Bible Class: HBV Infection

Transkript

1 Bible Class: HBV Infection Nasser Semmo UVCM, Hepatology

2 What is the HBV prevalence? 2

3 Hepatitis B Worldwide approx. 350 Mio. chronically infected with HBV Approx. 40% of the world population: anti-hbc-antibodies positive Approx. 15 Mio. chronically HBV infected in Europe Switzerland 0,3% (24000) Worldwide annually, 0,6-1 Mio. people die from complications of chronic HBV-Infection (WHO, 2002) HBV responsible for 60% of all HCC cases worldwide 3

4 Worldwide distribution of HBV infection 4

5 What are Hepatitis B Risk Factors? 5

6 Hepatitis B Risk Factors Blood contamination IV-Drug Abuse Injured mucus membranes Sexual Transmission Perinatal Transmission 6

7 Natural course of HBV Infection? 7

8 Natural Course of Hepatitis B Infection 90% Resolution Acute Hepatitis B 10% Fulminant Hepatitis (0.5-1%) 70% Asymptomatic carriers Liver failure Chronic Hepatitis B 30% Liver cirrhosis? 3-5%/year HCC 8

9 Who to screen for HBV? 9

10 Hepatitis B Whom to screen? Elevated Liver enzymes and/or signs of hepatitis or chronic liver disease of unknown origin Liver cirrhosis/-fibrosis New diagnosis of HCC Pat. with migration background and from regions with high HBsAg prevalence (East Europe, Mediterranean) Family member or sexual partner from HBV infected patients DGVS-Leitlinie Hepatitis B 2007/ EASL

11 Hepatitis B Whom to screen? Medical staff Homosexuals a/o persons with frequent changing sexual partners Active o. previous i.v.-drug abuse Dialysis patients DGVS-Leitlinie Hepatitis B 2007/ EASL

12 Hepatitis B Whom to screen? HIV- a/o HCV-infected Pat. Recipients of organs before transplantation Blood- and Organ donors Patients before or during immunsuppressive therapy or Chemotherapy Pregnant women (HBsAg) DGVS-Leitlinie Hepatitis B 2007/ EASL

13 Prevention of HBV Reactivation Algorithm?? 13

14 Prevention of HBV Reactivation HBsAg + HBsAg - Anti-HBc + Anti-HBs +/- HBsAg - Anti-HBc - Anti-HBs - HBV-DNA +/- HBV-DNA & ALT alle 1-3 m Impfung Vor Start immunsuppressiver Tx HBV DNA + HBV DNA ALT < ULN HBV DNA ALT > ULN Preemptive antivirale Tx (NAs) bis zu 12 M nach Ende immunsuppr. Tx Suche nach anderen Ursachen einer Erhöhung der Leberenzyme 14

15 When to treat pregnant HBV pos. women? 15

16 Vertical transmission despite active and passive vaccination N=1068 Kinder von HBeAg positiven Müttern 3% vertikale Transmission bei HBV DNA >10 6 cop/ml 5,5 % vertikale Transmission bei HBV DNA >10 7 cop/ml 9,6% vertikale Transmission bei HBV DNA >10 8 cop/ml à Antivirale Therapie im 2./3. Trimester ab IU/ml Han et al., J Hepatology 2011, Petersen Hepatology

17 Prävention einer HBV Reaktivierung Screening aller Patienten auf HBsAg und anti-hbc vor Einleitung einer immunsuppressiven Therapie und/oder einer Chemotherapie! HBV Impfung, wenn HBV Serologie komplett negativ HBsAg + Pat.: Preemptive Therapie mit NA bis zu 12 Monate nach Ende einer immunsuppressiven Tx/ Chemotherapie, unabhängig von HBV Viruslast Behandlung mit Lamivudine, wenn HBV Viruslast < 2000 IU/mL Behandlung mit Entecavir oder Tenofovir wenn HBV Viruslast > 2000 IU/mL EASL CPG, J Hepatol

18 Prävention einer HBV Reaktivierung HBsAg -/ Anti-HBc + pat.: HBV Viruslast-Bestimmung, wenn pos. = Okkulte HBV Infektion Okkulte HBV Infektion: Preemptive Therapie mit NA HBsAg -/ Anti-HBc + / HBV DNA - pat.: Regelmässige Kontrollen von ALT und HBV DNA, und Tx mit NA sobald HBV-Reaktivierung, vor Erhöhung der ALT Kontrollintervalle zwischen 1-3 Monate, abhänging von der Art der immunosuppressiven Therapie und Komorbiditäten EASL CPG, J Hepatol

19 Prävention einer HBV Reaktivierung Empfehlung einiger Experten: Prophylaxe mit Lamivudin bei allen HBsAg-negativen, anti-hbc positiven Patienten, die Rituximab und/oder kombinierte Therapien für hämatologische Tumorerkrankungen erhalten, wenn sie anti-hbs negative und/oder eine engmaschiges Monitoring der HBV DNA nicht garantiert ist Die optimale Prophylaxedauer für diese Indikation ist nicht klar HBsAg-negative Empfänger von Lebertransplantaten von anti-hbc positiven Spendern sollten eine dauerhafte Prophylaxe mit Lamivudin erhalten EASL CPG, J Hepatol

20 When to treat HBV? 20

21 HBV Treatment Indication 21

22 How to treat HBV? 22

23 HBV- Treatment: HOW? High TA (>3-5 x) Low viral titer Short duration of infection GT A or B PEG-IFN 2a 180ug 48 weeks 23

24 Is there a stopping rule for PegIFN? 24

25 Practical application of response-guided therapy using HBsAg levels (pegifn-treated) Identify responders (PPV) Identify non-responders (NPV) Week 12: - HBeAg-positive HBsAg <1500 IU/mL - HBeAg-negative e+ e- 10% decline HBsAg Week 12: - HBeAg-positive No decline in HBsAg or HBsAg >20,000 IU/mL - HBeAg-negative e+ e- No decline in HBsAg + <2log decline HBV DNA Piratvisuth T, et al. APASL 2010 Liaw et al. Hepatology 2011 Marcellin et al, APASL 2010 Lampertico et al. EASL

26 HBV Treatment: HOW? 26

27 Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients: to identify good responders HBeAg positive HBeAg negative Week 12-24: - HBsAg <1500 IU/ml Week (geno D): - 10% decline HBsAg * 47-57% Positive Predictive Values Piratvisuth T, et al. APASL 2010 Liaw et al. Hepatology 2011 Marcellin et al, APASL 2010 Lampertico et al. EASL

28 Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients: to identify non responders HBeAg-positive HBeAg-negative (geno D) Week 12: - No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C) Week 24: Week 12: - No decline in HBsAg + <2 log decline in HBV DNA - HBsAg >20,000 IU/ml (A,B,C,D) % Negative Predictive Values Sonneveld et al. Hepatology 2010 Piratvisuth et al. APASL 2010 Liaw et al. Hepatology 2011 Sonneveld et al., Hepatology 2013 Rijckborst et al. Hepatology 2010 Rijckborst / Lampertico et al. J Hepatol

29 What are the NUC options? 29

30 HBV is suppressable in most cases with indefinite treatment duration... Lamivudin (Zeffix, Epivir) Adefovir (Hepsera) Entecavir (Baraclude) Telbivudin (Sebivo) 36-72% % 67-90% 60-88% Tenofovir (Viread) 76-94% Lai CL, et al. Hepatology 2005; 42:748A (AASLD Abstract LB01); Lau G, et al. NEJM 2005; 352: ; Chang T-T, et al. NEJM 2006; 354: ; Marcellin P, et al. NEJM 2003;348: ; Marcellin et al., AASLD 2007, Heathcote et al., 30

31 Can NUCs be stopped? 31

32 When to stop NUC therapy? Treatment End points HBeAg+ HBeAg- Seroconversion HBeAg- /ana- HBe+ No seroconversion End of therapy: At least a6er 12 months A6er seroconversion And HBV- DNA negaave Long- term therapy Long- term therapy End of therapy: AnA- HBs- Seroconversion EASL HBV Guidelines

33 When to stop NUC therapy? CHB Treatment Guidelines EASL 2012 guidelines HBeAg positive A) confirmed anti-hbe seroconversion (and undectable HBV DNA) after at least 12 months of consolidation* B) confirmed HBsAg loss and anti-hbs seroconversion HBeAg negative confirmed HBsAg loss and anti-hbs seroconversion Cirrhotics confirmed HBsAg loss and anti-hbs seroconversion *A proportion of patients who discontinue NUC therapy after anti-hbe seroconversion may require retreatment, since they fail to sustain their serological and/or virological response adapted from EASL HBV Guidelines, J Hepatol

34 Management of adverse events When to reduce IFN, and when to stop it? 34

35 Pegylated Interferon - Reduce Peg IFN if - Absolute neutrophil count falls below 750/mm 3 - Platelet count falls below 50,000/mm 3 - Stop Peg IFN if - Absolute neutrophil count falls below 500/mm 3 - Platelet count falls below 25,000/mm 3 - or if severe unmanageable depression develops 35

36 Leukopenia/Neutropenia In general, infection rate during HBV treatment is elevated However, neutropenia alone in patients with compensated HBV infection is not associated with elevated infection risk Patients with neutropenia do not have higher infection rate in comparison to those without neutropenia Dose reduction of IFN does not lead to reduction of susceptibility to infections Therefore dose reduction not necessary if no signs of infection present Thus: IFN-reduction in pat. with co-morbidities, older pat, liver cirrhosis a/o Diabetes if neutrophiles < 750, Filgrastim (Neupogen) if neutrophiles <500 Roomer et al., Hepatology 2010, Antonini et al., Infection

37 Thrombopenia IFN Dose reduction if Tc< Give Eltrombopag (Revolade) if despite IFN reduction no improvement of Tc and if further IFN dose reduction not possible STOP IFN, if Tc<20000, and if no improvement with Revolade Revolade dosage: 1x25 mg daily CAVE: Portal vein thrombosis through Eltrombopag possible (Afdhal et al., NEJM 2012) 37

38 THANK YOU 38