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What to Start: Treatment naïve – PegIFN or Nucleos(t)ide Analogues

What to Start: Treatment naïve – PegIFN or Nucleos(t)ide Analogues. Case. 28 yo man accountant from the US Acquired HBV in college during period of “experimentation” Not previously vaccinated

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What to Start: Treatment naïve – PegIFN or Nucleos(t)ide Analogues

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  1. What to Start:Treatment naïve – PegIFN or Nucleos(t)ide Analogues

  2. Case • 28 yo man accountant from the US • Acquired HBV in college during period of “experimentation” • Not previously vaccinated • History of mild depression several years ago but no recent problems except “stress” with work and 2 small children • No symptoms • No current medications

  3. Case • Evaluation: • AFP = 9 ng/mL • HBeAg + • ALT = 124 (< 40 U/L) • HBV DNA = 8.8 million c/mL • HBV genotype not done • Liver CT scan = “normal appearance to the liver without hypervascular lesion”

  4. Case • Liver biopsy not recommended • He meets guidelines for therapy • He returns with his wife to discuss treatment options • He currently feels well and is not anxious to take medications long-term • His wife has been concerned about his “stress” level, particularly at home

  5. Debate • Peginterferon alfa: Short and to the point (seroconversion) • Oral nucleoside or nucleotide analogues: Durable, dependable,and cost-effective

  6. Peginterferon Alfa:Short and to the point (seroconversion)

  7. 1990 PMEA anti-HBV activity discovered 2008Tenofovir approved for HBV 2001 Telbivudine anti-HBV activity discovered 1991 3TC anti-HBV and anti-HIV activity discovered 1957Interferon discovered 1998 Entecavir anti-HBV activity discovered 2002Adefovir dipivoxil (PMEA prodrug) approved for HBV 1991Interferon alfa-2b approved for HBV 2006Telbivudine approved for HBV 2005Entecavir and peginterferon alfa-2a approved for HBV 1998Lamivudine (3TC) approved as first nucleoside analogue for HBV HBV Treatment in theUnited States: 2009

  8. Duration of HBV Treatment • HBeAg positive • 6-12 months after HBeAg seroconversion to minimize relapse rate • Long-term therapy may be required • HBeAg negative • Relapse common after cessation of therapy • Long-term treatment currently recommended • Cirrhosis • Long-term therapy may be required Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  9. Conclusion: Multivariate analysis adjusted for treatment identified genotype D, HBeAg negative status and normal ALT level as independent predictors for failing to achieve SVR Overall SVR 60 HBeAg pos SVR HBeAg neg SVR 50 40 % SVR 30 20 10 0 Genotype A Genotype B Genotype C Genotype D HBV Genotypes as Predictorsof Response to Interferon-Alfa: Multivariate Analysis SVR by Genotype and HBeAg Status Independent Predictors for SVR Erhardt A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 883.

  10. Randomized 1:1:1 Week 48 Patients stratified according to geographic region and ALT level Peginterferon alfa-2a 180 µg/week + Oral placebo once daily (n = 271) 24 weeks follow-up Peginterferon alfa-2a 180 µg/week + Lamivudine 100 mg/day (n = 271) Patients with HBeAg-positive chronic hepatitis B (N = 814) Lamivudine 100 mg/day (n = 272) Peginterferon-2a and/or Lamivudine in Patients with HBeAg-Positive Chronic HBV Lau GK, et al. NEJM. 2005;352(26):2682-2695.

  11. PegIFN-2a (n=271) PegIFN-2a + lamivudine (n=271) Lamivudine (n=272) Patients (%) 41% 39% 34% 32% 32% 29% 27% 22% 19% 14% 14% 5% Normalized ALT HBV DNA <400 copies/mL HBeAg Seroconversion HBV DNA <105 Copies/mL Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Positive Chronic HBV Responses at End of Follow-Up (week 72) PegIFN-2a statistically significantly better than lamivudine monotherapy for all measures. Lau GK, et al. N Engl J Med 2005;352:2682-2695.

  12. Wk 48 PegIFN alfa-2a 180 μg/wk + Placebo (n = 177)* Patients with HBeAg-negative, HBsAg-positive chronic HBV infection (N = 537) PegIFN alfa-2a 180 μg/wk + LAM 100 mg/day (n = 179)* 4-yr follow-up LAM 100 mg/day (n = 181) Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Negative Chronic HBV • Observational study: 4-yr follow-up of randomized phase III trial *PegIFN-treated patients eligible for participation in long-term follow-up. Marcellin P, et al. AASLD 2008. Abstract 919.

  13. PegIFN-2a (n=177) PegIFN-2a + lamivudine (n=130) Lamivudine (n=130) 60% 59% Patients (%) 44% 43% 43% 29% 20% 19% 7% Normalized ALT HBV DNA <400 copies/mL HBV DNA <20,000 Copies/mL Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Negative Chronic HBV Responses at End of Follow-Up (week 72) PegIFN-2a statistically significantly better than lamivudine monotherapy for all measures. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.

  14. Initial study* Long-term study PEGASYS 180 μg qw + placebo qd PEGASYS 180 μg qw + 100 mg lam qd Lamivudine 100 mg qd 48 weeks EOT (week 48) 6 monthspost-EOT 4 years post-EOT** Long-term Follow-up Studyin HBeAg-negative CHB: Study Design * Marcellin et al. N Engl J Med 2004 ** 4-year analysis of patients from initial study who entered long-term follow-up

  15. N=230 11% 8% Patients withHBsAg clearance (%) 6% 3% Years after EOT 1 2 3 4 HBsAg Clearance Increases After End of Treatment with PEG-IFNα-2a +/- LAM

  16. HBsAg Level as Predictor of Long-term Durabilityof PegIFN Response • Higher response rates at 6 mos associated with Wk 12 HBsAg ≤ 1500 IU/mL vs > 1500 IU/mL in all patients Marcellin P, et al. AASLD 2008. Abstract 919.

  17. Outcomes at Long-term Follow-up Responders Nonresponders P = .0001 100 P = .0001 P < .001 100 86 86 80 72 65 60 53* Percentage 40 20 11 8 0 NormalALT HBV DNANegative (PCR) HBeAgNegative HBsAgNegative Long-term Follow-up After Interferon Therapy: NIH Experience • 103 patients received interferon between 1984-1991 • 30% were responders(lost HBeAg and HBV DNA [by bDNA assay]) • Analysis reviewed long-term outcomesin responders and nonresponders • Mean follow-up time: 6.2 years (range: 1-11) *P value not provided Lau DT, et al. Gastroenterology. 1997:113;1660-1667.

  18. Depression Rigors HCV[1] Myalgias HCV[2] HCV[3] Fatigue HBV[4] Fever Dose Reduction D/C 0 20 40 60 80 100 Side effects in HBV patients are lower than HCV 1. Hadziyannis S, et al. Ann Intern Med. 2004;140:346-355. 2. Fried M, et al. N Engl J Med. 2002;347:975-982. 3. Zeuzem S, et al. Gastroenterol. 2004;127:1724-1732. 4. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.

  19. PegIFN: Summary • High rate of seroconversion with carefully selected patients • High ALT • Favorable genotype • Finite course of therapy • No resistance (ever) • Side effects are better with HBV • No Ribavirin • Different patient group

  20. Oral Nucleos(t)ide Analogues:Durable and Dependable

  21. Anti-viral Agents: Safety, Tolerability, Cost and Risk:Benefit Dienstag JL. New Eng J Med 2008;359:1486-500

  22. HBeAg-positive Chronic HBVHBV DNA Suppression and HBeAg Seroconversion at End of 1 year Dienstag JL. New Engl J Med. 2008

  23. HBeAg-negative Chronic HBVHBV DNA Suppression at End of 1 Year Dienstag, JL

  24. Cumulative Incidence of HBV Resistance EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med;359:1486

  25. Tenofovir • Potent, predictable response • Easy once per day regimen • No food effect • Long-term data (HBV and HIV) • No issues with LAM resistance • Category B in Pregnancy (in case his wife decides to get pregnant)

  26. Double Blind Open-Label Tenofovir 300 mg (n = 250) TDF 300 mg RANDOMIZATION 1:1 Adefovir 10 mg (n=125) TDF 300 mg Pre-treatment Liver Biopsy Week 48 Liver Biopsy Week 72 Week 96 Week 240Liver Biopsy End of Study HBV DNA ≥400 copies/mL option to add emtricitabine (FTC) to TDF in a fixed dose tablet Study 103: Two Year TDFTreatment and ADV Switch Data in HBeAg(+) with CHB • Randomized, Double-Blind, Comparison of TDF vs. ADV for HBeAg(+) Chronic Hepatitis B • HBV DNA >106 c/mL and ALT ≥2x and <10xULN • Knodell Necroinflammatory score ≥3 • Nucleos(t)ide Naïve • Week 48 Phase 3 data showed TDF superior to ADV: • HBV DNA <400 copies/mL: 76% TDF vs. 13% ADV (p<0.001) • 96 week data presented Heathcote E, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 158.

  27. TDF demonstrated durable, potent antiviral activity through Week 96: 82% of pts viremic on ADV at wk 48 were <400 c/mL on TDF at wk 96 No resistance to TDF detected after 2 years on TDF monotherapy ITT Analysis On Treatment Analysis Randomized Double Blind Open Label Randomized Double Blind Open Label 100 100 100 100 89% 90 90 85% 78% 80 80 P=0.374 78% 70 70 P=0.801 60 60 Percentage (%) Percentage (%) 50 50 50 50 40 40 30 30 20 20 20 20 10 10 0 0 0 0 96 96 0 8 16 24 32 40 48 56 64 72 80 88 0 8 16 24 32 40 48 56 64 72 80 88 Weeks on Study Weeks on Study 165 86 142 79 TDF-TDF n= ADV-TDF n= 176 90 174 89 170 88 172 88 171 90 168 89 164 87 TDF-TDF n= ADV-TDF n= 176 90 173 88 165 85 166 84 160 85 148 83 144 81 Study 103: HBV DNA <400 copies/mL Heathcote E, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 158.

  28. Patients with HBV DNA ≥400 copies/mL Patients Experiencing Virologic Breakthrough 1 0 0 1 0 0 H B e A g - ( n = 2 ) H B e A g - ( n = 4 ) 9 0 9 0 H B e A g + ( n = 1 2 ) H B e A g + ( n = 3 ) ( 3 ) 8 0 8 0 ( 8 ) ( 2 ) 7 0 7 0 60 ( 1 ) 60 ( 1 ) Patient Percent 50 50 ( 1 ) 40 40 ( 1 ) 30 30 ( 2 ) ( 2 ) 2 0 20 1 0 ( 0 ) 10 ( 0 ) ( 0 ) 0 0 No Polymorphic Site Conserved Site Change Changes Changes No Polymorphic Site Conserved Site Change Changes Changes No Evidence of TDF Resistance at Two Years • Genotypic changes observed at Week 96/last on TDF among HBeAg- and HBeAg+ TDF treated patients Snow-Lampart A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 977.

  29. HBsAg Loss is observed with oral antivirals • Loss of HSbAg has not been commonly seen with oral anti-HBV therapies • Approximately 0.5% of HBsAg carriers will spontaneously clear HBsAg yearly • TDF achieved HBsAg loss of 3.2% at week 48 and 5% at week 64 Rates of HBsAg Loss in Approved Antiviral Therapies Among Treatment-Naïve Patients with HBeAg+ CHB* * Adapted from AASLD Guidelines, 2007. Snow-Lampart A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 977.

  30. Entecavir • Potent predictable effect • Easy once per day regimen • Must take 2 hours away from food • Long term data • Likely to have resistance issues because of previous LAM exposure • No data on pregnancy in female partners

  31. ETV-022 ETV-901 Week 48 Week 96 Week 144 5 Years 11 RespondersAt Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up R=74 R=37 ETVN=354 243 151 Virologic RespondersAt Week 96 VR=247 VR=198 21 Non-respondersAt Week 48 or who became non-responders during Year 2 NR=19 NR=8 Non-responders [NR]HBV DNA ≥0.7 MEq/mL by bDNA Responders [R]HBV DNA <0.7 MEq/mL by bDNA and HBeAg loss Virologic Responders [VR]HBV DNA <0.7 MEq/mL by bDNA and HBeAg(+) Studies ETV-022/-901: Entecavir Therapy in HBeAg(+) CHB Study Design Han S, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 893.

  32. Studies ETV-022/-901: Proportion with HBV DNA <300 c/mL Through 5 Years HBeAg(+) ETV Long-term Cohort (ETV-022→ETV-901) Year 1 Year 1 Year 2 Year 3 Year 4 Year 5 Han S, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 893.

  33. 96% of patients in the Long-term Histology Cohort who received continuous treatment with ETV achieved histologic improvement All patients with advanced fibrosis/cirrhosis at baseline (Ishak fibrosis score ≥4) demonstrated an improvement in fibrosis 6 5 4 3 2 1 0 Missing Fibrosis Regression with continuous ETV Distribution of Ishak FibrosisScores at Baseline, Year 1, and Years 3–7 Ishak Fibrosis Score Patients (n) Liaw Y-F, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 894.

  34. 25 Placebo (n=215) YMDDm (n=209) (49%) Wild Type (n=221) 21% 20 Placebo 15 13% YMDDm % With Disease Progression 10 WT 5% 5 0 0 6 12 18 24 30 36 Time After Randomization (Months) Viral suppression leads to improved clinical outcomes: HCC and ESLD YF Liaw et al. N Engl J Med. 2004;351:1521-1531.

  35. Oral agents: Summary • Potent, once daily therapy • High genetic barrier with carefully selected agents • TDF, ETV • Very few side effects (particularly compared to PegIFN) • Proven liver disease regression and prevention of ESLD/HCC

  36. Discussion

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