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Chronic Hepatitis B: Update on Treatment

Chronic Hepatitis B: Update on Treatment. Emmet B. Keeffe, MD, MACP Professor of Medicine Emeritus Stanford University Medical Center Vice President and Chief Medical Office Romark Laboratories. Background. Chronic Hepatitis B. Globally 350-400 million chronic carriers; 75% in Asia

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Chronic Hepatitis B: Update on Treatment

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  1. Chronic Hepatitis B: Update on Treatment Emmet B. Keeffe, MD, MACP Professor of Medicine Emeritus Stanford University Medical Center Vice President and Chief Medical Office Romark Laboratories

  2. Background

  3. Chronic Hepatitis B • Globally • 350-400 million chronic carriers; 75% in Asia • 530,000 deaths per year • United States • 1.25 million chronic carriers; 0.4% prevalence rate • 4-5,000 deaths per year • Immigration impacts prevalence of disease in U.S. (8-10% in some Chinese American communities) • Premature mortality from cirrhosis or HCC: 25-40% • Expanded treatment options in 2008 Beasley P, et al. Hepatology. 1982;2:553-556. WHO. 2007. http://www.who.int/mediacentre/factsheets/fs204/en/ Accessed February 15, 2008 Lai CL, et al. Lancet. 2003;362:2089-2094.

  4. Declining Incidence of Acute HBVUnited States, 1982-2005 Estimated new infections in 2005 = 51,000 74% decline 90% decline 58% decline 99% decline Impact of national strategy to eliminate HBV transmission, i.e., primarily vaccination MMWR. 2007;56:1-24.

  5. Decline in the Need for LT for ESLD Secondary to HBV in the US Widespread use of HBV antiviral therapy Kim WR, et al, Hepatology. 2007;46:238A.

  6. Hepatitis B VirusWild Type and Mutants • Wild type • Usual HBeAg (+) hepatitis • Precore mutation (27% U.S. patients)1 • Abolishes HBeAg production • Core promoter mutation (44% U.S. patients)1 • Down-regulates HBeAg production • Treatment-induced mutations2 • Lamivudine: L180M +/- M204V/I (YMDD) • Adefovir: N236T and A181V • Entecavir: I169, T184, S202 and M250 (LAMR patients) • Telbivudine: M204I 1Chu CJ, et al. Gastroenterology. 2003;125:444-451. 2Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  7. Phases of Chronic HBV Infection Candidates for Therapy* • Immune tolerance phase# • HBeAg (+); HBV DNA high (105-10); ALT normal • Immune clearance/HBeAg-positive CHB* • HBV DNA (105-10) and ALT levels high or fluctuating; active inflammation on liver biopsy • Non-replicative phase (inactive HBsAg carrier) • HBeAg (-); HBV DNA low (<104); ALT normal • HBsAg may later become undetectable • Reactivation/HBeAg-negative CHB* • HBV DNA (104-8) and ALT levels high or fluctuating; active inflammation on liver biopsy #Not seen in adult-onset infection Yim HJ, Lok ASF. Hepatology. 2006;43:A173-S181.

  8. Treatment Landscape in US: 2008

  9. Treatment of Chronic Hepatitis B1-Year Efficacy of Current Regimens *IFN and lamivudine: hybridization assay; adefovir, entecavir, tenofovir, and PEG-IFN: PCR assay. †Pending approval by regulatory agencies.

  10. Tenofovir versus Adefovir for CHB Study Endpoints (Week 48) Primary Endpoint • Complete response: HBV DNA <400 c/mL and histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis) Secondary Endpoints • HBV DNA <400 c/mL • Normal ALT • Histological improvement • Resistance surveillance Heathcote EJ, et al. Hepatology. 2007;46:861A. Marcellin P, et al. Hepatology. 2007;46:290A-291A.

  11. 100 P<0.001 P>0.05 P<0.001 90 76 80 74 68 67 70 TDF 60 ADV % Patients 50 40 30 20 13 12 10 0 HBV DNA <400 copies/mL Histological Improvement Complete Response TDF versus ADV for HBeAg(+) CHB Heathcote EJ, et al. Hepatology. 2007;46:861A.

  12. HBeAg and HBsAg Loss and Seroconversion at Week 48 p>0.05 p>0.05 p=0.018 22.2% 20.9% 3.2% 17.5% 17.5% p>0.05 Percentage (%) 1.3% 0% 0% N=153 TDF Subjects N=80 ADV Subjects N=158 TDF Subjects N=82 ADV Subjects

  13. TDF versus ADV for HBeAg(-) CHB TDF 100 93 P>0.05 P<0.001 ADV P<0.001 90 80 72 71 69 70 63 60 % Patients 49 50 40 30 20 10 0 HBV DNA <400 copies/mL Histological Improvement Complete Response Marcellin P, et al. Hepatology. 2007;46:290A-291A.

  14. Treatment of Chronic Hepatitis BRates of Antiviral Drug Resistance

  15. What Happens When Oral Therapy is Continued for 4-5 Years?

  16. ADV for HBeAg-Positive CHB3-Year Data: HBeAg Loss 100 100 Kaplan Meier Estimates 80 80 60 60 51% 51% HBeAg HBeAg loss loss % With Event % With Event 42% 42% Seroconversion Seroconversion 40 40 43% 43% 21% 21% 29% 29% 20 20 12% 12% 0 0 0 0 24 24 48 48 72 72 96 96 120 120 144 144 Weeks On Study Weeks On Study HBeAg Loss: 288 288 252 252 215 215 158 158 128 128 75 75 45 45 HBeAg Seroconversion : : 288 267 240 191 157 90 53 Marcellin P, et al. Hepatology. 2004;40:655A

  17. 100 80 60 % With Event 56% 40 45% 28% 20 0 0 24 48 72 96 120 144 Weeks On Study ADV for HBeAg-Positive CHB3-Year Data: HBV DNA and ALT 100 Kaplan Meier Estimates 81% ALT normalization 80 71% 58% HBV DNA < 1,000 c/mL 60 % With Event 56% 40 45% 28% 20 0 0 24 48 72 96 120 144 Weeks On Study ALT Normalization: 282 179 110 83 61 35 22 HBV DNA < 1,000: 307 254 210 156 132 83 48 Marcellin P, et al. Hepatology. 2004;40:655A

  18. ADV for HBeAg-Negative CHB5-Year Data: Fibrosis Scores 17/24 (71%) 80 70 60 P=0.005* 11/24 (46%)† 50 12/22 (55%)‡ 8/24 (33%) 40 % With Ishak Fibrosis Reduced ≥ 1 Point 30 7/22 (32%)† 20 10 4-year cohort 5-year cohort 0 0 1 2 3 4 5 Years of ADV Treatment *Cochran-Armitage exact test of trend over time for 5Y cohort.†No fibrosis improvement: n=9 for 4Y cohort; n=15 for 5Y cohort.‡1 patient received concomitant lamivudine. Hadziyannis et al. AASLD 2005. Abstract 72492.

  19. Treatment

  20. Goals of Treatment of CHB • Prevent long-term clinical outcomes (cirrhosis, HCC, death) by durable suppression of HBV DNA • Treatment endpoints in clinical trials and practice • Decrease serum HBV DNA to low or undetectable1 • Decrease or normalize serum ALT • Induce HBeAg loss or seroconversion • Induce HBsAg loss or seroconversion2 • Improve liver histology3 1Current primary goal of therapy 2Ultimate goal of therapy 3Clinical trials only; not routinely assessed in practice Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  21. Treatment Algorithm for Chronic HBV Roundtable In February 2003, a US physician expert panel met and developed a hepatitis B treatment algorithm Goal: provide clear direction to treating physicians regarding diagnosis, treatment and monitoring Emphasis placed on review of literature, especially recent guidelines Recommendations evidence-based, but when controlled data lacking, the panel relied on clinical experience; algorithm published in February 2004 Panel reconvened 8-05 to update recommendations; algorithm published 8-06; met again 12-07 Keeffe EB, Dieterich D, Han S, Jacobson I, Martin P, Schiff E, Tobias H, Wright T. Clin Gastroenterol Hepatol. 2006;4:936-962.

  22. Recent Reports that Influenced Recommendations in Updated US Treatment Algorithm

  23. HBV Genotype

  24. HBV GenotypesEpidemiology • HBV classified into 8 genotypes (A-H)* • A: North America, Western Europe and Africa • B and C: Asia • D: Southern Europe, Africa and India • E: West Africa • F: Central and South America and Alaska • G: United States, France and Germany • H: Central America • B associated with less active disease, slower progression, and lower incidence of HCC than C • A and B respond better to IFN than C and D; genotype not predict response to oral agents * >8% difference in genome sequence Kramvis A, Kew MC. J Viral Hepat. 2005;12:456-464.

  25. Response by Genotype HBeAg Seroconversion at End of Follow-up PEG IFN alfa-2a2 PEG IFN alfa-2b1 52 50 50 43 42 40 40 33 31 30 30 30 Patients (%) 23 22 20 20 10 10 0 0 Genotype B n=76 B n=12 C n=21 D n=51 C n=162 D n= 9 A n=47 A n=23 1Janssen et al. Lancet. 2005;365:123-129. 2Lau et al. N Engl J Med. 2005;352:2682-2695.

  26. Correlation between HBV DNA and Development of Cirrhosis and HCC

  27. HBV DNA Associated With Increased Risk of HCC and Cirrhosis • REVEAL: Long-term follow-up of untreated HBsAg positive individuals in Taiwan 50 Cumulative Incidence of HCC at Year 13 Follow-up[1] (N = 3653) Cumulative Incidence of Cirrhosis at Year 13 Follow-up[2] (N = 3582) 40 36.2 30 23.5 Patients (%) 20 14.9 12.2 9.8 10 5.9 4.5 3.6 1.4 1.3 0 < 300 300- 999 1000- 9999 10,000- 99,999 ≥ 100,000 < 300 300- 9999 10,000- 99,999 100,000- 999,999 ≥ 1 million Baseline HBV DNA (copies/mL) 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  28. HBV DNA Associated with Increased Risk of HCC • Serum HBV DNA 104 copies/mL may be an independent predictor of the development of cirrhosis and HCC in dose-response fashion • Unknown if results can be generalized to all HBV carriers • These data support possibility of preventing long-term risk of cirrhosis and HCC by sustained suppression of HBV replication • Hypothesis needs to be proven prospectively Iloeje U, et al. Gastroenterology. 2006;130:678-86. Chen CJ, et al. JAMA. 2006;295:65-73.

  29. Serum HBV DNA Levels in Patients with HBeAg-negative CHB

  30. HBeAg(+) patients with elevated ALT levels HBV DNA During Different Stagesof CHB HBeAg(+) CHB with HBeAg loss HBeAg(+) CHB HBeAg(+) patients with sustained HBeAg loss: (a) spontaneous, and(b) IFN-related 11 10 9 8 7 6 5 4 3 2 1 0 11 10 9 8 7 6 5 4 3 2 1 0 Log10 HBV DNA (copies/mL) Log10 HBV DNA (copies/mL) (a) (b) (a) (b) (a) (b) 1st 2ndSample 3rd 1st 2ndSample 3rd Chu CJ, et al. Hepatology 2002;36:1408-1415

  31. HBeAg(-) patients with persistent or intermittently elevated ALT levels HBV DNA During Different Stagesof CHB Inactive HBsAg Carrier HBeAg(-) CHB* HBeAg(-) patients with persistently normal ALT levels 11 10 9 8 7 6 5 4 3 2 1 0 11 10 9 8 7 6 5 4 3 2 1 0 Log10 HBV DNA (copies/mL) Log10 HBV DNA (copies/mL) 1st 2ndSample 3rd 1st 2ndSample 3rd *Supports lower HBV DNA threshold for Rx HBeAg(-) CHB Chu CJ, et al. Hepatology 2002;36:1408-1415

  32. 9 600 HBV DNA ALT 8 500 7 400 6 5 Log10 HBV DNA (copies/mL) ALT (IU/L) 300 4 3 200 2 100 1 0 0 0 10 20 30 40 50 60 70 Follow-up (months) Fluctuating Course of HBeAg(-) Chronic Hepatitis B HBeAg - - - - - - - - - Anti-HBe + + + + + + + + + PC 1896 G G A>G CP 1762 1764 AG>TA TA>AG AG Chu CJ, et al. Hepatology. 2002;36:1408-1415

  33. Definition and Implications of Normal ALT Levels

  34. Updated Definitions of Healthy Ranges for ALT Levels • Retrospective cohort study; university hospital in Milan; 6,835 first time blood donors 1995-1999; anti-HCV negative and no contraindication to donation • ALT activity independently related to: BMI, and abnormal lipid or carbohydrate metabolism • Updated upper limits • Males 40  30 U/L (-25%) • Females 30  19 U/L (-37%) Prati D, et al. Ann Intern Med. 2002;137:1-9

  35. Chronic HBV Infection and Normal ALTSummary of Recent Literature 20-25% (range, 12% to 47%) of patients have stage 2 fibrosis or greater Yang et al: 34% in e+ and 47% in e- Wang et al: 43% Nguyen et al: 12% Lai et al: 23% Normal ALT levels often  (50%) on follow-up Age >45 yr predictive of significant fibrosis Significant histologic findings common in e(-) CHB Yang LM, et al. Chinese J Dig Dis. 2002;3:150-153. Wang C, et al. Hepatology. 2005;42:573A. Nguyen M, et al. Hepatology. 2005;42:593A. Lai M, et al. Hepatology. 2005;42:720A.

  36. Hepatitis B: Histology and Normal ALTin 452 Chinese Patients Patients (%) Normal ALT, HBeAg-positive Normal ALT, HBeAg-negative High ALT, HBeAg-positive High ALT, HBeAg-negative Yang et al. Chinese J Dig Dis. 2002;3:150

  37. 0 Not All Normal ALT Hepatitis B Patients Are Created Equal Young, immunotolerant Older, non-immunotolerant* *Liver biopsy may be helpful in patients >35-40 yr of age

  38. Treatment Algorithm for CHB in 2008 • Baseline evaluation should include HBV genotype, particularly if peginterferon therapy considered • Preferred treatment options: entecavir, telbivudine1, tenofovir2, and peginterferon alfa-2a • Interferon alfa-2b replaced in routine practice by peginterferon alfa-2a • In pivotal trials, entecavir and telbivudine superior to lamivudine, and tenofovir superior to adefovir • Revised normal ALT levels (30 IU/L for men, and 19 IU/L for women) should be used as criteria for treatment 1If serum HBV DNA undetectable at week 24 of therapy 2Pending approval by regulatory agencies Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  39. Treatment Algorithm for CHB in 2008 • Liver biopsy should be considered for patients with normal ALT levels, especially if age >35-40 years • For treatment of patients with lamivudine resistance, adefovir (or tenofovir) add-on preferred over switch (increased rate of adefovir resistance with switch) and preferred over entecavir monotherapy (high rate of novel mutations) • May be evolving role for combination therapy for lamivudine or adefovir resistance, and for cirrhosis, HBV/HIV coinfection, and after liver transplantation Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  40. When to Start Therapy: 1) Elevated HBV DNA Level 2) ALT Level above ULN

  41. Treatment Algorithm Patients with Compensated Disease HBeAg Positive HBV DNA <20,000IU/mL HBV DNA ≥20,000IU/mL ALT Normal ALT Elevated • Monitor ALT every 3-12 months (immune tolerant) • Consider biopsy, if age >35–40, and treat if significant disease • Treat to HBeAg SC • Entecavir, telbivudine*, tenofovir, and peginterferon are first-line options • No treatment • Monitor every 6–12 months *If HBV DNA (-) at week 24 Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  42. Treatment Algorithm Patients with Compensated Disease HBeAg Negative HBV DNA <2,000IU/mL HBV DNA ≥2,000IU/mL ALT Normal ALT Elevated • Monitor ALT and HBV DNA, or • Consider biopsy, since ALT often fluctuates, and treat if significant disease • Treat long-term • Entecavir, telbivudine*, tenofovir, and peginterferon are first-line options • No treatment • Monitor every 6–12 months *If HBV DNA (-) at week 24 Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  43. Treatment AlgorithmPatients with Compensated Cirrhosis HBV DNA (PCR) HBV DNA <2,000IU/mL HBV DNA ≥2,000IU/mL • Treat with entecavir or tenofovir • May be a role for combination therapy • Significant clinical consequences associated with lamivudine resistance in this population • May choose to treat or observe • If treat: entecavir, tenofovir, or combination Rx • May be a role for combination therapy Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  44. 25 20 15 10 5 0 Effect of LAM on Disease Progression in CHB and Advanced Fibrosis Placebo Disease Progress (%) P=.001 Lamivudine 0 6 12 18 24 30 36 Time to Disease Progression (months) Placebo (n=215) Lamivudine (n=436) Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  45. Time to Disease Progression by YMDD Status 25 Placebo (n=215) 21% YMDDm (n=209) (49%) 20 Wild Type (n=221) Placebo % with disease progression 15 13% YMDDm 10 5% 5 WT 0 0 6 12 18 24 30 36 Time after randomization (months) Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  46. Effect of LAM on Incidence of HCC in CHB and Advanced Fibrosis P = .047 Placebo 10 Diagnosis of HCC (%) Lamivudine 0 0 6 12 18 24 30 36 Months Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  47. Treatment Recommendations for Patients with Compensated Cirrhosis 1Lamivudine and telbivudine not preferred secondary to high rate of resistance. 2Peginterferon alfa-2a may be option in early cirrhosis; lamivudine not preferred due to high rate of resistance. Lok ASF, McMahon BJ. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  48. Potential Role of Combination Therapy • Advantages • Reduced rate of resistance • Potential for added efficacy • Disadvantages • Greater cost • Potential for increased toxicity • Potential patient populations • Patients with resistance* • Cirrhotics • After liver transplantation • All patients? *Data strongest in support of this indication

  49. Treatment of HBV: Special Cases • Chemotherapy: Prophylactic treatment to prevent reactivation (Rx from 1 wk before to 6-12 mo after)1 • % with hepatitis: 53% untreated vs. 14% lamivudine-treated • Third trimester of pregnancy: Treatment to reduce rate of vertical transmission2 • Studies limited; ?use in women with HBV DNA >108 c/mL • HBV/HIV coinfection3 • If therapy of HIV not required: adefovir, entecavir or PEG-IFN • If HAART needed, then tenofovir + emtricitabine or lamivudine • Liver transplantation: Prophylactic treatment after LT to prevent reinfection3 1Kohrt H, et al. Aliment Pharmacol Ther. 2006;24:1003-1016. 2Xu WM, et al. Hepatology. 2004;40:272A-273A. 3Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  50. When to Stop Therapy:Traditional Endpoints

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