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3rd Paris Hepatitis Conference: Morning Session on HBeAg-Neg CHB

This session at the 3rd Paris Hepatitis Conference explores the challenges and advancements in treating HBeAg-negative chronic hepatitis B (CHB). Experts discuss the use of pegylated interferon, its long-term follow-up, HBsAg clearance, and predictors of sustained virologic response.

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3rd Paris Hepatitis Conference: Morning Session on HBeAg-Neg CHB

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  1. 3rd Paris Hepatitis Conference: MorningSession on HBeAg-Neg CHB WHY DO I TREAT MY PATIENTS WITH PEGYLATED INTERFERON? Bob Perrillo Baylor University Medical Center Dallas, TX USA

  2. Problems Confronting Clinician with HBeAg Negative Hepatitis B • High rate of relapse to conventional strategies • Diagnosis can be a bit challenging • Patients tend to be older group than HBeAg (+) with more severe disease • Not much known about predictors of sustained virologic response to IFN

  3. Recent PEG IFN Developments that Impact on Care of Patients with HBeAg (-) CHB • Long-term follow up • Durability • HBsAg clearance • On treatment prediction of SVR • HBV DNA response • HBsAg response • Clarification of importance of genotype • Better understanding of tolerability

  4. Antiviral Therapy: A Matter of ChoiceCase Features Should Determine Approach Peginterferon Nucleoside Analog

  5. Many Other Factors Go Into a Treatment Decision Drug cost /cost of care Indirect costs * Tolerability * Convenience * Need for monitoring * Finite treatment * Diminished infectivity Potential for long term benefit (HBsAg loss)* Durability off treatment Modified from Perrillo, Hepatology, 2006

  6. 70 60 50 40 30 20 10 0 Initial and Long Term Follow Up from PEG IFN alfa-2a Study in HBeAg-Neg CHB Initial study Follow-up study 6 mos after EOT 4years after EOT n= 356* n = 230* 60% Marcellin, EASL, 2008 Marcellin, NEJM 2005 43% 27% 24% 19% 17% ALT HBV DNA ALT HBV DNA normal <20,000 < 400 normal < 20,000 < 400 * w/wo LAM

  7. 70 60 50 40 30 20 10 0 Follow up Data in PEG IFN-Treated HBeAg-Neg CHB Follow-up study 4 years after EOT n = 230 Initial study 6 months after EOT n =356 ~ 3% increase annually in responders 11% 2% with lamivudine 3% HBsAgclearance ALTnormal ALTnormal HBV DNA< 400 copies HBV DNA < 400 copies HBsAgclearance Marcellin, 2005, 2008

  8. Prolonged PCR Negativity Does not Allay Concerns About Relapse Virologic relapse 0.8 • 50 Chinese patients • treated with LAM • 37 treated for 2 yrs • 27 neg. by PCR • for ≥ 9 mos meet • criteria for treatment • withdrawal Clinical relapse 0.6 0.4 0.2 Months to Relapse 0- 2 4 6 8 10 12 14 16 18 Fung, 2004

  9. Long Term Response in Adefovir-Treated Cohort Negative for HBV DNA x 4-5 Years • 33 patients neg for HBV DNA x 4-5 yrs on adefovir • Followed for median duration 18 mos off treatment • 67% continue with ALT NL • HBV DNA becomes detectable in all (“low,” varying from BDL to 5 x 104 copies) • HBV DNA declines with further ollow up Hadziyannis et al, AASLD, 2006

  10. Genotype A Genotype E Genotype F GenotypeB GenotypeC Genotype G GenotypeD 46% 10% 14% 35% 40% 9% 35% 42% 31% 83% 22% 15% Worldwide Distribution of HBV Genotypes Asia 1 Europe 1 Mediterranean 1 USA 2 1 Westland, Gastroenterology 2003; 2 Chu, Gastroenterology 2003

  11. Genotype and Virologic Response to IFN According to HBeAg Status in 1229 Patients Standard =298l PEG = 491; withLAM 440 Erhardt , AASLD 2008, Absract 883

  12. Frequency of Depression-Related Events During Treatment with PEG IFN alfa-2a 25 23% Chronic hep B studies 22% 20 Chronic hep C studies Events (%) 15 P = 0.003 P < 0.001 P = 0.027 10% 9% 10 4% 5 2% 8/346 4/47 9/90 4/448 185/827 180/702 0 ALL PATIENTS ASIANS CAUCASIANS Depression events 4% (B) vs 22% (C) Marcellin et al, Liver International, 2007

  13. Side Effects: HBeAg (-) CHB (n = 177) vs CHC (n = 791)

  14. Patients with Cirrhosis Respond Just as Well to IFN As Those Without Response rates HBeAg Cirrhosis Non-Cirrhosis P Value Niederau + 63% 47% ns D Lau + 59% 24% 0.01 van Zonneveld + 50% 29% 0.034 Lin + 39% 35% ns Cooksley Peg IFN2a + 48% 35% ns Buster Peg IFN2b + 33% 14% 0.02* Papatheodoridis - 28% 27% ns Brunetto - 26% 18% ns Cooksley Peg IFN2a - 40% 45% ns * Dose reduction, early discontinuation, and SAEs comparable for both groups (33% vs 34%, 11% vs 8%, 4% vs 5%) modified after Chu and Liaw Sem Liver Dis 2006

  15. Peginterferon for Delta Hepatitis Patients often HBeAg-negative Interferon only effective treatment Treatment required long-term Where possible, continue until loss of HBsAg (Farci, J Viral Hep 2007; 14:S58-63)

  16. 3rd Paris Hepatitis Conference: Session on HBeAg-Neg CHB HBsAg Loss, HBsAg Monitoring, and Relationship of Treatment- Induced Changes in HBsAg Concentration to Virologic Response

  17. Why Is HBsAg Clearance So Important?

  18. Qualitative Differences Between HBsAg and Prolonged Viral Suppression • Durability of virologic response • Significantly lower levels of intracellular genomic template (cccDNA) • Better long-term prognosis • Lower rate of HCC • Lower rate of progression to cirrhosis • Less chance of viral reactivation • Spontaneous • Immune suppression

  19. HBsAg Levels with Peg IFN Alfa -2a and Lamivudine in HBeAg (-) CHB • 63 patients (42 IFN, 21 LAM) analyzed for HBsAg by ADVIA Centaur [Bayer]; (92% geno D) • Low BSL HBsAg level predictive of HBsAg clearance • HBsAg decreased in both treatment groups - Sharp drop in most IFN treated patients; sustained in VR - More gradual slope for LAM: ETU of HBsAg is median of 10.6 yrs of treatment vs 5.4 yrs with IFN Manensis et al, Anitiviral Ther, 2007

  20. Measuring HBsAg in HBeAg (-) CHB: with 60 Week Extended Course of Peg IFN Alfa -2a * Response = PCR negative at FU week 24 Gish, Lau, Schmid, Perrillo Am J Gastro 2007

  21. HBV DNA SVRs vs Non-responders NRs (n=18) Log copies/mL SVRs (n=12) Treatment FUP Moucari et al, Hepatology, in press

  22. HBsAg LevelSVRs vs Non-Responders NRs (n=18) Log IU/mL SVRs (n=12) Treatment FUP Moucari et al, Hepatology, in press

  23. HBsAg: Predictive Value for SVR by Wk 24 Decline (1 Log IU/mL) SVR (+) Week 24 ↓ HBsAg ≥ 1 Log IU/mL PPV = 92 % n = 11 n = 12 n = 1 SVR (-) 48 Patients SVR (+) n = 1 n = 36 Week 24 ↓ HBsAg < 1 Log IU/mL NPV = 97 % n = 35 SVR (-)

  24. HBsAg Decline at Wk 48 Predicts Outcomes at Year 3 After End of Rx* * Based on subset of 198 patients In initial treatment cohort; HBsAg (-) in 16 (8%) Brunettto et al, Hepatology, in press

  25. SUMMARYWhyPEG IFN First for HBeAg-Negative CHB? Useful as first line therapy in selected patients: Age, comorbid illnesses, compensated liver disease Test for genotype (non geno D) Better tolerated than in hepatitis C Patients with stable cirrhosis can be treated safely Specific advantages: Discrete interval of treatment Responses can be durable HBsAg loss Possibility of response directed therapy

  26. Summary: Why PEG IFN FIrst? (2) • Responses can be durable • If treatment fails, no impact on success with NA or • requirement for more complex therapy

  27. Managing Patients with Limited Access to Care Potential Problem Addressment

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