BORDERNETwork Training on Hepatitis B Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A. www.bordernet.eu www.aidshilfe-potsdam.de This presentation arises from the BORDERNETwork project which has received funding from the European Union, in the framework of the Health Program, and cofunding 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.) Table of Contents Epidemiology Genotypes Natural Course Diagnostic Therapy Treatment Viral Hepatitis Virus Transmission Clinical outcome Hep. A RNA fecal-oral never chronic Hep. B DNA parenteral 5-10% chronic Hep. C RNA parenteral 50 - 80% chronic Hep. D RNA parenteral as super infection 90% chronic Hep. E RNA fecal-oral never chronic Viral Hepatitis B Country HBsAg+ (%) China 5,3 - 12 (2) South Korea 2,6 - 5,1 (2) India 2,4 - 4,7 (2) Taiwan 10 - 13,8 (2) Vietnam 5,7 - 10 (2) Japan 4,4 - 13 (3) Africa 5 - 19 (2) Russia 1,4 - 8 (2) US / Europe 0,3 - 12 (2) HBV: DNA-Virus worldwide ca. 350 - 400 Millions with chronic infection Incubation period: 2 - 6 months Transmission ways: blood contact sexual intercourse vertical transmission Distribution of Chronic HBV Infection > 8 % High 2 - 8 % Intermediate < 2 % Low 1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl): p. 158. 3. WHO/WPRO data. Epidemiology of HBV (WP7 Countries) Country No. Of Persons with Reported no of Prevalence Incidence 2006-08, HBV/HIV Co chronic HBV estimated persons with rate cases per 100.000 infection estimated chronic HBV Bulgaria no data no data Estonia no data: no data no data 9,9 no data 3,5 (NIHD: 2,16 in 2009 / 1,72 in 2010) 1,2 1,1 no data Germany Poland 492.300 1.400.000 1.276 in 2009 0,6 3,7 no data ~10.000 Romania 1.200.000 – 1.300.000 ~ 20.000 5,6 5,1 Slovakia 32.474 no data 0,6 2,1 ~10.000 / 2.400 reported no data Ukraine no data no data no data no data no data BORDERNETwork Questionnaire 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 Distribution of HBV Genotypes Ae, Bj, C, D, F B, A/Bj H B, C, A, D, G A G D D F, H B, C A, D B3 E H, F2 A, a B, C, D HBV Genotypes Genotype Region Comments A Northern America, Northern Europe India Africa • • • More sensitive to pegIFN ALT more frequently More rapid 3TC resistance B Asia • • More benign More sensitive to pegIFN C Asia • More severe disease, HCC D Southern Europe Middle East and India • • Less response to pegIFN Pre-core mutations higher E F G H West- and South Africa Central- and South America USA and Europe Central America and California • Unknown Natural History of Hepatitis B Asymptomatic Carrier Resolution Acute Hepatitis B Fulminant Hepatitis HBsAg Positive > 6 Month Chronic HBeAg negative VBH Chronic Hepatitis Zirrhosis HCC Chronic HBeAg positive VBH Clinical Outcome of Chronic HBV Infection Acute Hepatitis B ____________ Chronic Hepatitis B ____________ Liver Cirrhosis ____________ Liver Cancer HCC ____________ Acute liver infection is subclinical in about 70% Development of chronic liver disease in 5 – 95% 5-year rate of progression from chronic Hepatitis to cirrhosis is 1020% Increasing risk for HCC in patients with cirrhosis and with high HBVDNA levels 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 HBVDNA concentration is associated with increasing HCC risk Diagnostic of HBV – Infection Viral components Viral surface HBsAg Antibodies antiHBs antiHBc IgM core - HBcAg antiHBc Viral core antiHBc IgG envelope - HBVDNA HBeAg antiHBe Immunologic Markers of HBV Infection HBsAg HBeAg HBVDNA Anti HBc IgM Anti HBc IgG Anti HBe Anti HBs ALAT Acute Virus B Hepatitis + + + + Ø Ø Ø Chronic HBeAg pos. Hepatitis + + + Ø + Ø Ø Chronic HBeAg neg. Hepatitis + Ø + Ø + + Ø Chronic HBeAg neg. HBV Infection (Carrier) + Ø Low or negative Ø + + Ø normal Occult Virus B Hepatitis Ø Ø + Ø + + + normal Hepatitis Recovery Ø Ø Ø Ø + + + normal Vaccination Ø Ø Ø Ø Ø Ø + normal 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 Treatment of Chronic Hepatitis B HBe positive Hepatitis HBsAg positive HBeAg positive HBe negative Hepatitis (YMDD – Mutation) HBsAg 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. 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 HBVreplication Improvement of histology Problem: Development of drug resistance Elimination of HBV? Development of Therapy in chronic VBH (Interferon, Nukleosidanalogues, Nukleotidanalogues) 1992 alfa-Interferon 1999 Lamivudine (Zeffix) 2003 Adefovir (Hepsera) 2005 Peg-IFNa-2a (Pegasys) 2006 Entecavir (Baraclude) 2007 Telbivudine (Sebivo) 2008 Tenofovir (Viread) Treatment of Chronic Hepatitis B Pegylated Interferon is 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 Adefovir Dipivoxil (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 for adults Characterization of Different Nukleos(t)ide- Analogues Nukleotide-Analogues TDF moderate LdT Lam Low Antiviral Potency high Nukleoside-Analogues ADV low middle Genetic Barrier high ETV Aims of Therapy in Chronic Hepatitis B Reduce morbidity and mortality of HBV infected persons Increase of survival Treatment endpoints (1) HBVDNA level complete and persistent suppression is a reliable endpoint for clinical progression of liver disease Seroconversion - Treatment endpoints (2) HBeAg positive chronic Hepatitis B HBeAg negative chronic Hepatitis B HBeAg positive HBeAg negative antiHBe positive HBsAg positive HBsAg negative antiHBs positive HBsAg positive HBsAg negative antiHBs positive Treatment endpoints (3) In all cases: biochemical: Sustained ALAT normalisation histological: Reduction of fibrosis stage or absence of progression Reduction of inflammatory activity 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) Hepatitis B - Indication for Therapy (Limited liver function: Prolonged prothrombin time (Quick-Test < 50%) HBsAg-positive Acute hepatitis B? NO NO HBV-DNA > 2.000 IU/ml? Chronic hepatitis B? Liver cirrhosis NEW: ALT repeated raised or histology > A1/F1? NO NO Extra hepatic manifestations or risk of HCC NO No Therapy Yes HBV-DNA positive? Yes No therapy; Monitoring all 6 – 12 Months Therapy Limited liver function? Yes NO Yes Yes Yes Cornberg et al. Z Gastroenterol 2011; 49: 871-930. Yes NO Indication for therapy No therapy; Monitoring all 6 – 12 Months Treatment Algorithm for Chronic HBV (PEG)-Interferon alpha Yes Temporally limited therapy with PEG-IFN (48 weeks) NO No liver cirrhosis Liver cirrhosis Nukleos(t)id-Analogue with high genetic barrier Nukleos(t)id-Analogue: Choice depends on: Viral load, co-morbidity, former therapy Virological response after 6 – 12 months? After 6 months HBV-DNA < 200 IU/ml Continue therapy After 12 months HBV-DNA negative Check HBV-DNA all 3 – 6 months Cornberg et al. Z Gastroenterol 2011; 49: 871-930. With high viral load it can take longer, but continuous HBV-DNA decrease without plateau is important If HBV-DNA increases > 1 log over nadir No response Therapy adherence? Yes Adjust therapy Suggestions for adaptation of therapy in case of insufficient virological response or development of resistance in nucleos(t)id-analogue-mono-therapy Insufficient response to therapy / resistance Options1 Lamivudine Change to Tenofovir (A) (Change to Entecavir)2 Change to Tenofovir (B) Change to Entecavir (B) Change to Tenofovir (A) Change to Tenofovir (A) (Change to Entecavir)2 Change to Entecavir, or Adefovir3 Entecavir Telbivudine Tenofovir4 add Lamivudine, Telbivudine or Entecavir (C) 1 These suggestions are not proved in all cases through controlled studies. 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. 2 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 antiHBs < 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 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 How the therapy with nucleos(t)id-analogue can be stopped? HBeAg+ HBeAg- Seroconversion HBeAg-/anti-HBe+ No seroconversion End of therapy: earliest 12 months after Seroconversion & HBV-DNA negative Long-term therapy Long-term therapy End of therapy: anti-HBs-seroconversion Cornberg et al. Z Gastroenterol 2011; 49: 871-930. 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 Hepatitis B and special Circumstances: 2. Patients with Liver Cirrhosis Aim of therapy: Prevention of liver related complications and liver cirrhosis 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 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 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.