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BORDERNETwork Training on

BORDERNETwork Training on. Hepatitis B. Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A. www.bordernet.eu. www.aidshilfe-potsdam.de.

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BORDERNETwork Training on

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  1. BORDERNETwork Training on Hepatitis B Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A. www.bordernet.eu www.aidshilfe-potsdam.de

  2. This presentation arises from the BORDERNETwork project which has received funding from the European Union, in the framework of the Health Program, and co-funding of the Ministry of Environment, Health and Consumer Protection of the Federal State of Brandenburg. The sole responsibility of any use that may be made of the information lies with the authors (SPI, AIDS-Hilfe Potsdam e.V.)

  3. Table of Contents Epidemiology Genotypes Natural Course Diagnostic Therapy Treatment

  4. Viral Hepatitis

  5. Viral Hepatitis B • HBV: • DNA-Virus • worldwide ca. 350 - 400 Millions with chronic infection • Incubation period: • 2 - 6 months • Transmission ways: • blood contact • sexual intercourse • vertical transmission

  6. Distribution of Chronic HBV Infection > 8 % High 2 - 8 % Intermediate < 2 % Low 1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J ClinGastroenterol. 2004;38(10 suppl): p. 158. 3. WHO/WPRO data.

  7. Epidemiology of HBV (WP7 Countries) BORDERNETworkQuestionnaire for Cooperation Partners; http://ecdc.europa.eu/en/publications/Publications/101012_TER_HepBandC_survey.pdf http://ecdc.europa.eu/en/publications/Publications/TER_100914_Hep_B_C%20_EU_ neighbourhood.pdf OECD Health Data 2010; WHO Europe (2010). Health at a Glance Europe 2010

  8. Distribution of HBV Genotypes Ae, Bj, C, D, F G B, A/Bj B, C, A, D, G A B, C H D D E A, D F, H H, F2 A, a B3 B, C, D

  9. HBV Genotypes

  10. Natural History of Hepatitis B Asymptomatic Carrier Acute Hepatitis B Resolution Fulminant Hepatitis HBsAg Positive > 6 Month Chronic HBeAg positive VBH Chronic HBeAgnegativeVBH Chronic Hepatitis Zirrhosis HCC

  11. Clinical Outcome of Chronic HBV Infection Liver Cancer HCC ____________ Increasing risk for HCC in patients with cirrhosis and with high HBVDNA levels Acute Hepatitis B ____________ Acute liver infection is subclinical in about 70% Chronic Hepatitis B ____________ Development of chronic liver disease in 5 – 95% Liver Cirrhosis ____________ 5-year rate of progression from chronic Hepatitis to cirrhosis is 10-20%

  12. Virus B Hepatitis and HCC Chen CJ et al. JAMA 2006; 295: p. 65 – 73. R E V E A L: 4.155 Patients with chronic hepatitis B infection were followed up over 11 years high HBV-DNA concentration is associated with increasing HCC risk

  13. Diagnostic of HBV – Infection Viral components Antibodies Viral surfaceHBsAgantiHBs antiHBcIgM core - HBcAgantiHBc Viral coreantiHBcIgG envelope - HBeAgantiHBe HBVDNA

  14. Immunologic Markers of HBV Infection

  15. Who Should Be Tested for Hepatitis B? • Blood- and organs donors • Pregnant women • Infants of HBsAg + mothers • Household and sexual contacts with HBV infected persons • MSM, IDU, HIV infected persons • Individuals from countries where prevalence is ≥2% • Patients receiving immunosuppressive therapy • People with signs of liver disease and/or elevated liver enzymes

  16. Treatment of Chronic Hepatitis B • HBe positive HepatitisHBe negative Hepatitis • (YMDD – Mutation) • HBsAg positive HBsAg positive • HBeAg positive HBeAg negative • Decision for therapy depends on: • HBVDNA concentration (>2000 IU/ml) • liver biopsy with grading and staging • ALAT / ASAT increased • Patients with HBeAg negative chronic Hepatitis have more severe histological changes, the incidence of cirrhosis appears to be twofold higher than HBeAg positive patients.

  17. Two Different Treatment Strategies • Peg-Interferon: • Induction of sustained virological response with limited duration of therapy (48 weeks) • Nukleos(t)idanalogues: • Long term suppression of HBV-replication • Improvement of histology • Problem: Development of drug resistance • Elimination of HBV?

  18. Development of Therapy in chronic VBH (Interferon, Nukleosidanalogues, Nukleotidanalogues) • 1992alfa-Interferon • 1999 Lamivudine (Zeffix) • 2003Adefovir (Hepsera) • 2005Peg-IFNa-2a (Pegasys) • 2006Entecavir (Baraclude) • 2007Telbivudine (Sebivo) • 2008Tenofovir (Viread)

  19. Treatment of Chronic Hepatitis B • Pegylated Interferonis given by injection once a week for 48 weeks. The drug can cause side effects such as flu-like symptoms and depression. • Lamivudine with few side effects, but drug resistance • AdefovirDipivoxil (Hepsera)with few side effects, but low antiviral activity • Entecavir (Baraclude) with few side effects, high antiviral activity • Telbivudine (Tyzeka, Sebivo) with few side effects, but development of drug resistance • Tenofovir (Viread) with few side effects, approved August 2008 foradults

  20. Characterization of Different Nukleos(t)ide- Analogues Nukleotide-Analogues Nukleoside-Analogues ETV TDF LdT Low moderate high Antiviral Potency Lam ADV low middle high Genetic Barrier

  21. Aims of Therapy in Chronic Hepatitis B • Reduce morbidity and mortality of HBV infected persons • Increase of survival

  22. Treatment endpoints (1) • HBVDNA level • complete and persistent suppression is a reliable endpoint for clinical progression of liver disease

  23. Seroconversion - Treatment endpoints (2) HBeAg positive chronic Hepatitis BHBeAg negative chronic Hepatitis B HBeAg positive HBeAg negative antiHBe positive HBsAg positive HBsAg negative antiHBs positive HBsAg positive HBsAg negative antiHBspositive

  24. Treatment endpoints (3) In all cases: biochemical: Sustained ALAT normalisation histological:Reduction of fibrosis stage or absence of progression Reduction of inflammatory activity

  25. Treatment endpoints (4) • HBsAg seroconversion to anti HBs • complete eradication of HBV is impossible • covalently closed circular HBVDNA (cccDNA) persists in hepatocytes • reactivation can occur in certain circumstances (Rituximab)

  26. Hepatitis B - IndicationforTherapy (Limited liverfunction: Prolongedprothrombintime (Quick-Test < 50%) Therapy Yes HBsAg-positive Acutehepatitis B? Limited liver function? Yes No Therapy Chronic hepatitis B? NO NO NO Liver cirrhosis NO NO Yes NO NO HBV-DNA> 2.000 IU/ml? HBV-DNA positive? Yes Yes No therapy;Monitoring all6 – 12 Months NEW: ALT repeated raised or histology> A1/F1? Indication for therapy No therapy;Monitoring all6 – 12 Months Yes Extra hepatic manifestations or risk of HCC Yes Cornberg et al. Z Gastroenterol 2011; 49: 871-930.

  27. Treatment Algorithm for Chronic HBV (PEG)-Interferon alpha Temporally limited therapywith PEG-IFN (48 weeks) Yes NO No liver cirrhosis Liver cirrhosis Nukleos(t)id-Analoguewith high genetic barrier Nukleos(t)id-Analogue: Choice depends on: Viral load, co-morbidity, former therapy Virological response after 6 – 12 months? After 6 monthsHBV-DNA< 200 IU/ml With high viral load it can take longer, but continuousHBV-DNA decrease without plateau is important No response After 12 monthsHBV-DNA negative Therapy adherence? Yes Continue therapy Check HBV-DNAall3 – 6 months If HBV-DNAincreases> 1 log over nadir Adjust therapy Cornberg et al. Z Gastroenterol 2011; 49: 871-930.

  28. Suggestions for adaptation of therapy in case of insufficient virological response or development of resistance in nucleos(t)id-analogue-mono-therapy 1These suggestions are not proved in all cases through controlled studies. 2 Entecavir can be used, if presence of virus variants with resistance against Entecavir is excluded, and the application of Tenofovir is not possible through other reasons. 3 Adefovir is no more recommended for the first line therapy. In case of therapy adaptation possible pre-treatment with Lamivudine and existence of confirmed drug resistance have to be regarded. 4 So far for Tenofovir no resistances are demonstrated.

  29. Strategy for prevention of HBV Reactivation Patients, who will get a high dosage* immunosuppression Measurement of HBsAg and anti-HBc (if positive, also HBV-DNA for exclusion of occult HBV-infection) HBsAg positive HBsAg negative,Anti-HBc positive** HBsAg negative,Anti-HBc negative or occult HBV-infection Control of HBV-DNA in short terms Vaccination (if anti-HBs < 100 IU/l) HBV-DNA positive HBV-DNA negative Therapy with a Nukleos(t)id-Analogue***6 – 12 month after stopping immune suppressive therapy treatment finishing is possible, if there is no further indication * The risk for Hepatitis-B-Reactivation depends on the degree of Immunosuppression ** Exception: Pre-emptive therapy should be done in bone marrow and stem cell transplantation *** Choice of drug depends on: e.g. viral load, co morbidities

  30. Patients who will receive or already receive immunosuppressive or chemotherapy • Up to 50% with HBV carrier status develop HBV reactivation under immunosuppressive or chemotherapy • Reactivations occur more frequently with regimens that contain corticosteroids or rituximab • Every NUC is possible, • If the patient is expected to be treated for more than 6 month - ETV or TDF should be preferred

  31. How the therapy with nucleos(t)id-analogue can be stopped? HBeAg+ HBeAg- SeroconversionHBeAg-/anti-HBe+ Noseroconversion End of therapy:earliest 12 months after Seroconversion&HBV-DNA negative Long-term therapy Long-term therapy End oftherapy: anti-HBs-seroconversion Cornberg et al. Z Gastroenterol 2011; 49: 871-930.

  32. Hepatitis B and special Circumstances: 1. Acute and Fulminant Hepatitis B • Fulminant hepatitis B is a life threatening event and may require liver transplantation • A treatment should be started: • if the patient has a deep jaundice more than 4 weeks and prolongation of INR • First line: Tenofovir, Entecavir • Second line: Lamivudine, Telbivudine • Do not use Interferon and Adefovir

  33. Hepatitis B and special Circumstances: 2. Patients with Liver Cirrhosis liver cirrhosis • Aim of therapy: Prevention of liver related complications and progression • Treatment should not be based on elevated ALAT • First line: Drugs with high viral potency and high genetic barrier to HBV resistance, such as Entecavir and Tenofovir • For settings were these drugs are not available, treatment with Lamivudine or Adefovir is also possible, • Close monitoring for treatment complications is necessary

  34. Pregnant Women with Hepatitis B • Pregnancy is no contraindication for treatment with NUC, but Interferon is contraindicated • An existing therapy with Lamivudine or Tenofovir can be continued • A therapy with Adefovir or Entecavir should be changed • It is also possible to start a treatment during pregnancy, • It should be done, if there is a risk of liver de-compensation or a high level of HBVDNA • Treatment should be continued at least 6 month after delivery

  35. Summary liver cirrhosis • Great advances in diagnosis and treatment of chronic Hepatitis B in the last 15 years • Morbidity and mortality of chronic Hepatitis B can be reduced • by increasing awareness, • by commitment of drugs, • by managing the therapy in a good clinical practice.

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