Chronic Hepatitis B Infection

Transcription

1 Chronic Hepatitis B Infection Mohssen Nassiri Toosi, MD Imam Khomeinin Hospital Tehran University of Medical Sciences

2 Chronic Hepatitis B Infection Virus : HBs Ag Positive Host Liver Health

3 Chronic Hepatitis B Infection HBs Ag Positive HBs Ag Positive HBs Ag Positive HBs Ag Positive 1. Serology test HBe Ag positive HBe Ag positive Serology test: HBeAg 2. Virology test HBV-DNA very, very high Virology test: HBV DNA HBe Ag negative HBe Ag negative HBV-DNA high HBV-DNA relatively high 3. Biochemical tests liver damage tests AST, ALT liver function tests Biochemical INR, Alb, Bili test: AST/ALT 4. Structural / Histology test Structural/histopathology test liver ultrasound, pathology, fibroscan liver damage tests AST, ALT liver function tests INR, Alb, Bili liver ultrasound, pathology, fibroscan HBV-DNA low liver damage tests AST, ALT liver function tests INR, Alb, Bili liver ultrasound, pathology, fibroscan liver damage tests AST, ALT liver function tests INR, Alb, Bili liver ultrasound, pathology, fibroscan Immune tolerance Immune clearance Non replicative Pre-core mutant Liver Health Liver Health Liver Health Liver Health Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

4 Immune tolerance Immune clearance Non replicative Pre-core mutant Immune tolerance Immune clearance Non replicative Pre-core mutant Immune tolerance Immune clearance Non replicative Pre-core mutant

5 HBV virus Immune tolerance Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

6 HBV virus Immune clearance Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

7 HBV virus Non replicative Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

8 HBV virus Pre-core mutant Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

9 HBV virus Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

10 HBV virus Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

11 HBV virus Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

12 HBV virus Host : Age, F o l l o w t h e p a t i e n t e v e r y s i x m o n t h s

13 HBV: Who Should Be Treated? Ideally, all patients with chronic HBV infection are candidate for HBV therapy. Benefits Limitations and Risks Likelihood of Liver adverse outcome Liver Inflammation (grade > 4) or Liver Fibrosis (stage = > 2) Patient s age & preference & pregnancy Suppress not eradicate Life long treatment Costs (affordable?) Drug adverse effects ( safety? ) Drug resistance Risk of cirrhosis / HCC in patient in family

14 Who Should Be Treated? All HBV carriers are potential treatment candidates. Not a question of who to treat but the question is when ( treat now or monitor and treat later when indicated ) A patient who is not a treatment candidate now can be a treatment candidate in the future Changes in HBV replication status / activity / stage of liver disease Availability of new and better treatments

15 Factors affecting HBV disease activity and progression Virus HBe Ag Viral load Host Gender Age Genetic (family Hx.) Weight Environment Weight Smoking Alcohol

16 Immune tolerance Virus status HBe Ag Positive HBV-DNA very, very high ( > 20, ,000,000 IU/ml ) Age Liver status AST, ALT < Years normal INR, Alb., Bili normal Liver ultrasound normal

17

18 What is expected in liver biopsy of immunotolerant phase HBs Ag positive patients?

19

20

21 Who can wait and Who can not? Patient 1 - Female / 29 yrs, asymptomatic, ALT 22, HBeAg +ve, HBV DNA 1,178,000,000 IU/ml

22 Nomogram for Predicting Risks of cirrhosis & HCC Model Pt 1 Gender 0 / 2 F (0) Age (0) Patient 1 - Female/29 yrs, asymptomatic, ALT 22, HBeAg +ve, HBV DNA 1,178,000,000 IU/ml ALT (1) HBe Ag 0 / 2 pos (2) HBV DNA (c/ml) log (4) Total score Yr risk of HCC 1.2%

23 Who can wait and Who can not? Patient 1 - Female / 29 yrs, asymptomatic, ALT 22, HBeAg +ve, HBV DNA 1,178,000,000 IU/ml Patient 2 - Male / 46 yrs, asymptomatic, ALT 36, HBeAg +ve, HBV DNA 210,000 IU/ml

24 Immune tolerance Virus status HBe Ag Positive 1. Virus status : virus like this at Age > 40 HBV-DNA very, very high ( > 20, ,000,000 IU/ml ) Age Liver status AST, ALT < Years normal INR, Alb., Bili normal Liver ultrasound normal

25

26

27

28 Nomogram for Predicting Risks of cirrhosis & HCC Model Pt 1 Pt 2 Gender 0 / 2 F (0) M (2) Age (0) 46 (3) Patient 2 - Male / 46 yrs, asymptomatic, ALT 36, HBeAg +ve, HBV DNA 210,000 IU/ml ALT (1) 36 (1) HBe Ag 0 / 2 pos (2) pos (2) HBV DNA (c/ml) log (4) 5.3 log (4) Total score Yr risk of HCC 1.2% 21%

29 Immune tolerance Virus status HBe Ag Positive 1. Virus status : virus like this at Age > 40 Treat for HBV ( IFN or NUCs) HBV-DNA very, very high ( > 20, ,000,000 IU/ml ) Age Liver status AST, ALT < Years normal INR, Alb., Bili normal Liver ultrasound normal

30 Is liver biopsy predictor of loss of tolerance in immunotolerant HBs Ag positive patients?

31 ALT x ULN is associated with increased risk of hepatic complications vs those with ALT < 0.5 x ULN Lower threshold for liver biopsy in: male higher age family Hx. of cirrhosis or HCC Moderate inflammation, fibrosis and even cirrhosis can be found in patients with normal ALT

32 Immune tolerance Virus status HBe Ag Positive 1. Virus status : virus like this at Age > 40 Treat for HBV ( IFN or NUCs) HBV-DNA very, very high ( > 20, ,000,000 IU/ml ) Age Liver status AST, ALT INR, Alb., Bili Liver ultrasound < Years normal normal normal 2. Liver status : AST, ALT > 1-2 x ULN or any abnormal biochemistry test or abnormal liver ultrasound a. R/O other causes of enzyme elevation: TSH, CPK, Fatty liver, AIH, HDV, HCV, Wilson, Celiac b. Liver biopsy grade > 4 stage = > 2 c. Treat for HBV ( IFN or NUCs)

33 Immune tolerance Virus status HBe Ag Positive 1. Virus status : virus like this at Age > 40 Treat for HBV ( IFN or NUCs) HBV-DNA very, very high ( > 20, ,000,000 IU/ml ) Age Liver status AST, ALT INR, Alb., Bili Liver ultrasound < Years normal normal normal 2. Liver status : AST, ALT > 1-2 x ULN or any abnormal biochemistry test or abnormal liver ultrasound a. R/O other causes of enzyme elevation: TSH, CPK, Fatty liver, AIH, HDV, HCV, Wilson, Celiac b. Liver biopsy grade > 4 stage = > 2 c. Treat for HBV ( IFN or NUCs) * Pregnancy ( 2nd or 3rd Trimester)

34 regnant Women With High HBV DNA and Not Currently on Antiviral Therapy Should antiviral be recommended to reduce risk of perinatal transmission? Yes; although quality of evidence is low, all studies showed benefit and no harm. What should be the cutoff maternal HBV DNA level for initiation of antiviral therapy? > 8 log10 IU/mL: Yes 6-8 log10 IU/mL: May be < 6 log10 IU/mL: No

35 regnant Women With High HBV DNA and Not Currently on Antiviral Therapy When to start antiviral? Late second/early third trimester Allow at least 4-6 wks for an effect Which antiviral drug? Lamivudine or tenofovir Tenofovir preferred: low risk of drug resistance, baseline HBV DNA high, and some mothers may need treatment for their liver disease in the future

36 regnant Women With High HBV DNA and Not Initially on Antiviral Therapy When to stop antiviral after delivery? To prevent perinatal transmission: immediately, especially if mother plans to breast-feed, or up to 3 mos post delivery To treat liver disease: continue until therapeutic endpoint What is the risk of post treatment flare? Seemingly rare, but mild ALT elevation common; also seen in postpartum period for women not receiving antiviral Decompensation not reported in clinical trials; likelihood low because most pregnant women have early-stage liver disease Important to closely monitor ALT after antiviral therapy is discontinued (eg, 1, 3, and 6 mos posttreatment)

37 Algorithm for HBV Management in Women During Pregnancy *The cut-off level of maternal HBV DNA level for initiation of therapy is unclear, and HBV DNA from 6-8 log10 IU/mL can be considered for therapy based on physician and patient preference. Tenofovir is preferred if treatment is expected to be > 12 weeks or if treatment is expected to continue while breastfeeding.

38 Immune clearance HBe Ag Positive HBV-DNA high ( > 20,000 - < 100,000,000 IU/ml ) Age Liver status AST, ALT any age abnormal INR, Alb., Bili normal / abnormal Liver ultrasound normal / abnormal

39 What is the roles of liver biopsy in chronic HBV infection? 1. Decision to treat HBV -Who should be treated? HBe Ag Positive Immunotolerance Gray zone Immunoclearnce HBV DNA Very high > 20,000-2,000,000 IU/ml Any level High > 20,000 IU/ml ALT / AST Normal ( or < ULN ) > ULN - < x 2 ULN > x 2 ULN Decision Observation Biopsy Treatment Indication for Liver biopsy

40 Non replicative HBe Ag negative HBV-DNA low ( < 2,000 IU/ml ) Age any age AST, ALT normal INR, Alb., Bili normal / abnormal Liver ultrasound normal / abnormal

41 Pre-core mutant HBe Ag negative HBV-DNA high ( > 20,000 IU/ml ) Age any age AST, ALT abnormal INR, Alb., Bili normal / abnormal Liver ultrasound normal / abnormal

42

43

44 What is the role of liver biopsy in chronic HBV infection? 1.Decision to treat HBV - Who should be treated? HBe Ag Negative Immune Control Non-replicative Gray zone Immune Escape Pre-core mutant HBV DNA < 2,000 IU/ml Any level > 2,000-20,000 IU/ml ALT / AST Normal ( or < ULN ) > ULN - < x 2 ULN > x 2 ULN Decision Observation Biopsy Treatment Indication for Liver biopsy

45 Special Populations That Should Be Considered for HBV Treatment Regardless of HBV DNA and ALT levels Rapid deterioration of liver function ( acute or acute on chronic liver failure ) Decompensated cirrhosis Compensated cirrhosis with HBV-DNA > 2,000 IU/mL, regardless of ALT HBV carriers undergoing immunosuppressive or cytotoxic chemotherapy Recurrent HBV infection post liver transplantation Lok A, et al. Hepatology. 2007;45: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6: EASL HBV Guidelines. Journal of Hepatology. 2009;50: Sorrell MF, et al. Ann Intern Med. 2009;150:

46

47

48

49