NH2 N N N O N O O P O O O O O

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1 N N NH 2 N N O O P O O O O O O

2 James Watson and Francis Crick Double Helix 1953

3 Baruch Blumberg, MD, PhD Australia Antigen 1965

4 Hepatitis B Virus (HBV) Hepadnaviridae member that primarily infects liver cells 100 times more infective than HIV Found in blood and body fluids Able to survive in dried blood for longer than 1 week Ott et al. J Pediatr Health Care. 1999;13(5): Ribeiro, et al. Microbes and Infection. 2002;4: MMWR. 2003;52:1-33.

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6 Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration ~2 million Asians ~400,000 South Americans ~930, 000 Europeans HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low ~350,000 Africans Immigration numbers summed by continent from World Health Organization. Geographic Prevalence of HBsAg. Data from 1996 (unpublished). Accessed: September 13, Yearbook of Immigration Statistics. Accessed: September 22, Mahoney FJ. Clin Microbiol Rev. 1999;12:

7 Prevalence of HBV Among Asian Americans 0% 5% 10% 15% 5 large US cities ( ) Chinese Korean Vietnamese Median age 43 (12-80) HBsAg(+) 558/5341 (10.4%) Philadelphia S.F. Boston Chicago N.Y. (1) N.Y. (2) 11% 14% 10% 11% 15% 11% Overall 10.4% Guane. AASLD Abstract 1269.

8 Anti-HBc seroconvertors (%) HBV in Latin America HBV Seroprevalence Brazil Dominican Republic Mexico Chile Venezuela Argentina Gish R. J Viral Hepatitis 2006;13;

9 Transmission of HBV Horizontal Transmission Vertical Transmission Host Recipient Mother Child-to-Child Contaminated Needles Sexual Health Care Worker Transfusion 6% infected after age 5 years become chronically infected No clear risk factors in 20-30% of patients Infant Perinatal 90% infected infants become chronically infected CDC Fact Sheet. Accessed: October 2, Lee WM. N Engl J Med. 1997;337(24): Lavanchy. J Viral Hepat. 2004;11(2):

10 Phases of Chronic HBV Infection HBV DNA HBeAg Anti-HBe ALT activity PHASE HBeAg, hepatitis Minimal B e antigen; anti-hbe, Chronic antibody active to HBeAg; Mild hepatitis HBV, hepatitis Active B virus; ALT, alanine inflammation aminotransferase. inflammation and minimal inflammation fibrosis LIVER Immune tolerant ALT, alanine aminotransferase HBeAg, hepatitis B e antigen Immune clearance Yim and Lok. Hepatology. 2006;43:S173-S181. Inactive carrier state Optimal treatment times Reactivation

11 Four stages of HBV infection I II III IV replicative integrative tolerant active inactive resolved HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe HBV DNA pcr -- ALT

12 *Adjusted RR Baseline Serum HBV DNA Concentration Risk Factor of Cirrhosis REVEAL P < /869 Undetectable P = NS 1.4 P < Baseline Viral Load (copies/ml) *Adjusted for sex, age, anti-hcv levels, smoking, and alcohol use. P <.001 NS, not significant; REVEAL; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cance RR, relative risk Iloeje et al. Gastroenterology. 2006;130(3): / /628 65/ /602

13 Adjusted HR for HCC Baseline and Persistent Viremia Risk Factor of HCC REVEAL P < P < P = NS P < /2034 8/146 10/120 55/537 < < Not tested < 10 5 VL: Baseline Follow-up (copies/ml) HCC, hepatocellular carcinoma; HR, hazard risk; VL, viral load Chen et al. JAMA. 2006;295(1):65-73.

14 Risk of Complications (%) ALT an inconsistent indicator of disease progression 3233 Chinese patients with chronic HBV infection More than 2/3 of patients HBeAg(-) at time of complications ALT activity at presentation > 1-2 ULN* *ALT activity ULN in this study: 53 U/L (men); 31 U/L (women) ULN, upper limit of normal Yuen et al. Gut. 2005;54: Months of Follow-up > 2-6 ULN ULN > 6 ULN < 0.5 ULN

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16 Percent of Patients Percent of Patients 40 Association Between HBV Genotype and Disease Severity Western Patients 1 Asian Patients 2 Frequency of Liver-Related Death P =.02 Incidence of Advanced Fibrosis (F3/F4) 40 P = P = N = % 20 N = % 20 13% % A 1% D F 10 0 B C 1. Sanchez-Tapias JM et al. Gastroenterology. 2002;123: Sumi H, et al. Hepatology. 2003;37:19-26.

17 U.S. Distribution of HBV Genotypes Midwest (25%) West (39%) 5% 18% 13% 33% 37% 15% East (17%) 18% 37% n = % 34% South (19%) 23% 17% 56% Asian 32% White 9% Black 3% Other 12% 13% 10% 63% A B C D E,F,G Chu, et al. Gastroenterology. 2003;125:

18 Drugs Currently Available for HBV Some approved* for HIV only = off-label! Lamivudine (Epivir HBV ) 100 mg/d Adefovir (Hepsera ) 10 mg/d Entecavir (Baraclude ) 0.5 and 1.0 mg/d Telbivudine (Tyzeka ) 600 mg/day Tenofovir (Viread) 300 mg/d Truvada (Emtriva and Viread) 300/150/d* Intron-A and Peg-interferon-2a

19 HBV Drug Resistance Mutations HBV Polymerase Terminal Protein Spacer Reverse Transcriptase RNase H LAM FTC L-dT: F G A B C D E ADV: rta181v rtn236t ETV a : a. In combination with YMDD mutations

20 Incidence of Resistance Cumulative Incidence of HBV Antiviral Resistance with ADV or LAM Monotherapy ADV (N236T/A181V) in study 438 a LAM (M204V/I) b 80% 70% 70% 60% 50% 42% 53% 40% 30% 20% 10% 0% 24% 18% 11% 0% 3% year 1 year 2 year 3 year 4

21 Percentage of patients HBV DNA (-) by PCR in LAM Resistant Infection Adefovir Group N = 18 Tenofovir Group N = 35 Van Bommel et al. Hepatology. 2004;41:1421. Week 12 Week 24 Week 36 Week 48

22 Mean HBV DNA (log 10 copies/ml) On-therapy HBV DNA Suppression and End of Follow-up Responses 12 On-treatment Follow-up PEGASYS 10 HBeAg seroconversion at EOF = 32% 8 6 PEGASYS -4.5* Lamivudine HBeAg seroconversion at EOF = 19% 4 2 lamivudine PEGASYS + lamivudine PEGASYS + lamivudine HBeAg seroconversion at EOF = 27% *all numbers shown are log 10 reduction from baseline Lau G. et al. Hepatology 2004;40(Suppl 1):A20.

23 Problems with current therapy Diagnosis: based on viral load, ALT, biopsy if poss. Also, learn to use VL, genotypes, mutations Therapy: requires continued surveillance and is probably for life (like HIV) Requires consistent dosing/lab tests/clinic visits Viral load may not be completely suppressed Escape mutations are still of concern

24 Answer to who, when and how: Treat those with high viral loads AND active hepatitis Use high potency agents: entecavir or tenofovir Expect to treat for a long time/indefinitely Check HBV DNA/ALT/AFP at least every 6 mons Stop 6 mons post HBeAg or HBsAg seroconversion Surveillance is for life. At least annual sonogram/afp

25 Management of Hepatitis B Consensus Conference 2008 The major goals of anti-hbv therapy are to prevent the development of progressive disease, specifically cirrhosis and liver failure, as well as hepatocellular carcinoma development and subsequent death. To date, no RCTs of anti-hbv therapies have demonstrated a beneficial impact on overall mortality, liver-specific mortality, or development of hepatocellular carcinoma. WHAT??

26 Hep B Research Network Sites Around North America: hepbnet.org

27 The Hepatitis B Research Network Cohort Study (Database): all HBsAg pos, not co-infected, not on treatment, currently enrolling Treatment Trial: Immune tolerant entecavir plus/minus interferon for 24 wks, soon to start Treatment Trial: Active Hep B tenofovir plus/minus interferon for 24 wks, starting in January

28 The Hepatitis B Research Network Current research will be directed at: Understanding DNA quasispecies Detailed immunologic studies Natural history studies Special groups: pregnancy, HIV, acute HBV, delta hepatitis

29 HBV-related ALF: Two kinds Acute New Infection Young Caucasian/Afric-Amer Better outcome Lower viral loads Higher anti-hbc IgM Few mutations Acute on Chronic Reactivation Immunosuppressed Asian Worse outcome Higher viral loads Lower anti-hbc IgM Many e neg mutations Dao DY et al Hepatology 2011

30 Comparison of anti-hbc IgM Levels Between Groups 10 4 IgM anti-hbc Titer (Log10 Index Value) n=15 n=8 n=23 n=46 CHBV-ALF* CHBV-ALF** CHBV-ALF AHBV-ALF * Immunosuppressed ** Non-immunosuppressed p < p < Dao DY et al Hepatology 2011

31 Pre- and Post-Transplant Old paradigm: HBIG plus nucleoside analogue New paradigm: Nucleoside analogue by itself will do We currently have less concerns about mutations Entecavir will demonstrate mutations if prev. LAM Tenofovir: No mutations to date identified

32 Occult Hepatitis B Infection (OBI) Sensitive tests have not been available for long OBI: HBsAg negative but HBV DNA + Baltimore IDU population: 45% Ugandan population: 35%, 38% of these had VL>10 5 What is the significance of these findings?

33 Upcoming Debates: Hepatitis B Will IFN add to likelihood of seroconversion? How much OBI is out there? Are we screening enough? Risk of reactivation When will we understand the HBV immune response? When will universal vaccination really take hold?