HBV NATURAL HISTORY AND MANAGMENT Mitchell L. Shiffman, MD Director Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, Virginia IVer Liver Institute of Virginia Education, Research and Treatment for Patients with Liver Disease Bon Secours Health System CHRONIC HBV INFECTION DEMOGRAPHICS IN THE USA Estimated 1.25 million persons in USA infected Vast majority are immigrants or first generation Americans: Southeast Asia, China Sub-Saharan Africa Eastern Europe Likely acquired HBV via vertical transmission or from contaminated medical equipment in their homeland African Americans account for 20% of persons with chronic infection 1
ACUTE HBV INFECTION AGE AT RISK 25 Ca ases/100,000 20 15 10 5 0 ML Shiffman Clin Liv Dis 2010;14:75-91. 0-14 15-19 20-29 30-39 >40 AGE (years) RISK OF DEVELOPING CHRONIC HBV AGE AND SYMPTOMS ML Shiffman Clin Liv Dis 2010;14:75-91. 2
HEPATITIS B VIRUS INFECTION SPONTANEOUS RESOLUTION ALT (IU/L) HBVcAb HBVcAb IgM HBVsAg HBVeAg HBV DNA Window Anti-HBs Anti-HBe TIME CHRONIC HEPATITIS B VIRUS INFECTION SPONTANEOUS LOSS OF eag ALT (IU/L) HBVcAb HBVcAb IgM HBVsAg HBVeAg HBV DNA Anti-HBVe TIME 3
CHRONIC HEPATITIS B VIRUS SPONTANEOUS SEROCONVERSION % of Patients 60 50 40 30 20 10 0 0 1 2 3 4 5 6 YEARS Factors associated with seroconversion: Duration of infection BUT NOT: HBV DNA level Serum ALT Histology YF Liaw et al. Gastroenterol 1983;84:216-219. CHRONIC HEPATITIS B VIRUS FIBROSIS Fibrosis progression occurs with active HBV Fibrosis regression occurs after seroconversion Factors which affect the rate of fibrosis regression: Decline in HBV DNA Decline in ALT Patient age HBV genotype CK Hui et al. Hepatology 2007;46:690-698. 4
CHRONIC HBV RISK OF LIVER CANCER 12 Survival (%) 10 8 6 4 2 0 0 2 4 6 8 10 YEARS HBeAg (+) HBeAg (-) HBsAg (-) HI Yang et al. N Engl J Med 2002;347:168-174. HCC IN PATIENTS WITH CHRONIC HBV IMPACT OF IMMUNE STATUS eag +/- eag - Inactive Status M Colombo et al. Clin Liv Dis 2001;5:109-125. HCC Total number of HCCs 5
CHRONIC HBV REVEAL STUDY HBV DNA CIRRHOSIS AND HCC At what level of HBV DNA is the risk of progression and HCC significantly increased <10 4 10 4-10 5 10 5-10 6 >10 6 <2 2-20 20-200 >200 CJ Chen et al. JAMA 2006;295:65-73. IMMUNE STATES OF HBV ALT, SEROLOGY AND HBV DNA HBV DNA Acute Immune eag+ eag- eag- Tolerant Active Active Inactive Resolved sag Anti-s eag Anti-E ALT JH Hoofnagle et al. Hepatology 2007;45:1056-1075. 6
CHRONIC HBV WHAT IS E-NEGATIVE ACTIVE HBV E-gene located in the pre-core region of HBV Not necessary for replication Target of the immune response to inactivate HBV E-gene E-antigen Core gene Core antigen E**gene Core gene Core antigen Mutation of the E-gene No detectable E-antigen Does not prevent replication Prevents the immune response from inactivating HBV S Ahn et al Gastroenterol 2003;125:1370-1378. E-ANTIGEN NEGATIVE CHRONIC HBV EVOLUTION Chronic HBV sag (+) E-Antigen (+) Seroconversion of E-Antigen (+) Strain: E-antigen (-) Anti-E (+) Inactive HBV JH Hoofnagle et al. Hepatology 2007;45:1056-1075. 7
E-ANTIGEN NEGATIVE CHRONIC HBV EVOLUTION Chronic HBV sag (+) E-Antigen (+) E-Antigen (-) Seroconversion of E-Antigen (+) Strain: E-antigen (-) Anti-E (+) Inactive HBV E antigen (-) Anti-E (-) Active E-negative HBV JH Hoofnagle et al. Hepatology 2007;45:1056-1075. E-ANTIGEN NEGATIVE CHRONIC HBV EVOLUTION Chronic HBV sag (+) E-Antigen (+) E-Antigen (+) E-Antigen (-) E**Antigen (-) Seroconversion of E-Antigen (+) Strain: E-antigen (-) Anti-E (+) Inactive HBV E**antigen (-) Anti-E (+) Active E**negative HBV E antigen (-) Anti-E (-) Active E-negative HBV JH Hoofnagle et al. Hepatology 2007;45:1056-1075. 8
HEPATITIS B VIRUS OTHER MUTATIONS Surface mutation ti Core mutation HBsAg Anti-HB core Anti-HB surface HBV DNA Surface Antigen - + + + Core + - - + Lamivudine Adefovir HEPATITIS B VIRUS GENOTYPES Genotype A B C D E F G North America, Northern Europe, Central Africa Asia Asia Mediterranean, Middle East, South Asia Western Africa South and Central America France, USA CT Wai, RJ Fontana Clin Liver Dis 2004;8:321-352. 9
IMMUNE TOLERANT HBV NATURAL HISTORY Baseline 5 years ALT (IU/l) 17 (6-24) 14 (4-23) Log HBV DNA (IU/ml) 9.74 9.81 Inflammation Score 3 (1-6) 3 (1-5) Fibrosis: F0 F1 F2 15 33 0 16 31 1 CK Hui et al. Hepatology 2007;46: 395-401. CHRONIC HBV LOSS OF IMMUNE TOLERANCE 3 log decline in HBV DNA TIME 10
CHRONIC HBV IMMUNE TOLERANT HBV Normal ALT Very high HBV DNA Absence of inflammation None minimal fibrosis No treatment indicated Likely to be ineffective Monitor 50% active over 5 years CK Hui et al. Hepatology 2007;46:395-401. CHRONIC INACTIVE HBV REACTIVATION Patients at risk: HBsurface antigen (+) Sometimes Anti-HBcore (+), HBsurface antigen (-) Risk factors: Immune suppression: Long term, high dose Anti-TNF agents Cancer Chemotherapy Recognizing reactivation: Increase HBV DNA, serum ALT Anti-HBcore-IgM may become (+) If HBsurface antigen (-) it becomes (+) 11
CHRONIC HBV MONITORING Serum ALT Liver function HBV DNA E-antigen status Every 3-6 months Every 6-12 months? Depending upon changes in: Serum ALT HBV DNA AFP Ultrasound Every 6-12 months AS Lok, BJ McMahon Hepatology 2009;50:1-36. CHRONIC HEPATITIS B VIRUS PHASES Immune Gray Active Tl Tolerant Zone Inactive ALT (IU/l) Normal Elevated High/Normal Normal HBsAg + + + + HBeAg + +/- +/- - Anti-HBe - +/- +/- + HBV DNA (IU/ml) >1 Million >20,000 </> 20,000 <20,000 >2,000 </> 2,000 <2,000 Histology Normal Active Variable Normal Treatment NO YES NO MJ Tong et al. Dig Dis Sci 2011;56:3143-3162. EB Keeffe et al. Dig Dis Sci 2011;56:3106-3108. BJ McMahon. Am J Gastroenterol 2006;101 (suppl 1):S7-12. 12