Management of Chronic Hepatitis B & C

1. Management of Chronic Hepatitis B & C نظام الدين الحاج استاذ مساعد كلية الطب - جامعة دمشق مستشفى المواساة الجامعي أيار 2008

2. Healthy Liver

3. Chronic Hepatitis B

4. Core, HBc antigen SHBs POL HBs antigen 42 nm (Smallest known DNA virus) LHBs MHBs Partially double- stranded DNA Hepatitis B Virus

5. HBV Genome 4 Open Reading Frames: - S: S + Pre S1 + Pre S2 - C: C + Pre C - P - X

6. HBsAg Endemicity 8% and above - High 2%-8% - Intermediate Below 2% - Low Geographic Pattern of Hepatitis B Prevalence 1997 Source: WHO, Geneva

7. Prevalence of HBV in Syria • Intermediate HBV endemicity At least 4 % of chronic infection Statistics of Blood Transfusion Centers • Total Population of Syria: 18 866 000 (2002) at least 750 000 Syrian with chronic HBV infection

8. Mode of Transmission of HBV in Syria • Infected blood transfusion or blood products • Needle stick injuries: HCW - injection drug users • Hemodialysis • Sexual transmission: heterosexual - homosexual • Horizontal transmission: childhood - family member • Vertical Transmission (mother to newborn) • Unsafe Procedures: ear piercing-tattooing -barbering.

9. Natural History of Chronic Hepatitis B

10. Natural History of Chronic HBV Infection CompensatedCirrhosis Resolution Stabilisation Liver Cancer AcuteInfection ChronicHepatitis Cirrhosis Death DecompensatedCirrhosis (Death) Chronic Carrier Progression 30 - 50 Years Adapted from Feitelson, Lab Invest 1994

11. Chronic Hepatitis B 1. HBs Ag + > 6 months 2. Serum HBV DNA >2.000 or 20.000 IU/mL 3. Persistent or intermittent elevation in ALT/AST 4. Liver biopsy showing chronic hepatitis necroinflammatory score  4 *

12. Types of Chronic HBV Infections • Wild type HBe Ag + chronic hepatitis • Mutant type HBe Ag – chronic hepatitis More prevalent in Syria Up to 70 %

13. HBe Ag + & HBe Ag – Chronic Hepatitis HBe Ag + HBe Ag – HBs Ag + + HBe Ag + – Anti-HBe – + HBV DNA (IU/mL) > 20. 000 > 2.000 (copie/mL) > 100000 >10000 ALT Elevated Elevated Necro-inflammation + +

14. Initial Evaluation of patients with chronic HBV 1. History & physical examination 2. Laboratory tests for liver disease CBC Hepatic panel PT 3. Tests for HBV replication: HBeAg /anti-HBe HBV DNA by PCR 4. R/O other causes of liver disease: anti-HCV anti HDV

15. Indications of Liver Biopsy • HBs Ag + • Chronic or intermittent elevations of ALT • Candidate for treatment HBV DNA > 2.000 or 20.000 IU/mL • No contraindications for treatment

16. Results of Liver Biopsy • Confirming diagnosis of chronic HB • Grading severity of necroinflammation • Staging the fibrosis • Excluding other inter-current disease

17. Scoring Systems for Chronic Hepatitis

18. Increasing Severity of Inflammation (Grading) Am J Surg Pathol 1995 ; 19 : 1409 - 1417.

19. Progression of Fibrosis(Staging) Am J Surg Pathol 1995 ; 19 : 1409 - 1417.

20. Goal of Treatment of Chronic HBV • HBe Ag + Seroconversion of HBe Ag to anti-HBe • HBe Ag – HBV DNA < 2.000 IU/mL Disappearance of HBs Ag is not the goal

21. أدوية التهاب الكبد الفيروسي المزمن ب الأنتيرفيرون(INF) تحت الجلد 5 مليون وحدة/يوم 10 مليون وحدة 3 مرات/أسبوع أطفال 6 مليون وحدة/م2 3 مرات/أسبوع البيغ أنتيرفيرون(PEG-INF) تحت الجلد 180 ميكروغرام مرة / أسبوع اللاميفودين(LAM) عن طريق الفم 100 ملغ/يوم (طفرة YMDD) الأديفوفير(ADV) عن طريق الفم 10 ملغ/يوم (سمية كلوية) الإنتيكافير(ENT)عن طريق الفم 30 ملغ/يوم التينوفيفير(TDF) عن طريق الفم 300 ملغ/يوم

22. How & when to assess the response to treatment?

23. Category of Response Biochemical (BR)Decrease in serum ALT to normal range Virological (VR)HBe Ag +Loss of HBe Ag HBe Ag – HBV DNA <104 copies/ml Histological (HR)Decrease in HAI by at least 2 points compared to pre-treatment liver biopsy Complete (CR)Biochemical & virological response & loss of HBs Ag

24. What are the predictive factors of response to treatment?

25. Predictive Factors of Response to Therapy • High level of ALT • Low lever of HBV DNA • Female patients • Infection in adulthood • Severe necro-inflammation activity in liver biopsy

26. Treatment of HBe Ag + chronic hepatitis B • IFN First choice • ADF Contraindication to INF Intolerance to INF No response to INF • ADF Lamivudine resistant mutants • ENT • TDF (First choice: ESAL-2008)

27. مخطط معالجة التهاب الكبد المزمن BHBeAg+ HBeAg Positive HBV DNA < 20,000IU/mL (105 copies/ml) HBV DNA ≥ 20,000IU/mL (105 copies/ml) ALT normal ALTelevated • Monitor ALT every 3-12 mos (immune tolerant) • Consider biopsy if age > 35-40 yrs and treat if significant disease • Treat • Adefovir, entecavir, peginterferon, and Tenofovir are first-line options • No treatment • Monitor every 6-12 mos Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

28. Treatment of HBe Ag – chronic hepatitis B • IFN First choice • ADF Contraindication to INF Intolerance to INF No response to INF • ADF Lamivudine resistant mutants(YMDD) • ENT • TDF In view of the need for long term treatment, IFN or ADF, ENT, TDF is preferred

29. مخطط معالجة التهاب الكبد المزمن BHBeAg- HBeAg Negative HBV DNA < 2000IU/mL (104copies/ml) HBV DNA ≥ 2000IU/mL (104copies/ml) ALTnormal ALTelevated • Monitor ALT and HBV DNA or • Consider biopsy since ALT often fluctuates and treat if significant disease • Treat • Adefovir, entecavir, peginterferon, and Tenofovir are first-line options • Long-term treatment required (oral agents) • No treatment • Monitor every 6-12 mos Updatedfrom Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

30. مخطط معاجة التشمع المعاوض الناجم عن التهاب الكبد B HBV DNA (PCR) HBV DNA < 2000 IU/mL HBV DNA ≥ 2000IU/mL • Treat with adefovir or entecavir • May be a role for combination therapy • Significant clinical consequences associated with lamivudine resistance in this population • No treatment • May choose to treat or observe • If treat: adefovir, entecavir, or combination treatment • May be a role for combination therapy Keeffe EB, et al. Clin Gastroenterol Hepatol.2006;4:936-962.

31. إيقاف العلاج • 0 HBeAg+ HBeAg- انقلاب مصلي لا إنقلاب مصلي أوقف العلاج بعد 6-12 شهراً علاج مستمر استمرار العلاج Keeffe et al.Clin Gastroenterol Hepatol. 2004;2:7.

32. Side Effects of Interferon • Influenza-like symptoms • Alopecia • Neutropenia & thrombocytopenia • Depression • Induction of autoimmune disease (thyroid,….) • Cardiac complication: MI, AP • Erythema at injection site • Loss of libido • Diabetes mellitus

33. Contraindications of Interferon • Current psychosis or a history of psychosis • Uncontrolled depressive illness • Presence of active auto-immune disease • Neutropenia or thrombocytopenia • Decompensated cirrhosis • Symptomatic heart disease • Uncontrolled seizures

34. Follow-up of Patients on IFN Therapy • CBC q 2 weeks to 8 weeks then q 8 weeks ½ dose WBC < 1 500 / mm Neutrophils < 750 / mm Platelets < 50 000 / mm Stop WBC < 1 000 / mm Neutrophils < 500 / mm Platelets < 25 000 / mm • Thyroid tests q 3 - 4 months

35. Inactive HBs Ag Carrier State* 1. HBs Ag + > 6 months 2. HBe Ag – , anti-HBe + 3. Serum HBV DNA < 20.000 IU/mL 4. Persistently normal ALT/AST levels 5. Liver biopsy: absence of significant hepatitis necroinflammatory score < 4 * Previously described as ‘healthy’ carrier state

36. Follow-up of Inactive HBs Ag Carrier State • ALT q 6-12 months • If ALT >1-2 x ULN: check serum HBV DNA level & exclude other causes of liver disease • Consider screening for HCC in relevant population FP & US every 6 months

37. معظم المرضى الذين يعالجون بمضادات الفيروسات الفموية بحاجة لعلاج طويل الأمد ~20% فقد HBeAgو حدوث انقلاب مصلي يمكن إيقاف العلاج بعد 6-12 شهراً بحاجة لعلاج طويل الأمد عدم حدوث انقلاب مصلي بعد سنة بحاجة لعلاج طويل الأمد Dienstag et al, N Engl J Med. 1999;341:1256-1263. Marcellin et al. N Engl J Med. 2003;348:808-816. Chang et al. Hepatology. 2004;40(4 suppl):193A.

38. How & to whom you give the vaccine of HBV?

39. Schedule of Vaccine Standard 0, 1, 6 months Rapid 0, 1, 2 months Accelerated 0, 7, 21 days Higher antibody levels after 3rd dose Rapid protection 4th dose at 12 months for those at intermediate risk Rapid protection 4th dose at 12 months for those at high-risk

40. Indications of HBV vaccine • Universal All infants All children & adolescents not vaccinated • High risk group Health care workers Household contacts CRF & hemodialysis patients Repeated blood transfusions Homosexuals Sexual partners of HBV carriers Illicit injection drug users

41. Adverse Events of Vaccine • Minimal reactions Local pain: only local pain more frequent in PCT Mild & transient fever: mostly lasting only 24 h • Anaphylaxis Incidence 1 / 600 000 vaccine doses Epinephrine should always be available No severe or fatal anaphylactic reaction reported • Demyelinating diseases Not support for causal relationship

42. Efficacy of HBV Vaccine & Age Efficacy of the vaccine depends on age Newborns 100 % < 20 years 95 % < 40 years 90 %

43. Vertical Transmission • Mother with HBsAg + & HBeAg + 80 - 90 % infected newborns 90 % of infected infants become chronic carriers • Mother with HBsAg + & HBeAg – 15 % infected newborns 90% of infected infants become chronic carriers

44. How to prevent the vertical transmission of HBV?

45. Active & Passive Immunization • Immediately after Delivery 1st dose Vaccine HBIG (200 IU) • 1 month after delivery 2nd dose Vaccine • 2 month after delivery 3rd dose Vaccine in 2 different sites

46. Treatment of HBV Infection in Children Treated as adults with modification of doses • IFN: 6 MU / m2 3 times / week No more than 10 MU per dose • LAM 3 mg / kg / day No more than 100 mg / day • ADF: Not yet approved for treatment in children

47. Treatment of HBV infection in CRF & KT Data on all 4 agents are limited There are no guideline or consensus • IFN: CRF Indicated with surveillance KT Can lead to rejection • LAM: CRF Indicated with surveillance KT Indicated • ADF: Limited data with this drug • TDF: CRF Indicated with surveillance KT Indicated

48. HBs Ag Positive

49. Hepatology 2007; 45: 507 - 539.

50. Chronic Hepatitis C