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Testing and linkage to care for HDV patients in the TC region Prof. Dr. Cihan Yurdaydin

Testing and linkage to care for HDV patients in the TC region Prof. Dr. Cihan Yurdaydin University of Ankara Medical School Gastroenterology Department The First Transcaucasus International Conference on Liver Diseases Tblisi, Sep 5-6, 2014, Tbilisi, Georgia. HDV Super-Infection.

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Testing and linkage to care for HDV patients in the TC region Prof. Dr. Cihan Yurdaydin

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  1. Testing and linkage to care for HDV patients in the TC region Prof. Dr. Cihan Yurdaydin University of Ankara Medical School Gastroenterology Department The First Transcaucasus International Conference on Liver Diseases Tblisi, Sep 5-6, 2014, Tbilisi, Georgia

  2. HDV Super-Infection 90% chronic More severe disease Acute HDV Chronic Hepatitis B Simultaneous Co-Infection 95% recovery More frequent fulminant Acute HBV Acute HDV

  3. REPLICATION OF THE DELTA VIRUS 5’ 3’ 5’ 3’ « « « 5’ « 5’ « « « 5’

  4. Hepatitis D > Hepatitis B Hepatitis D = Hepatitis B Hepatitis D < Hepatitis B

  5. Longutidinal follow-up of HBV DNA and HDV RNA patterns Schaper et al. J Hepatol 2010; • Both viruses were active in 15 (40.5%) patients and inactive in 4 (10.8%) • HDV alone was active in 12 (32.4%) and HBV in 6 (16.2%) • Considerable fluctuating activity of one or both viruses, including alternating predominance

  6. Ankara Uni. Facts • Chronic delta hepatitis (CDH) is the most severe form of chronic viral hepatitis • In Western Europe more patients die from CDH compared to HIV infection and unfortunately CDH is not vanishing • The only effective treatment is with interferons • New treatment approaches are an urgent need

  7. Ankara Uni. Goals of treatment in chronic viral hepatitis PREVENTION OF: Progression of disease Development of cirrhosis Development of HCC Deathfromliverdisease

  8. Ankara Uni. Goals of Therapy in Chronic Hepatitis B HBsAgclearance/seroconversion (closest to the equivalent of undetectable HCV RNA inchronichepatitis C) Goals of Therapy in Chronic Hepatitis D Firm immunological control rather than eradication of the virus

  9. Global prevalence of HDV infection Wedemeyer and Manns. Nat Rev Gastroenterol Hepatol 2010

  10. DELTA HEPATITIS EPIDEMIOLOGY 1. Endemic disease: Some Balkan and Mediterranean countries, former republics of the SU, Middle East, Africa 2. Epidemic diseasein isolated communities: Northern South America, Amazon Basin 3. Disease in high risk groups(i.v. drug users): U.S., West and Northern Europe

  11. Ankara Uni. DEVELOPMENT OF ANINTERNATIONAL REFERENCE PREPARATION FOR HEPATITIS D VIRUS RNA Michael Chudy Paul-Ehrlich-Institut Federal Institute for Vaccines and Biomedicines WHO Collaborating Centre for Quality Assurance of Blood Products and in vitro Diagnostic Devices

  12. Ankara Uni. Feasibility Study Chudy 2012

  13. EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 21 to 25 October 2013 Collaborative Study to Establish a World Health Organization International Standard for Hepatitis D Virus RNA for Nucleic Acid Amplification Technique (NAT)-Based Assays Michael Chudy1, Kay-Martin Hanschmann1, Mithat Bozdayi2,J. Kreß1, C. Micha Nübling1 and the Collaborative Study Group* Summary This report describes the World Health Organization (WHO) project to develop an international standard for hepatitis D virus (HDV) RNA for the use with nucleic acid amplification technique (NAT)-based assays. The candidate standard is a lyophilized preparation of HDV genotype 1 strain, obtained from a clinical plasma specimen, diluted in human negative plasma. Fifteen laboratories from nine countries participated in a collaborative study to evaluate the candidate preparation (sample 1 and sample 2) alongside the corresponding liquid-frozen bulk material (sample 3) and a liquid frozen unprocessed HDV RNA positive plasma specimen (sample 4) using their routine HDV NAT. The results of the study indicate the suitability of the candidate material of the HDV genotype 1 (sample1 and sample 2) as the proposed \1st WHO standard for HDV RNA. It is therefore proposed that the candidate material (PEI code 7657/12) is established as the 1st WHO International Standard for HDV RNA for NAT-based assays with an assigned potency of 5.75×105 International Units (IU) when reconstituted in 0.5 mL of nuclease-free water. On-going real-time and accelerated stability studies of the proposed International Standard indicate that the preparation is stable and suitable for long-term use at the proposed storage conditions.

  14. EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION Geneva, 21 to 25 October 2013 Collaborative Study to Establish a World Health Organization International Standard for Hepatitis D Virus RNA for Nucleic Acid Amplification Technique (NAT)-Based Assays Michael Chudy1, Kay-Martin Hanschmann1, Mithat Bozdayi2,J. Kreß1, C. Micha Nübling1 and the Collaborative Study Group* Summary This report describes the World Health Organization (WHO) project to develop an international standard for hepatitis D virus (HDV) RNA for the use with nucleic acid amplification technique (NAT)-based assays. The candidate standard is a lyophilized preparation of HDV genotype 1 strain, obtained from a clinical plasma specimen, diluted in human negative plasma. Fifteen laboratories from nine countries participated in a collaborative study to evaluate the candidate preparation (sample 1 and sample 2) alongside the corresponding liquid-frozen bulk material (sample 3) and a liquid frozen unprocessed HDV RNA positive plasma specimen (sample 4) using their routine HDV NAT.The results of the study indicate the suitability of the candidate material of the HDV genotype 1 (sample1 and sample 2) as the proposed \1st WHO standard for HDV RNA. It is therefore proposed that the candidate material (PEI code 7657/12) is established as the 1st WHO International Standard for HDV RNA for NAT-based assays with an assigned potency of 5.75×105 International Units (IU) when reconstituted in 0.5 mL of nuclease-free water. On-going real-time and accelerated stability studies of the proposed International Standard indicate that the preparation is stable and suitable for long-term use at the proposed storage conditions.

  15. NATURAL HISTORY 4 3 FIBROSIS 2 1 5 10 15 Years

  16. HDV genotypes- phylogenetic analysis (new classification) (Radjef et al, J Virol 2004) HDV-8 HDV-7 HDV-5 HDV-2 HDV-6 HDV-4 HDV-3 HDV-1

  17. Effect of HDV genotype on survival Taiwanese study of untreated patients with median median follow-up of 135 months 100 HDV genotype II 80 60 HDV genotype I Cumulative survival rate (%) 40 20 P=0.0105 0 10 0 5 15 Patients at riskHDV genotype I: 46 29 25 10HDV genotype II: 72 55 49 27 Follow-up (yrs) Su et al. Gastroenterol 2006

  18. HBV- HDV genotypeconnection Su et al, Gastroenterology 2006 Variable Risk ratio 95% Confidence p value Interval Genotype C HBV 13.43 2.31- 78.16 0.004 Age > 60 11.96 1.83- 78.01 0.009 Genotype I HDV 9.74 1.94- 48.89 0.006

  19. Ankara Uni. TREATMENT OF CHRONIC DELTA HEPATITIS * Evidence based successful treatment : interferons Wedemeyer & Manns, Ciancio & Rizzetto Nature Rev Gastroenterol Hepatol 2010 & 2011, Yurdaydin C. Sem Liver Dis 2012

  20. Ankara Uni. IFN treatment: Problems • How can treatment efficacy be assessed? • How consistent and reliable is a sustained virologic response? • The impact of therapy in the high proportion of patients with cirrhosis • What is the response of treatment-naïve vs treatment experienced patients? • What is the optimal duration of treatment? • Can response to treatment be predicted? • Or can NRs be predicted? • Are better markers of treatment efficacy needed?

  21. Ankara Uni. IFN treatment: Problems • How can treatment efficacy be assessed? • How consistent and reliable is a sustained virologic response? • The impact of therapy in the high proportion of patients with cirrhosis • What is the response of treatment-naïve vs treatment experienced patients? • What is the optimal duration of treatment? • Can response to treatment be predicted? • Or can NRs be predicted? • Are better markers of treatment efficacy needed?

  22. Ankara Uni. IFN treatment: Problems • How can treatment efficacy be assessed? • Best: HBsAg clearance • Realistic: Posttreatment HDV RNA negative • How consistent and reliable is a sustained virologic response? • Not reliable

  23. Ankara Uni. Is 6 months treatment-free follow-up a reliable surrogate marker of tx efficacy? Number of patients with negative HDV RNA Heidrich et al, Hepatology 2014

  24. Ankara Uni. IFN treatment: Problems • How can treatment efficacy be assessed? • How consistent and reliable is a sustained virologic response? • The impact of therapy in the high proportion of patients with cirrhosis • What is the response of treatment-naïve vs treatment experienced patients? • What is the optimal duration of treatment? • Can response to treatment be predicted? • Or can NRs be predicted? • Are better markers of treatment efficacy needed?

  25. Ankara Uni. Frequently observed adverse events in pts with advanced liver disease on Peg-IFN treatment during the HIDIT-1 Study Kabaçam et al, Turk J Gastroenterol 2012

  26. Ankara Uni. IFN treatment: Problems • How can treatment efficacy be assessed? • How consistent and reliable is a sustained virologic response? • The impact of therapy in the high proportion of patients with cirrhosis • What is the response of treatment-naïve vs treatment experienced patients? • What is the optimal duration of treatment? • Can response to treatment be predicted? • Or can NRs be predicted? • Are better markers of treatment efficacy needed?

  27. Ankara Uni. Of note, no published study so far has shown that prolonging treatment is better than one year treatment … but the quality of those studies were in general poor Lack of evidence is not equal to lack of efficacy

  28. Ankara Uni. IFN treatment: Problems • How can treatment efficacy be assessed? • How consistent and reliable is a sustained virologic response? • The impact of therapy in the high proportion of patients with cirrhosis • What is the response of treatment-naïve vs treatment experienced patients? • What is the optimal duration of treatment? • Can response to treatment be predicted? • Or can NRs be predicted? • Are better markers of treatment efficacy needed?

  29. Ankara Uni. HDV RNA levels in INF early responders Yurdaydin et al, J Viral Hepat 2008 HDV RNA log10 (copies / mL) HDV RNA log10 (copies / mL)

  30. NUCLEOSIDE ANALOGUES IN CHRONIC DELTA HEPATITIS LAMIVUDINE FAMCICLOVIR ADEFOVIR DIPIVOXIL ENTECAVIR CLEVUDINE 6-12 months tx data reported NO EFFECT TENOFOVIR Median Tx duration: 6.1 years- EFFECTIVE Yurdaydin et al, J Hepatol 2002; Yurdaydin et al J Viral Hepat 2008; Wedemeyer et al, NEJM 2011; Kabacam et al AASLD 2009; Sheldon et al Antiviral Ther 2008

  31. Ankara Uni. REPLICATION OF THE DELTA VIRUS 5’ 3’ 5’ 3’ « « « 5’ « 5’ « « « 5’

  32. Ankara Uni.

  33. Ankara Uni. Effect of entecavir on HBsAg levels in CDH p= 0.03 HBsAg (IU/mL) Kabaçam et al, Clin Infect Dis 2012

  34. Ankara Uni. Effect of entecavir vs. pegylated interferon on HBsAg levels in HBeAg (-) CHB Reijnders et al, J Hepatol 2011

  35. Ankara Uni. Effect of prolonged NA tx on HBsAg levels Manesis et al, J Hepatol 2011

  36. Ganem & Prince, NEJM 2004

  37. Ankara Uni. Effect of the immune status on HBsAg levels in patients with HIV-HBV co-infection Arendt et al, Viral Immunol 2012

  38. Ankara Uni. Increase in CD4 cells correlate with decline in HBsAg levels Arendt E et al, Viral Immunol 2012

  39. Combinationtreatment in CDH Interferon- ribavirin: Not superiorto IFN monotherapy Kaymakoğlu et al, AntimicrobAgentsChemother 2005; Günşar et al, AntiviralTher 2005; Niro et al, Hepatology 2006 Interferon-lamivudine: Not superiorto IFN monotherapy Wolters et al, J ViralHepat 2000; Yalçın et al, CurrResTherClinExp 2002; Canbakan et al J GastroenterolHepatol 2006, Yurdaydın et al, J ViralHepat 2008 Interferon-adefovir: Not superiorto IFN monotherapy Wedemeyer et al, NEJM 2011

  40. HBsAgLevels Wedemeyer, Yurdaydin et al, NEJM 2011 p<0.05 3 pts lost HBsAg All 3 in the Peg+AD group Wedemeyer, Yurdaydin et al, NEJM 2011

  41. Mean HDV RNA levels 6 5 4 Mean HDV RNA levels [log10 copis/ml] 3 2 1 0 Baseline W12 W24 W48 Peg ± Tenofovir: HDV RNA response PEG-IFNa-2a + Tenofovir PEG-IFNa-2a +Placebo % of patients HDV RNA negative 80 60 p=0.37 42% 40 34% Decline baseline vs. week 48 p=<0.001 in both arms 20 0 Baseline W12 W24 W48 Yurdaydin et al, AASLD 2012

  42. Mean HBsAg levels 5 4 Mean HBsAg levels [log10 IU/ml] 3 2 1 Baseline W12 W24 W48 Peg ± Tenofovir: HBsAg response PEG-IFNa-2a + Tenofovir PEG-IFNa-2a +Placebo % of patients with HBsAg-decline >0.5 Log10IU/ml 80 60 40 26% 25% 20 0 Baseline W12. W24 W48 Yurdaydin et al, AASLD 2012

  43. TREATMENT: THE (NEAR) FUTURE

  44. THE HDV LIFE CYCLE 2 1 3 Hepatocyte entry inhibitors TLR-9 agonists Prenylation inhibitors 4

  45. Thank you

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