1. Hepatitis B Patricia D. Jones, M.D. November 13, 2009

2. Hepatitis B  Prototype member of the Hepadnaviridae family  DNA virus  Outer lipoprotein envelope with 3 glycoproteins – Hep B surface antigens (HBsAg)  Viral nucleocapsid protein - Hep B core antigen (HBcAg)  Soluble nucleocapsid protein- Hepatitis B e antigen (HBeAg) http://pathmicro.med.sc.edu/virol/hep-b5.jpg

3. Epidemiology  Worldwide:  Affects 350-400 million persons  Endemic areas: Asia, Africa  1 million worldwide deaths per year  Acquired perinatally and in childhood  United States:  Affects 1.25 million persons  4000-5000 deaths per year  Acquired via sexual activity, then IVDU and occupational exposure http://liver.stanford.edu/images/education/world_incidence.jpg

4. Primary Infection  Incubation Period 4-10 weeks  During the prodromal period, patient may have a serum sickness-like syndrome.  Constitutional symptoms, anorexia, nausea, RUQ discomfort and jaundice.  30 % develop icteric hepatitis.  70% develop anicteric or subclinical hepatitis.  0.5-1% develop fulminant liver failure.  Symptoms and jaundice disappear in 1-3 months, though fatigue may persist.

5. Infection in Children vs. Adults  Children  In neonates, the immature immune system does not recognize a difference between the virus and the host.  Cellular immune responses to hepatocyte-membrane HBV proteins do not occur.  Risk of developing chronic HBV infection is 90% in infants born to HBeAg positive mothers. In children under 5, risk is 25-30%.  Adults:  Tend to have a more vigorous immune response.  Less than 5% of those infected develop continual viremia and persistent infection.

6. Serologic Diagnosis HBsAgHBeAg Anti-HBc IgM Anti-HBc IgG Anti-HBeHBsAb HBV DNA ACUTE Early++++++ Window++ Recovery++++/- CHRONIC Replicative++++++ Nonreplicativ e ++++/- Flare++/-+++ Precore/core promoter mutants +++++

7. http://www.haps.nsw.gov.au/userData/img//hepB1.jpg

8. Chronic Hepatitis B Infection  Early Replicative Phase: Immune Tolerance  Perinatally acquired infection  High levels of HBV DNA, HBeAg present  No liver disease—normal ALT, asymptomatic, Stage 0-1 fibrosis  Lasts 10-30 years  Replicative Phase: Immune Clearance  Spontaneous clearance of HBeAg  Often characterized by periods of increased HBV DNA and increased ALT due to immune-mediated lysis of infected hepatocytes, i.e. flares  Nonreplication Phase: Inactive Carrier State  HBeAg negative, anti-Hep B e positive, HBV DNA undetectable  ALT levels normalize, however some patients may have active inflammation

9. Chronic Hepatitis B Infection  HBeAg-negative Chronic Hepatitis  Precore/Core Promoter Mutations  Moderate levels HBV DNA  Active liver disease and elevated ALT  Older patients  Resolution  Hallmark is the clearance of HbSAg  Does not preclude development of cirrhosis, HCC or failure.  Patients may still produce HBV DNA, which has implications in the immunosuppressed

10. Sequelae of Chronic HBV Infection  Cirrhosis  Hepatocellular Carcinoma  Hepatic Decompensation  Extrahepatic Manifestations  Death  Prognosis is worse in endemic areas:  Prolonged replicative phase  Clearance of HBeAg causes a 2 fold decrease in death rate.  Patients who reactivate have worse prognosis. http://pathmicro.med.sc.edu/lecture/images/hepato-b.jpg

11. Extrahepatic Manifestations  Occur in 10-20% of patients with Chronic Hep B.  Serum Sickness  Polyarteritis Nodosa  Membranous and Membranoproliferative Glomerulonephritis

12. Genotypes  Genotype B associated with HBeAg seroconversion at an earlier age, more sustained remission, less active hepatic necroinflammation, a slower rate of progression to cirrhosis and lower rate of HCC development when compared with Genotype C.  Genotypes A and B are associated with higher rates of seroconversion with pegIFN-alpha than C and D.

13. Indications for Therapy Acute Hepatitis  One trial demonstrated no biochemical or clinical benefit in patients treated with Lamivudine vs. placebo in 12 months.  General Rule:  Coagulopathy INR>1.5  Persistent symptoms or marked jaundice (bilirubin >10 mg/dl) for more than 4 weeks after presentation  Fulminant Hepatic Failure  Concomitant infection with Hep C or D

14. Indications for Therapy HBeAg-positive patients:   HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals   HBeAg status should be checked every 6-12 months.   HBeAg positive with HBV DNA levels >20,000 IU/mL after a 3-6 month and ALT 1-2 x ULN OR are >40 years  liver biopsy w/ treatment if biopsy shows moderate/severe inflammation or significant fibrosis.   Patients who remain HBeAg positive with HBV DNAlevels>20,000 IU/mL after a 3-6month period of elevated ALT levels >2 ULN should be considered for treatment. HBeAg-negative patients:   HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL: Tested ALT q 3months during the first year to verify true “inactive carrier state” and then every 6-12 months. http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdf

15. http://knol.google.com/k/-/-/1w026jckgcwg2/18ad7q/slide4%20(1).jpg

16. References:  Dienstag JL. Hepatitis B Virus Infection. N Eng J Med 2008;359: 1486-500.  Ganem D, Prince AM. Hepatitis B Virus Infection—Natural History and Clinical Consequences. N Eng J Med 2004; 350: 1118- 29.  Liaw YF, Chu CM. Hepatitis B Virus Infection. Lancet 2009;373:582-592.  Lok ASF, McMahon BJ. Chronic Hepatitis B: Update 2009. Hepatology 2009; 3: 1-36.  Lok ASF. Clinical manifestations and natural history of hepatitis B virus infection. UpToDate

17. Inspiration