1. Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series August 14, 2008 HIV and Hepatitis Chia Wang, MD

2. Hepatitis B and C Chia C. Wang, MD, MS Clinical Assistant Professor of Medicine University of Washington

3. Outline Quick review of Hepatitis B –Staging infection –Cases and Quiz---stage the infection Hepatitis C case –New therapies for hepatitis C

4. HBV Serologies

5. Viral envelope Viral surface Viral DNA Viral core Using blood tests to stage hepatitis B infection

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

7. What is the significance of hepatitis B eAg? A.The presence of HBeAg signifies a high circulating HBV DNA B.The clearance of HBeAg is an important endpoint of treatment C.Patients without HBeAg are not infectious D.HBeAg is a protein secreted by the hepatitis B virus

8. 3 categories of hepatitis B Acute hepatitis B –HBsAg+, HB core IgM Ab+, HBsAb- Resolved hepatitis B –HBsAb+, HB total core Ab+, HBsAg- Chronic hepatitis B –Inactive hepatitis B –Active hepatitis B eAg positive hepatitis B eAg negative hepatitis B –Hepatitis B and cirrhosis

9. 3 categories of hepatitis B Acute hepatitis B –HBsAg+, HB core IgM Ab+, HBsAb- Resolved hepatitis B –HBsAb+, HB total core Ab+, HBsAg- Chronic hepatitis B –Inactive hepatitis B –Active hepatitis B eAg positive hepatitis B eAg negative hepatitis B –Hepatitis B and cirrhosis

10. 3 categories of hepatitis B Acute hepatitis B –HBsAg+, HB core IgM Ab+, HBsAb- Resolved hepatitis B –HBsAb+, HB total core Ab+, HBsAg- Chronic hepatitis B –Inactive hepatitis B –Active hepatitis B eAg positive hepatitis B eAg negative hepatitis B –Hepatitis B and cirrhosis

11. Inactive chronic hepatitis B 0841216202428323652100 HBsAg Asymptomatic Titer HBV DNA HBeAg 10,000 copies/ml or 2,000 IU/ml

12. Inactive chronic hepatitis B HBsAg+ HB total core Ab+ HBeAg- HBV DNA <2000 IU/ml (10,000 copies/ml)

13. 3 categories of hepatitis B Acute hepatitis B –HBsAg+, HB core IgM Ab+, HBsAb- Resolved hepatitis B –HBsAb+, HB total core Ab+, HBsAg- Chronic hepatitis B –Inactive hepatitis B –Active hepatitis B eAg positive hepatitis B eAg negative hepatitis B –Hepatitis B and cirrhosis

14. Active eAg+ chronic hepatitis B 0841216202428323652100 HBsAg May be symptomatic Titer HBV DNAHBeAg 10,000 copies/ml or 2,000 IU/ml

15. Active eAg+ chronic hepatitis B HBsAg+ HB total core Ab+ HBeAg+ HBV DNA >2000 IU/ml (10,000 copies/ml)

16. 132456789102030 Sx Titer Chronic hepatitis B Years Sx HBsAg HBV DNA and ALT

17. 3 categories of hepatitis B Acute hepatitis B –HBsAg+, HB core IgM Ab+, HBsAb- Resolved hepatitis B –HBsAb+, HB total core Ab+, HBsAg- Chronic hepatitis B –Inactive hepatitis B –Active hepatitis B eAg positive hepatitis B eAg negative hepatitis B –Hepatitis B and cirrhosis

18. Core promoter and precore mutants Core promoter mutation Down regulation of eAg production Precore mutation Abolishment of eAg production

19. Active eAg- chronic hepatitis B 0841216202428323652100 HBsAg May be symptomatic Titer HBV DNA HBeAg 10,000 copies/ml or 2,000 IU/ml

20. Active eAg- chronic hepatitis B HBsAg+ HB total core Ab+ HBeAg- HBV DNA >2000 IU/ml (10,000 copies/ml)

21. Active versus inactive chronic hepatitis B 0841216202428323652100 HBsAg May be symptomatic Titer HBV DNA HBeAg 10,000 copies/ml or 2,000 IU/ml 0841216202428323652100 HBsAg Asymptomatic Titer HBV DNAHBeAg 10,000 copies/ml or 2,000 IU/ml

22. 3 categories of hepatitis B Acute hepatitis B –HBsAg+, HB core IgM Ab+, HBsAb- Resolved hepatitis B –HBsAb+, HB total core Ab+, HBsAg- Chronic hepatitis B –Inactive hepatitis B –Active hepatitis B eAg positive hepatitis B eAg negative hepatitis B –Hepatitis B and cirrhosis

23. Chronic hepatitis B and cirrhosis Any patient with cirrhosis who is HBsAg+ and has a detectable HBV DNA should be treated

24. Cases

25. Case 1 A 16 year old Ethiopian boy is being evaluated for immigration to the United States He is HIV negative, but HBsAg positive His liver enzymes and synthetic function are normal

26. Which of the following tests do you need to stage his infection? A.Hepatitis B core Ab B.Hepatitis B surface Ab C.Hepatitis B eAg and eAb D.HBV DNA

27. Case 1 lab results Hepatitis B eAg negative Hepatitis B eAb positive HBV DNA 100 IU/ml

28. What stage of hepatitis B is the patient in? A.Chronic inactive hepatitis B B.Chronic eAg positive hepatitis B C.Chronic eAg negative hepatitis B

29. Which of the following is true for this patient? A.He needs no treatment for his hepatitis B infection B.His risk of liver cancer is lower than someone with HBeAg+ hepatitis B C.His risk of liver cancer is higher than someone with HBsAb+ hepatitis B D.He does not need to be screened for liver cancer, because he has inactive disease

30. Liver Cancer

31. AASLD recommendations for screening for liver cancer HBsAg positive Africans starting at age 20 HBsAg positive Asian men starting at age 40 HBsAg positive Asian women at age 50 Any HBsAg positive patient with cirrhosis Any HBsAg positive patient with a family history of liver cancer Genotype C----- start screening earlier?

32. Case 2 A 44 year old man with HIV is being evaluated HIV positive –CD4 300, HIV viral load 100,000 copiesml HBsAg positive –HBeAg negative, HBeAb positive

33. Which of the following tests do you need to stage his infection? A.Hepatitis B core Ab B.Hepatitis B surface Ab C.Hepatitis B eAg and eAb D.HBV DNA

34. Case 2 lab results HBV DNA 1million IU/ml ALT 120, AST 80 Albumin 4.0 Total bilirubin 1.0

35. What stage of hepatitis B is the patient in? A.Chronic inactive hepatitis B B.Chronic eAg positive hepatitis B C.Chronic eAg negative hepatitis B

36. Which of the following is true for this patient? A.He needs no treatment for his hepatitis B infection B.He needs a liver biopsy before deciding about hepatitis B treatment C.When choosing treatment for HIV infection, antivirals that also treat Hepatitis B should be selected D.Screening for liver cancer should be initiated immediately

37. Which of the following HIV meds also treat hepatitis B? A.Tenofovir B.Abacavir C.Lamivudine D.AZT

38. Case 3 A 38 year old woman is found to be HIV positive and HBsAg+ CD4 count = 250, HIV viral load 80,000 copies/ml Hepatitis B –HBsAg + –HBeAb+ –HBV DNA 1000 IU/ml

39. What stage of hepatitis B is the patient in? A.Chronic inactive hepatitis B B.Chronic eAg positive hepatitis B C.Chronic eAg negative hepatitis B

40. Case 3 lab results ALT=60 AST=80 Albumin 3.0 T. Bilirubin 2.0 Platelet count 80,000

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

42. Which of the following is true for this patient? A.She needs no treatment for his hepatitis B infection because she is in the inactive stage of infection B.She is at high risk to develop liver cancer C.When selecting treatment for HIV, antiviral medications should be chosen that also are effective against HBV

43. Hepatitis C

44. Case 4 A 48 year old HIV-negative man is found to be Hepatitis C antibody positive Hepatitis C viral load is 1 million IU/ml Hepatitis C genotype is genotype 1

45. Case 4, continued Therapy for hepatitis C is initiated with pegylated interferon/ribavirin At 12 weeks, hepatitis C viral load is 100,000 IU/ml In addition, the patient suffers from terrible side effects –Nausea –Hair loss –Itching –Depression/irritability –Fatigue –Insomnia

46. Responses to therapy Sustained virologic response –Negative viral load 6-months after completing treatment Relapse -- Recurrence of viral load after initial disappearance Non-response/partial response -- Viral load never drops or drops by > 2 logs but never disappears

47. 6 months12 months18 months Lower limit of detectable virus RELAPSE SUSTAINED RESPONSE NON-RESPONSE Hepatitis C: Patterns of Response to Treatment *

48. Evolution of treatment for hepatitis C McHutchinson, et al. NEJM 1998;339:1485-92 Zeuzem, et al. NEJM 2000;343:1666-1672 Manns, MP et al. Lancet 2001;358:958-865

49. Pegasys Prefilled Syringe

51. 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

52. Side Effects of IFN (page 2) Gastrointestinal –diarrhea –nausea –vomiting –abdominal pain –anorexia –aphthous ulcers –dyspepsia Respiratory –cough –dyspnea Dermatologic – rash – alopecia – pruritis – dry skin – injection site reaction Autoimmunity –thyroiditis –psoriasis

53. Side Effects of IFN (page 3) Hematologic – anemia – neutropenia – thrombocytopenia

54. Side Effects of RBV Hemolytic anemia Teratogenicity Cough and dyspnea Rash and pruritus Insomnia Anorexia Rebetron  [package insert]. Kenilworth, NJ: Schering Corp; 1999.

55. Interferon-man

56. PEG (40 kDa) IFN alfa-2a/RBV 12-Week Negative Predictability Analysis (n = 390) 86% (n = 63) 14% 2 Log 10 Drop or Neg HCV RNA Yes No Week 12 (n = 453) (n = 253) 65% SVR (n = 137) 35% (n = 2) 3% SVR (n = 61) 97% No SVR No SVR HCV = hepatitis C virus; RNA = ribonucleic acid; SVR = sustained virologic response. Fried et al. DDW; May 20-23, 2001; Atlanta, Ga.

57. Which of the following is true for this patient? A.He should be told that he is interferon- nonresponder, and therapy should be discontinued immediately B.He should be told that he is interferon- nonresponder, and offered to option to continue medication for 48 weeks C.He should stop therapy, and be encouraged that new treatments for hepatitis C are being developed, so that future regimens will be easier to tolerate

58. Protease Polymerase

59. Translation An enzyme called a protease is necessary to slice up the large polyprotein into smaller proteins

60. 01234567891011121314 -5 -4 -3 -2 0 1 Median HCV RNA Change from Baseline (Log 10 IU/mL) Study Time (in Days) VX-950– A protease inhibitor— The promise Placebo VX-950 450 mg q8h VX-950 750 mg q8h VX-950 1250 mg q12h Reesink et al. DDW. 2005.

61. Time (days) 14 3-7 months Long-term follow-up placebo (n=6) breakthrough (n=13) plateau (n=8) continuous decline (n=7) Kieffer et al. EASL 2006 Evaluating Resistance Patterns to VX-950 - 0 1 2 3 4 5 6 7 02468101216182022242628 0 1 2 3 4 5 6 7 02468101216182022242628 - - 0 1 2 3 4 5 6 7 02468101216182022242628 0 1 2 3 5 6 048101216182022628 - - 0 1218 0 1218 - dosingDosing with VX - 950 Median Log HCV RNA 0 10 1218 0 Slow return post -

62. 36 155 54 36/155 WT 156 36 155 WT VX-950 Dosing Period Post-Dosing Emergence of Resistance Underlies Breakthrough and Plateau Response Long-term follow-up Median Log HCV RNA 1 2 3 4 5 6 7 EOD 14 days Baseline Follow-Up 7/10 days post-dosing Long-term follow-up 3-7 months post-dosing WT V36 M/A/L R155 K/T/S/M T54A 36/155A156V/T36/156 IC 50 fold change 1 4 7 12 46 466 781 36 155 54 36/155 WT 156

63. Clinical Implications Resistance will limit the use of oral inhibitors as a monotherapy

64. Interferon as a platform for future combinations Viral enzyme inhibitors Immune modulation Ribavirin or related drugs + + The Future Of HCV Therapy

65. Thank you! Next session: August 21, 2008 Listserv: itechdistlearning@u.washington.eduitechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu

66. Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series Next session: August 21, 2008 Scott McClelland, MD HIV and Women