B Informed Doylestown PA 2002 Chronic Hepatitis B

B Informed , Doylestown PA. 2002 Chronic Hepatitis B East meets West Dr Sharat C Misra MD, DM, FACG Gastroenterologist & Hepatologist New Delhi, India

New Delhi

The Ballad of East and West Rudyard Kipling Oh, East is East and West is West, and never the twain shall meet, Till Earth and Sky stand presently at God's great Judgement Seat; But there is neither East nor West, Border, nor Breed, nor Birth, When two strong men stand face to face, tho' they come from the ends of the earth!

How do we compare? n n n n n East(India) Population GDP/capita Population/Hosp bed Population/Doctor Life Expectancy(birth) Cost of Hosp stay/day Average PCP Fee Average Specialist Fee Direct Insurance cover n n n n n 1040 mill $2200 1700 2500 65 $30 $1 $10 Nil West(USA) 285 mill $36000 0. 5 400 77 $1200 $30 -50 $75 Yes

Hepatitis B Virus

How is Hepatitis B detected? Incidental blood test Asymptomatic, Blood Donor, Hospitalised for another illness Dialysis n Jaundice n Prodrome, nausea, vomiting: Acute n Ascites, Bleeding, Coma : Chronic n

HBV in India What happens next? n n n n Direct access to Labs and Doctors More blood tests Family Physician Medical Specialist GI/Liver specialist Go to a hospital/clinic Do nothing

Doctors in India n o o General Practitioners Dispense medicines/ Inj Charge a low fee Symptomatic Treatment 100 pts/ day n n o o o Specialists Superspecialists Consultations Procedures Fee 5 - 10 high Govt / Private 10 -30 pts/day

How I do it HBV in India Hbs. Ag +ve Doc DAY 1 14 M PHYSICAL LFT, VIRAL Markers Hbs. AG +E antigen +/US $ 50 Ig. M-Anti. Hbc -ve

HBV in India Doc DAY 2 n n n Hbs Ag +ve Family screening Hep B Vaccination for contacts Hep A Vaccination Viral Load Endoscopy $ 250 -350 How & Why Nature of Illness Treatment Costs Liver Bx

HBV in India Doc DAY 7 -21 n n n Hbs Ag+ve To treat or not to treat? Interferon : $ 50/wk Lamivudine: $ 5/wk Thymosin: $ 300/wk Peg IFN : $ 300/wk Indigenous: Phylanthus, ”Liver Tonics”

Magnitude of HBV Prevalence Of HBV

How HBV effects us? India USA n n n n 45/400 Million 4 % Carriers Young Age Perinatal Spread Precore mutant HBV Early Complications More Liver Cancer 25% - E antigen +ve n n n n 1. 25/400 Million 0. 5 % Carriers Adults or older Horizontal Spread Wild Type HBV Late Complications Less Liver Cancer 68%- E antigen +ve

HBV in India Facts and Figures n n n 45 million have HBV (2 nd after China) 25% are E antigen +ve 30% present as Acute Hepatitis 75% of Cirrhosis/Cancer is due to HBV 1% of all deaths due to HBV 5 th most important cause of death(15 -45 y)

HBV in India Why HBV prevalence is high? n n Lack of public awareness No measures for HBV control at National Level No proper control over blood transfusion practices, sterilization of needles, instruments, use of disposables Lethargy in HBV vaccination

HBV Vaccination programme New Delhi, India n n n Free HBV vaccination At Birth : Hep. B , Polio 1 ½ month : DPT, Polio, Hep B 2 ½ month : DPT, Polio, Hep B 3 ½ month : DPT, Polio, Hep B

HBV in India Mode of transmission Parenteral exposure 45% n Sexual 5% n Not Known 50% (Horizontal/At Birth) n

HBV in India Horizontal Transmission Intrafamilial clustering n Sharing of personal articles n Sexual Saliva, body fluids, open wounds n

HBV in India Parenteral Transmission Negligible with screened BT n No commercial blood donation n Acute Hep B in only 1. 3% patients in patients undergoing CABG (Misra et al ; Liver 1992) n

HBV in India Clinical Spectrum n n n 30% of all Acute Hepatitis 50 -75% of all Chronic Liver Disease(CLD) 25% of all CLD is due to Mutant HBV 30 % of all Fulminant Hepatitis 80% of all Liver Cancer

Terminology of Chronic HBV Infection Chronic Hepatitis B NIH 2001 § HBs. Ag positive > 6 months HBV-DNA>100, 000 copies/ml ALT elevated § HAI on liver biopsy > 3 § § INASL 1998 Routine DNA testing is expensive

Terminology of Chronic HBV Infection NIH 2001 Inactive HBs. Ag Carrier State § HBs. Ag positive > 6 months § HBe. Ag negative, Anti-HBe positive § ALT normal § HBV-DNA < 100. 000 copies/ml § HAI on liver biopsy < 3

Terminology of Chronic HBV Infection INASL 1998 n Chronic HBV Infection without chronic liver disease n Incidentally detected asymptomatic HBs. Ag positive subjects Not “carriers” as they may reactivate, unlike Caucasions

Terminology of Chronic HBV Infection Resolved hepatitis B § History of acute or chronic Hep B §HBs. Ag negative §HBV-DNA undetectable § ALT normal

ASIA Natural History of CHB Infection at early age Four Stages n Prolonged Immune Tolerance n Immune Clearance Carrier n Non-replicative phase (HBe. Ag negative) n Reactivation/Replicative phase Precore mutant Cirrhosis , HCC

Natural History of CHB West Infection is acquired in adulthood § Short Immune tolerance phase § Chronic HBe. Ag positive hepatitis § Non-replicative phase (Anti-HBe positive) Carrier Mild-Moderate CH Fibrosis Cirrhosis, HCC

Dynamics of HBV infection Recovery Transplant FHF symptoms Death Recovery Acute HBV Chronic asymptomatic mild symptoms DNA++ ALT - E+ DNA+ ALT++ E+ Chr. Hep DNA- ALT - E- Fibrosis DNA +, ALT+E- Cirrhosis complications HCC ?

Asia-Pacific n n n Birth HBs. Ag, E + 5 -21 yr CLD, E + 30 yr Chr Hep , E – 45 yr Cirrhosis 55 yr HCC Precore mutant Caucasian § § § Healthy Hbs. Ag, E + CH No symptom, E Hbs. Ag, E+ Cirrhosis HCC

HBV Mutants Asia/Mediterranean Genotype B to E n n Precore: Stop codon mutation G 1896 A Core: Basic core promoter region Surface – vaccine escape, nonvaccine X gene, Pre S gene

Life Cycle of Wild HBV

From where does the mutant virus come? Emergence of Precore Mutant HBV § § During course of Chronic Hep. B with Wild/Mutant HBV De Novo Infection: Unlikely (Reported in a Baby born of HBe. Ag –ve Mother with Precore mutant HBV)

Emergence of Precore Mutant HBV HBe. Ag -ve G 1896 A mutation Precore 1896 DNA HBe. Ag +ve Core

How it happens? Immunopathogenesis of HBe. Ag Negative CH Tolerance Clearance Non Replicative/ Replicative Reactivation DNA HBe. Ag + ALT HBe. Ag -

How it happens? HLA 1 T T T E ab E C WT Immune Tolerance T T C T T Immune Clearance PCM T

How it happens? Host Immunity E ab PCM C Inactive phase Reactivation phase Liver Progressive Liver Disease ccc. DNA Integration

Diagnosis of Hbe. Ag negative CH-B n n n E antigen -ve, maybe Anti-HBe + HBV-DNA positive> 106 copies/ml Intermittent high/normal ALT Progressive liver disease ( Biopsy) Core antigen staining in liver tissue HBV-DNA ( Hybridisation)

Management of Chronic Hep B n n n Clear the virus Reduce liver injury Prevent fibrosis Goal of treatment § Eliminate §Suppress HBV

Short term goals: 6 months n ALT Normal n Prevent decompensation of liver n Seroconversion (E Ag to E antibody) n Undetectable HBV-DNA

Long term goals n Prevent flares / reactivation n Prevent fibrosis and cirrhosis n Prolong survival

Who to treat? n n n ALT X 2 -7 times high HBV-DNA +ve (100, 000 copies/ml) Liver Biopsy is recommended Who not to treat § Normal ALT

When to treat? Lam. Drug ALT ALT D 0 IFN DNA 700

Treatment Strategies Viral Kinetics Drug D N A 2 log 0 2 wk

Treatment Strategies HBV-DNA + ALT X 5 -7 ALT X 2 -5 ALT - N Liver biopsy Lam IFN 35 -45% ETR HAI>3

How to defeat HBV? Universal Vaccination IFN HBV Eliminate from host Newer Suppress activity in the host LAM Strategies

Interferon Hbe. Ag positive CH-B 30 -40% lose E antigen, 80% is sustained 10% lose HBV-DNA, HBs. AG § Loss of E antigen - Increased survival - Decreased mortality & complications - Decreased liver cancer §

Interferon Hbe. Ag negative CH-B Meta-analysis of 4 RCTs (1989 -1997) ETR: 38 -90 % SR : 10 -47 % q Longer duration of therapy: 1 year q 2. 5 fold in disease progression q 20% lose HBs. Ag q

Lamivudine (HBe. Ag +/- CHB) E antigen loss in 35% n ALT normalisation: 50% n Improvement in liver histology: 50% n HBs. Ag loss < 1% n YMDD mutant emergence v 15 -30% - 1 yr ; 50% - 3 yrs ü Relapse after stopping therapy n

Newer Therapies New Drugs Adefovir, Entecavir, Clevudine, FTC q q New formulation : PEG-IFN New Schedules Combination/ Sequential therapy q

Problem Situation 1 n Hbs. Ag + DNA + E antigen - / + ATL- N Wait and Watch q Liver Biopsy: HAI >3 q Trial Protocols

Problem Situation 2 n n Hbs. Ag + E antigen – DNA – ALT : High Repeat DNA by PCR n Look for other causes - Alcohol - NASH - HCV n

Future Strategies 2002 Peg-IFN Adefovir Entecavir Lamivudine Herbs India, China

Response to treatment of CH-B Peg/Lam/Adv/Ent /Clevudine 100 Adv Entv IFN LAM 2002 2003 -4

we st East The East and the West in the spring of the world shall blend As a man and a woman that plight Their troth in the warm spring night John Bartlett (1820– 1905)

Steve/Sheree need to see this

Thank You