1. MAKATI MEDICAL CENTER Ledesma Hall October 17, 2005 Hepatitis - Interactive Session Roel Leonardo R. Galang, M.D. Fellow, Philippine College of Physicians Diplomate, Philippine Society of Gastroenterology Diplomate, Philippine Society of Digestive Endoscopy

9. Middle surface antigen Nucleocapsid DNApolymerase Envelope Genomic DNA Small surface antigen RNA primer Large surface antigen Hepatitis B virus

12. HBV variants and mutants Pre-core and core mutations –virulence –immune escape –response to interferon therapy Surface mutations –detection –vaccine escape –HBIG immunoprophylaxis escape Polymerase mutations –drug resistance

14. Hepatitis B management guidelines GroupDatePublicationLeaders CASL ConsensusMar 1999Can J GastroSherman, Minuk Chinese ExpertMay 1999Chinese J HepatolZhang Ding Feng Guiding GroupSept 2000 Asia PacificJun 2000J Gastro HepatolFarrell, Liaw Consensus NIH2001GastroenterologyLok, Heathcote Hoofnagle

15. NIH Nomenclature and terminology Evaluation and monitoring Therapy Hepatitis B management guidelines

16. Nomenclature and terminology Avoid “asymptomatic” “healthy carrier state” Acceptable “inactive carrier state” HBsAg +ve, anti-HBe +ve, normal ALT HBV DNA less than 10 5 copies/ml

17. Nomenclature and terminology: Category of responses Biochemical (BR) – serum ALT w/in Normal range Virological (VR) - HBV DNA < 10 5 copies/ml - loss of HBeAg Histological (HR) - histology activity index by 2 points Complete (CR) - BR+/VR+ and loss of HBsAg Time of assessment On therapy: during therapy – Maintained – persist throughout the course of treatment – End of treatment – at end of defined course of therapy Off-therapy: after discontinuation of therapy – Sustained - (SR-6) 6 months after therapy – Sustained – (SR-12) 12 months after therapy

18. Evaluation of CHB “should” include: HBsAg, HBeAg, anti-HBe, anti-HDV HBV DNA LFTs Abdominal ultrasound Liver biopsy warranted if high ALT

19. Liver biopsy Advantages Establish baseline disease Establish presence or absence of cirrhosis –surveillance for HCC –variceal bleed prevention Exclude co-existent liver disease Disadvantages Discomfort Discomfort Risk of bleeding etc Risk of bleeding etc

20. Minimum - every 6 months ALT No need for HBV DNA HCC 6 monthly checks if high risk –Cirrhosis –Strong family history –> 40 years Monitoring of CHB

21. Therapy - mild disease Monitor Await future approaches eg. combination of antivirals NIH No treatment if normal ALT Asia Pacific

22. No resistance Side effects Contraindications INTERFERONLAMIVUDINE V Resistance Well tolerated No contraindications Therapy - more severe disease

23. Asia Pacific guidelines Consider if ALT >2 x ULN >5 x ULN - lamivudine 2-5 x ULN - lamivudine or IFN NIH Consider if ALT >2 x ULN >5 x ULN - monitor for 2-3 months 2-5 x ULN - lamivudine or IFN

24. Therapy - HBeAg negative NIH If significant disease Consider long term lamivudine

25. Therapy monitoring Asia Pacific During therapy –1-3 monthly ALT, HBeAg +/- HBV DNA End Therapy –3-6 monthly ALT, HBeAg +/- HBV DNA

26. Stopping therapy Asia Pacific IFN 4-6 months therapy Lamivudine - stop if HBeAg seroconversion with HBV DNA loss on two separate occasions 1 month apart No consensus Non responders - ?? Prolonged therapy HBeAg negative

35. Natural history of chronic HBV infection Acute Infection Chronic Carrier Resolution 30–50 Years Chronic Hepatitis Stabilization Progression Cirrhosis Compensated Cirrhosis Liver Cancer Death Adapted from Feitelson, Lab Invest 1994 Decompensated Cirrhosis (Death)

41. HBV vaccination - effect on incidence and mortality from HCC per 100.000 children (6-14 yrs) per 100.000 children (6-14 yrs) Chang M-H et al. N Engl J Med 1997; 336: 1855-9 per 100.000 children (6-14 yrs) per 100.000 children (6-14 yrs) Incidence Mortality Beginning of the program June 1984

42. Actuarial survival in end stage liver disease Historical Studies 132450 20 40 60 100 80 Cirrhosis 1 Decompensated cirrhosis 2 14% 55% Patients surviving (%) Years Weissberg et al, 1984 1 and De Jongh et al, 1992 2 Weissberg et al, 1984 1 and De Jongh et al, 1992 2

43. Treatment objectives for chronic hepatitis B Sustained suppression and eradication of HBV infection Improve clinical and biochemical profiles Improve/reverse liver inflammation and fibrosis Improve long-term prognosis –reduce progression to cirrhosis and HCC –improve survival –improve long-term quality of life –reduce long-term cost of medical care

46. Therapies for Chronic Hepatitis B Antivirals Reduce HBV replication and improve liver disease, and allow recovery of HBV-specific immune response –Lamivudine Immune modulators Stimulate immune system to attack HBV- infected cells and reduce associated liver disease –Interferon-alpha

48. Loss of viral replication with interferon Wong et al, Ann Intern Med 1993 Integrated analysis of 15 controlled studies N=837 p=0.0001 p=0.001

52. Interferon therapy PROS Short treatment course >30% HBeAg loss 8-10% HBsAg loss No mutations Long term improvement CONS Substantial side effects Limited efficacy –Asians –Pre-Core mutants –Decompensated Disease –Immunocompromised Cost

54. HBsAg envelopes Partially double- stranded DNA Lamivudine A(n) Infectious HBV virion (-)-DNA Infectious HBV virion mRNAcccDNA DNA pol RT Encapsidated pregenomic mRNA Lamivudine is a potent inhibitor of HBV replication Lai et al, J Med Virol 2000

56. Lamivudine rapidly suppresses serum HBV DNA

57. HBeAg seroconversion after one year of therapy Seroconversion = HBeAg-ve and anti-HBe+ve 6 17 7 20 21 0 5 10 15 20 25 30 PlaceboLamivudineIFNLamivudine + IFN Lai Dienstag Schalm *p<0.04 compared to placebo 29 21 Patients (%) 13 20 14 Schiff * *

58. Durability of post-treatment response 0 20 40 60 80 100 81 86 87 Patients (%) Lamivudine Asian Lamivudine Caucasian Interferon 20/23 Median Follow-up = >12 months 37/4321/26 Korenman et al 1991 Schiff et al 1998 68 21/31 Spontaneous Lok et al 1987 Guan et al 2000 HBeAg loss in different patient groups

62. Major long term studies using lamivudine in HBeAg +ve CHB Asian 5yr study (B3018) Schiff et al, 2yr follow-on study (B3017) China 3yr study (B3026)

63. HBeAg loss and HBeAg seroconversion (HBeAg-ve, anti-HBe+ve) (Modified ITT population) 17 20 8 12 17 10 0 5 15 20 25 Year 1Year 2Year 3 Patients (%) HBeAg lossHBeAg seroconversion 38/400 33/400 60/400 46/400 81/400 69/400

64. HBeAg loss is increased in patients with higher baseline ALT (Modified ITT population) 10/18 5/18 12/18 Patients (%) 22/72 11/72 26/72 19/100 10/100 21/100

65. HBeAg seroconversion is increased in patients with higher baseline ALT (Modified ITT population) 13/100 14/72 6/18 10/100 8/72 5/18 19/100 20/72 11/18 Patients (%) HBeAg seroconversion = HBeAg negative, HBeAb positive

67. Combination Therapy Schalm SW et al. RCT. Gut 2000 N = 226 1. Lamivudine x 52 weeks 2. INF – alpha x 16 weeks 3. Combination Findings: rate of HBeAg conversion at 52 weeks 18% vs 19% vs 29% Added benefit?

68. Antiviral response to Interferon and Lamivudine with HBeAg +ve CHB Interferon Lamivudine 12-24 wks Controls 52 wks Controls Loss of serum HBV DNA 37% 17% 16 -18% 4-6% Loss of HBeAg 33% 12% 17-32% 6-11% HBeAg seroconversion difference of 18% 16-18% 4-6% Histologic improvement 49-56% 23-25% Normal ALT < 10% VR <10% VR ALT <2x Interferon: 15 RCT N = 837 Lamivudine: 3 clinical trials N = 731

69. Patient case  45 year old male Chinese patient who has a brother with cirrhosis from CHB  Patient presents with HBsAg+ve, HBeAg+ve, HBV DNA+ve by Chiron assay, ALT normal and LFTs normal, ultrasound normal Would you treat this patient? 1Yes 2No

70. 1.Yes 2.No Would you treat this patient?

71. Patient case  6 months later ALT has risen to 2.5xULN  All other clinical signs and symptoms are similar to before Would you treat this patient now? 1Yes 2No

72. Would you treat this patient now? 1.Yes 2.No

73. Patient case  Lamivudine therapy was started  After 1yr: patient had normal ALT, HBV DNA was -ve by Chiron and still HBeAg+ve What would you do now? 1Continue lamivudine 2Stop lamivudine 3Change treatment

74. 1.Continue lamivudine 2.Stop lamivudine 3.Change treatment What would you do now?

75. Patient case Lamivudine was continued At 20 months ALT increased transiently to 2xULN and treatment was continued At 24 months HBeAg seroconversion occurred, ALT normalised and HBV DNA was negative

76. When would you stop therapy? 1Immediately after detecting HBeAg loss 2When seroconversion is reconfirmed 1 month later 3When seroconversion is maintained for 3 months 4When seroconversion is maintained for 6 months 5When HBsAg seroconversion is obtained

77. When would you stop therapy? 1.Immediately after detecting HBeAg loss 2.When seroconversion is reconfirmed 1m later 3.When seroconversion is maintained for 3m 4.When seroconversion is maintained for 6m 5.When HBsAg seroconversion is obtained

78. Conclusion Lamivudine increases HBeAg loss and seroconversion over time Lamivudine increases HBeAg loss and HBeAg seroconversion in patients with high baseline ALT Most patients continue to have normal ALTs irrespective of development of YMDD variant HBV Lamivudine improves QoL in CHB Lamivudine is well tolerated during long term use