tell patients about hep B Not every patient needs to be treated Treatment controls disease but does not cure Treatment is easy to take with few side effects Medication adherence is important to avoid the development of resistance

41. Who should be referred? Patients who are sAg+ AND:  eAg+  Have elevated LFTs  Have high viral loads  Are inactive carriers but need reassurance

42. Hepatitis C: 2012 and Beyond Chia Wang, MD, MS Virginia Mason Medical Center Sections of Infectious Diseases and Gastroenterology 42

43. Evolving Treatment Landscape of Direct Acting Anti- viral agents (DAAs) …it is busy

44. Talk Outline Telaprevir and Boceprevir Predictors of Response Coinfected patients New Treatments Case presentations – who to treat now Hep C for the ID doc

46. Telaprevir ADVANCE ILLUMINATE REALIZE Boceprevir SPRINT-2 RESPOND-2

47. Telaprevir ADVANCE NAÏVE HEP C ILLUMINATE CONFIRMED THAT 24 WEEKS DURATION IS OK REALIZE TREATMENT EXPERIENCED HEP C Boceprevir SPRINT-2 NAÏVE HEP C RESPOND-2 TREATMENT EXPERIENCED HEP C

48. Telaprevir ADVANCE NAÏVE HEP C ILLUMINATE CONFIRMED THAT 24 WEEKS DURATION IS OK REALIZE TREATMENT EXPERIENCED HEP C Boceprevir SPRINT-2 NAÏVE HEP C RESPOND-2 TREATMENT EXPERIENCED HEP C

49. ADVANCE Study: Telaprevir + PegIFN Alfa-2a + RBV in Genotype 1 Phase 3 Treatment-naïve Genotype 1 HBsAg negative HIV negative No decompensated liver disease, cirrhosis, or HCC Week 0 8 12 24 48 72 PegIFN + RBV T12/ PR T8/ PR PR48 eRVR (extended rapid virologic response): HCV RNA <25 IU/mL and undetectable at week 4 and week 12. TVR: telaprevir; Pbo: placebo. Jacobson IM, et al. N Engl J Med 364:25. TVR (750 mg q8h) PegIFN + RBV TVR + (750 mg q8h) PegIFN + RBV eRVR(-) PegIFN + RBV Follow-Up SVR eRVR(+) Follow-Up SVR Follow-Up PegIFN + RBV eRVR(-) PegIFN + RBV Follow-Up SVR eRVR(+) Follow-Up SVR Follow-Up Placebo + PegIFN + RBV SVR Follow-Up

50. ADVANCE Study Outcomes: Telaprevir + PegIFN Alfa-2a + RBV Patients (%) T12/PR (n=363) Sustained Virologic Response 79%* 72%* 46% *P<0.0001. T8/PR (n=364) PR48 (n=361) Jacobson IM, et al. N Engl J Med 364:25.

51. SPRINT-2 Study: Boceprevir + PegIFN Alfa-2b + RBV in Chronic HCV Phase 3 Treatment-naïve Genotype 1 HBsAg negative HIV negative No decompensated liver disease, cirrhosis, or HCC (nonblack n=938; black n=159) Poordad F, McCone Jr J, Bacon BR et al for the SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195-206 Placebo + PegIFN + RBV Follow-Up LI/ B24/ PR PR48 Weight-based ribavirin dosing (600-1400 mg). Week 0 4 28 48 72 Boceprevir (800 mg tid) + PegIFN + RBV Follow-Up LI/ B44/ PR Boceprevir (800 mg tid) + PegIFN + RBV Lead in Lead in Lead in HCV RNA Detectable* PegIFN + RBV HCV RNA Undetectable* Follow-Up During treatment week 8 to week 24.

52. SPRINT-2 Study Outcomes: Boceprevir + PegIFN Alfa-2b + RBV Patients (%) Sustained Virologic Response 42% ‡ 68%* 67%* 40% *P<0.001, † P=0.004, and ‡ P=0.044 versus PR48. LI/B24/PR (n=316/52) LI/B44/PR (n=311/55) PR48 (n=311/52) 53% † 23% Non-black patients Black patients Overall 66% Overall 63% Overall 38%

53. Conclusions from Telaprevir/Boceprevir studies Addition of the protease inhibitor confers an ~ 20- 30% increase in SVR rates compared to standard dual therapy Response guided therapy can shorten treatment for genotype 1 patients to 24 weeks for patients with early response African American patients may derive particular benefit from triple therapy compared to past dual therapy

54. Telaprevir ADVANCE NAÏVE HEP C ILLUMINATE CONFIRMED THAT 24 WEEKS DURATION IS OK REALIZE TREATMENT EXPERIENCED HEP C Boceprevir SPRINT-2 NAÏVE HEP C RESPOND-2 TREATMENT EXPERIENCED HEP C

55. Patterns of non-response to hepatitis C therapy Adapted from Ghany MG, et al.

56. REALIZE: Study Design (N=662) Follow-Up T12/PR48 N=266 Pbo/PR48 (control) Week 0 4 12 16 48 72 TVR+Peg- IFN+RBV Follow-Up LI T12/PR48 N=264 Pbo+Peg -IFN+ RBV Follow-Up PegIFN + RBV TVR+Peg- IFN+RBV Pbo+Peg -IFN+ RBV Pbo+PegIFN + RBV

57. REALIZE: Baseline Characteristics Characteristic T12/PR48 (N=266) LI T12/PR48 (N=264) Pbo/PR48 (N=132) Male (%)183 (69)189 (72)88 (67) Race(% Caucasian)246 (92)252 (95)117 (89) Age Mean (Range)51 (23-69)51 (24-70)50 (21-69) HCV Genotype, n(%) 1a136/252 (52)149/262 (57)67/128 (52) 1b126/262 (48)113/262 (43)61/128 (48) Prior Response Null responder72 (27)75 (28)37 (28) Partial responder49 (18)48 (18)27 (20) Relapser145 (55)141 (54)68 (52) Bridging fibrosis, n(%)60 (23)58 (22)29 (22) Cirrhosis, n(%)72 (27)67 (25)30 (23)

58. REALIZE Primary Endpoint: Proportion of Patients with SVR 100% 0 % 50% 83 88 24 41* 9 Patients Achieving SVR (%) 75% 25% T12/ PR48 LI T12 /PR48 Pbo/ PR48 N/n 121/145 124/141 16/68 50/121 51/123 6/64 T12/ PR48 LI T12 /PR48 Pbo/ PR48 Prior relapsers Prior non-responders (prior partial responders and null responders) *P<0.001 vs Pbo/PR48

59. REALIZE: SVR by HCV Subtype & Prior Response 100% 0 % 50% 86 32 72 18 6 41 Patients Achieving SVR (%) 75% 25% Prior relapsersPrior partial responders Minimal fibrosis Bridging fibrosis CirrhosisMinimal fibrosis Bridging fibrosis CirrhosisMinimal fibrosis Bridging fibrosis Cirrhosis Prior null responders 85 13 84 13 56 0 20 34 39 0 14 10 Pooled T12/PR48 Pbo/PR48

60. Conclusions Treatment-experienced patients who were relapsers or partial responders do well with triple therapy Previous null responders, particularly those with advanced fibrosis, have low response rates (and tolerate treatment poorly)

61. Costs of boceprevir and telaprevir Boceprevir (Victrelis) ----- Merck. Telaprevir (Incivek) ----- Vertex. $26,410 for 24 weeks, $48,418 for 44 weeks $49,200 for 12 weeks

63. Side Effects of IFN Flu-like symptoms  fatigue  myalgias  arthralgias  headache  fever, chills  dehydration  weight loss Psychiatric symptoms  depression  mood lability  anxiety  insomnia  impaired concentration Ophthalmologic  retinal disease Gastrointestinal  diarrhea  nausea  vomiting  abdominal pain  anorexia  aphthous ulcers  dyspepsia Respiratory  cough  dyspnea Dermatologic  rash  alopecia  pruritis  dry skin  injection site reaction Hematologic  anemia  neutropenia  thrombocytopenia Autoimmunity  thyroiditis  Psoriasis

64. Telaprevir: Most Common AEs (≥ 25%) and Discontinuation Rates from Advance % of Patients With T12/PR (n = 363) T8/PR (n = 364) PR48 (n = 361) Any AE a 99 98 Fatigue575857 Pruritus504536 Headache414339 Nausea434031 Rash373524 Anemia373919 Insomnia32 31 Diarrhea283222 Influenza-like illness282928 Pyrexia263024 a Reported in ≥ 25% of patients regardless of severity in any treatment arm 7% of T12PR, 8% of T8PR, and 4% of PR48 patients discontinued all drugs due to AEs during TVR/placebo phase. 11% of T12PR, 7% of T8PR, and 1% of PR48 patients discontinued TVR/placebo only during TVR/placebo phase. Jacobson IM, et al. AASLD 2010. # 211.

65. Boceprevir: Discontinuations and Adverse Events Bacon BR, et al. Hepatology. 2010;52(suppl 1):430A. Abstract 216. (RESPOND-2 STUDY)

66. What to tell our patients Both new drugs are still used in combination with pegylated interferon and ribavirin Side effects of the regimen are generally worse than they were with pegylated interferon and ribavirin For SOME genotype 1 patients, treatment can be shortened to 24 weeks from 48 weeks Cure rates are NOT 100% Better drugs yet to come

67. Factors Predictive of Response to IFN/RBV based therapy Prior to new PIs  Genotype 2/3  No advanced fibrosis  Low viral load  Younger age  Female  Race/ethnicity After new PIs  IL28B  Genotype 2/3  Genotype 1a/1b  Lack of steatosis/insulin resistance  Rapid viral response (RVR)  Prior treatment response  Race/ethnicity McHutchison JG, et al. N Engl J Med. 2009;361(6):580-593. Manns MP, et al. Lancet. 2001;358(9286):958-965. Patton HM, et al. J Hepatol. 2004;40(3):484-490. Poynard T, et al. Lancet. 1998;352(9138):1426-1432.

69. 60 Mb Chromosome 19 Chromosome 19 Polymorphism Predicts SVR Polymorphism rs12979860 IL28B gene 3 kb 19q13.13 Ge D, et al. Nature. 2009;461:399-401. Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif CC CT TT

70. Chromosome 19 Polymorphism Predicts SVR Ge D, et al. Nature. 2009;461:399-401.

71. Americans 12 36 19 50 48 46 38 16 35 0 20 40 60 80 100 EuropeanAfricanHispanics Percent C/C T/C T/T rs12979860 Genotype Frequency by Population Ge D, et al. Nature. 2009;461:399-401.

72. IL-28B Polymorphism is the Strongest Baseline Predictor of SVR Using Peginterferon/Ribavirin Covariates - rs12979860 (2-level), ethnicity (4-level), age (≤ 40), gender, BMI ( 0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d) Thompson AJ, et al Gastroenterology 2010 (139) p120-129 P <0.0001 for all comparisons 012543876 Fibrosis F0/F1 Caucasian vs Black VL <600,000 IU/ml CC vs non-CC

73. Subanalysis of ADVANCE: Role of IL28B in Response to Treatment With Telaprevir Jacobson I, et al. EASL 2011. Abstract 1369. SVR Rates in Patients Genotyped for IL28B SVR (%) T12PR T8PR PR 60 100 80 40 20 0 n/N =45/5038/4535/55 CC 48/6843/7620/80 CT 16/2219/326/26 TT 90 84 64 71 57 25 73 59 23

74. Younger & healthier Geno 2&3 Non-Black CC Relapser prior Rx Hepatitis C patients in need of treatment

75. Prior treatment null responders HIV coinfected African American Advanced fibrosis/cirrhosis Renal transplant Patients unable to tolerate interferon Genotype 2 and 3 prior non- responders

76. NS3 /4A Inhibitors (Protease inhibitors) High potency Limited genotypic coverage Low barrier to resistance NS5A Inhibitors High potency Multi-genotypic coverage Intermediate barrier to resistance NS5B Nucleos(t)ide Polymerase Inhibitors Intermediate potency Pan genotypic coverage High barrier to resistance NS5B Non Nucleoside Polymerase Inhibitors Intermediate potency Limited genotypic coverage Low barrier to resistance DAAs - Key Characteristics

77. New Direct Acting Antivirals – Here are just a few of them Gilead—sofosbuvir (polymerase inhibitor) Janssen—simiprevir (protease inhibitor) BMS—daclatasvir (NS5a) Abbott—Abbott 450 (protease inhibitor)

78. Gilead—Sofosbuvir SOF + RBV (phase 2) -Electron -Quantum SOF + PEG + RBV (phase 2) -Proton -Atomic SOF + RBV (phase 3) -Fission -Positron -Fusion SOF + PEG + RBV (phase 3) -Neutrino

79. Gilead—Sofosbuvir SOF + RBV (phase 2) -Electron geno 1,2,3 treatment naïve and experienced -Quantum geno 1 treatment naive SOF + PEG + RBV (phase 2) -Proton geno 1,2,3 treatment naive -Atomic geno 1 treatment naïve SOF + RBV (phase 3) Fissiongeno 2,3 treatment naive Positrongeno 2,3 interferon unwilling Fusiongeno 2,3 treatment experienced SOF + PEG + RBV (phase 3) Neutrino geno 1,4,5,6 treatment naive

80. Gilead—Sofosbuvir SOF + RBV (phase 2) -Electron geno 1,2,3 treatment naïve and experienced -Quantum geno 1 treatment naive SOF + PEG + RBV (phase 2) -Proton geno 1,2,3 treatment naive -Atomic geno 1 treatment naïve SOF + RBV (phase 3) Fissiongeno 2,3 treatment naive Positrongeno 2,3 interferon unwilling Fusiongeno 2,3 treatment experienced SOF + PEG + RBV (phase 3) Neutrino geno 1,4,5,6 treatment naive

81. Phase 2: ELECTRON HCV GT 1,2 and 3 Wk 0Wk 4Wk 8 Wk 12 SVR N= 9 N=25 11% 88%** pending Pending SOF + RBV (GT 1 null responders) SOF + RBV (GT 1 naïve) SOF + RBV (GT 2,3 treatment experienced) SOF + RBV (GT 2,3 naïve) SOF + 800 mg RBV (GT 2,3 naïve) N=25 N=10 100% 60% 100% SOF + RBV (GT 2/3) SOF + RBV + PEG SOF + RBV + PEG (GT 2/3) SOF + RBV SOF + RBV + PEG (GT 2/3) SOF (GT 2/3) SOF + RBV + PEG (GT 2/3) N=10 N=9 N=10 N=11 N=10 1. Gane E, et al. AASLD 2011, abstract 34 2. Gane E, et al. CROI 2012, 3. Gane E, et al. EASL 2012,abstract #1113

82. Kowdley K et al. EASL, 2012, abstract 1 Phase 2: ATOMIC Genotype 1, 4, 6 Day 1 Wk 12Wk 24 Group B N=125 SOF 400mg + RBV + PEG GT 1, 4, 6 Group A N=52 SOF 400mg + RBV + PEG GT 1 Group C N=150 SOF 400mg + RBV + PEG SOF 400mg (n = 75) SOF 400mg + RBV (n = 75) GT 1  HCV RNA analyzed by TaqMan ® HCV Test 2.0 (LOD: 15 IU/mL)  Study Dosing:  PEG-alfa 2a - 180 mcg QW  RBV - Weight based dosing: 1000 mg (< 75 kg) or 1200 mg (≥75 kg) per day

83. Phase 2: ATOMIC ( GT 1 Naïve) % Patients Wk4 EOT SVR4 SVR12 Wk4 EOT SVR4 Wk4EOT SVR4 SOF+RBV+PEG 12 Wks SOF+RBV+PEG 24 Wks SOF+RBV+PEG 12 Wks + SOF ± RBV 12 Wks SVR12 Kowdley K et al. EASL, 2012, abstract 1

84. Gilead timeline File for regulatory approval mid-2013 Possible approval late-2013 -Geno 1 12 weeks of PEG + RBV + SOF -Geno 2,312-16 weeks of SOF and RBV Fixed dose combination pill -SOF + GS5885 (NS5a inhibitor) entering phase 1 testing. Gilead predicting advancing to Phase III early 2013.

85. When will we have an all-oral regimen? Early 2014? At least for tx-naïve patients Abbott 12-week regimen  ABT 333 (polymerase inhibitor)  ABT 450/r (protease inhibitor, ritonavir-boosted)  Ribavirin April 2012 results: SVR12  18/19 geno 1 treatment naïve achieved SVR12  8 of 17 prior nonresponders achieved SVR (47%)

86. Which of these patients would you treat? Geno 1 naïve, Stage 1 fibrosis, IL28B CT Geno 1 naïve, Stage 1 fibrosis, IL28B CC Geno 2 naïve, Stage 1 Geno 1 naïve, stage 4 compensated Geno 1 prior relapser, Stage 3 Geno 1 prior nonresponder, Stage 3 Geno 3 prior relapser, Stage 3 HIV/HCV coinfected naive, Stage 3

87. What to tell the patient with hepatitis C Better treatments are right around the corner For patients with genotype 2 or 3 disease, interferon-free therapy available end of 2013 For patients with genotype 1 disease, no interferon-free by 2014, but short course (12 weeks) interferon may be an option for many For everybody: higher cure rates; fewer side effects

88. Primary Care for Hepatitis C Hep A and B vaccination Minimize alcohol Limit Tylenol to 1 gm a day Consider minimizing opiate use Consider minimizing marijuana use Improve BMI