1. CHRONIC HEPATITIS B SEROLOGY

2. Antigens HBsAg -Found on the surface of the intact virus and in serum as unattached particles -Earliest detectable marker in serum -indicates current Hepatitis B infection HBcAg -Found within the core of the intact virus -Not detectable in serum Reference: 17 th Ed. Harrison’s Principles of Internal Medicine p.1933- 1934

3. Antigens HBeAg -Readily detectable serologic marker of HBV infection -Appears shortly after HBsAg -Coincides w/high levels of virus replication -Indicates highly infective stage of HBV Reference: 17 th Ed. Harrison’s Principles of Internal Medicine p.1935

4. Antibodies Anti-HBs -Antibody to HBsAg -Becomes detectable in serum after HBsAg disappears -indicates immunity to Hepatitis B infection -“protective antibody” Anti-HBc -Total antibody to HBcAg -Only serologic evidence of recent HBV infection during the “window period” -May indicate acute or chronic infection Reference: 17 th Ed. Harrison’s Principles of Internal Medicine p.1933- 1934

5. Antibodies Anti-HBc IgM -IGM antibody to HBcAg -Seen in the 1 st 6 months after acute infection -indicates recent acute Hepatitis B infection Anti-Hbc IgG -IgG antibody to HBcAg -predominates beyond 6 months - Seen in chronic HBV infection Reference: 17 th Ed. Harrison’s Principles of Internal Medicine p.1934- 1935

6. Antibodies Anti-HBe - Antibody to HBeAg - Signifies low infectivity Reference: 17 th Ed. Harrison’s Principles of Internal Medicine p.1935

8. Chronic Hepatitis B Serologic Patterns HBs Ag Anti- HBs Anti- HBc HBeAgAnti- HBe Interpretation +-IgG+-Chronic Hepatitis B, High infectivity +-IgG-+Chronic Hepatitis B, Low infectivity Reference: 17 th Ed. Harrison’s Principles of Internal Medicine p.1943

9. CLINICAL AND LABORATORY FEATURES CHRONIC HEPATITIS B

10. Progression of acute hepatitis to chronic hepatitis: Clinical and Laboratory features: 1.lack of complete resolution of clinical symptoms of anorexia, weight loss, and fatigue and the persistence of hepatomegaly; 2. the presence of bridging or multilobular hepatic necrosis on liver biopsy during protracted, severe acute viral hepatitis; 3.failure of the serum aminotransferase, bilirubin, and globulin levels to return to normal within 6 to 12 months after the acute illness; and 4. the persistence of HBeAg beyond 3 months or HBsAg beyond 6 months after acute hepatitis. Reference: Braunwald, et al, Harrison’s Principles of Internal Medicine 17 th Ed., pp.1945

11. CHRONIC HEPATITIS B CLINICAL FEATURES Onset: insiduous Incubation period: 30-180 days (mean, 8-12 weeks) Fatigue is a common symptom Low grade fever between 38° and 39°C (100° - 102°F) when heralded with serum-sickness syndrome Reference: Braunwald, et al, Harrison’s Principles of Internal Medicine 17 th Ed., pp.1941-1942

12. CHRONIC HEPATITIS B Persistent or Intermittent jaundice is a common feature in severe or advanced cases. It may lead to progressive liver injury and in cases with superimposed cirrhosis --- hepatic decompensation. Reference: Braunwald, et al, Harrison’s Principles of Internal Medicine 17 th Ed., p. 1957

13. CHRONIC HEPATITIS B LABORATORY FEATURES Aminotransferase elevations tend to be modest but may fluctuate in the range of 100-1000 units. Alanine aminotransferase (ALT) tends to be more elevated than aspartate aminotransferase (AST) When cirrhosis is established, AST tends to exceed ALT. Levels of alkaline phosphatase activity tend to be normal or only marginally elevated. Reference: Braunwald, et al, Harrison’s Principles of Internal Medicine 17 th Ed., p. 1957

14. CHRONIC HEPATITIS B In severe cases, moderate elevations in serum bilirubin [51.3 to 171 µmol/L (3 to 10 mg/dL)] occur. Hypoalbuminemia and prolongation of the prothrombin time occur in severe or end-stage cases. Hyperglobulinemia and detectable circulating autoantibodies are distinctly absent in chronic hepatitis B (in contrast to autoimmune hepatitis). Reference: Braunwald, et al, Harrison’s Principles of Internal Medicine 17 th Ed., p. 1957

15. Reference: Braunwald, et al, Harrison’s Principles of Internal Medicine 16 th Ed., p. 1844

16. TREATMENT

17. Candidates for therapy Chronically infected individuals with: – persistently elevated alanine aminotransferase – a marker of liver damage – HBV DNA levels Lai, CL; Yuen (2007). "The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria and end points". Annals of internal medicine 147 (1): 58–61

18. Candidates for therapy HBeAg-positive patients (w/ evidence of chronic HBV): HBV DNA level is ≥20,000 IU/mL (10 5 copies/mL) Serum ALT is elevated for 3-6 months. HBeAg-negative patients(w/ evidence of chronic HBV): HBV DNA is ≥ 2000 IU/mL (10 4 copies/mL) Serum ALT is elevated (ALT levels >20 U/L for females and 30 U/L for males) for 3-6 months. Pyrsopoulos, Nikolaos. Chronic Hepatitis B: treatment and medication. Emedicine.com. June 19,2009

19. Goals of Treatment to suppress HBV replication to induce remission of liver disease before development of cirrhosis and hepatocellular carcinoma

20. Approved Drugs for Chronic Hepatitis B treatment Interferon (INF) α Pegylated interferon Lamivudine Adefovir dipivoxil Entecavir

21. Interferon (INF) α Protein product manufactured by recombinant DNA technology Modulates host immune responses Direct antiviral activity HBeAg negative patients: 1 and ½ yr tx results in sustained remissions, with suppressed HBV DNA and aminotransferase activity, in 20%

22. Complications of Interferon (INF) α systemic "flu-like" symptoms marrow suppression Irritability,depression/anxiety autoimmune reactions miscellaneous side effects – alopecia, rashes, diarrhea, and numbness and tingling of the extremities. *With the possible exception of autoimmune thyroiditis, all these side effects are reversible upon dose lowering or cessation of therapy.

23. Lamivudine inhibits reverse transcriptase activity of both HIV and HBV HBeAg-reactive patients: daily doses of 100 mg for 48–52 weeks HBeAg- negative patients: 1 year of lamivudine therapy

24. Adefovir dipivoxil prodrug that is converted to the diphosphate salt active drug : antiviral nucleotide reverse transcriptase inhibitor oral daily dose of 10 mg reduces HBV DNA

25. Pegylated interferon once-a-week PEG IFN was more effective than the more frequently administered, standard IFN After 6 months of therapy: – HBeAg loss (30%) – HBeAg seroconversion (22%–27%) – undetectable HBV DNA (<400 copies/mL by PCR) in 10–25% – normal ALT in 34–39% – a mean reduction in HBV DNA of 2 log 10 copies/mL (PEG IFN-2b) to 4.5 log 10 copies/mL (PEG IFN-2a)

26. Entecavir Guanosine nucleoside analogue with activity against HBV polymerase Competes with natural substrate deoxyguanosine triphosphate (dGTP) to inhibit HBV polymerase activity Less effective for lamivudine-refractory HBV infection available as a tablet and as oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

27. Table 300-4 Recommendations for Treatment of Chronic Hepatitis B HBeAg StatusClinicalHBV DNA (copies/mL) ALTRecommendation HBeAg-reactive Mild or inactive clinically <10 5 Normal (2 x ULN) b No treatment; monitor Chronic hepatitis10 5 Normal (2 x ULN) b, c No treatment; current treatment of limited benefit (Some suggest liver biopsy and treating if abnormal) Chronic hepatitis10 5 Elevated (>2 x ULN) b Treat d Cirrhosis compensated + or – e Normal or elevatedTreat e with oral agents, f not PEG IFN Cirrhosis decompensated + or – e Normal or elevatedTreat e with oral agents, g not PEG IFN; refer for liver transplantation Harrison’s Principles of Internal Medicine, 17 edition

28. HBeAg-negative a <10 4 or 10 5h Normal (2 x ULN) b Inactive carrier; treatment not necessary Chronic hepatitis10 4 or 10 5h NormalConsider liver biopsy; treat if biopsy abnormal Chronic hepatitis10 4 or 10 5h (>2 x ULN) b ElevatedTreat i Cirrhosis compensated + or –Elevated or normal Treat with oral agents, j not PEG IFN (some authorites recommend either following or treating for HBV DNA <10 4 copies/mL) Cirrhosis decompensated + or –Elevated or normal Treat with oral agents, j not PEG IFN (some authorities would follow without therapy for undetectable HBV DNA; refer for liver transplantation) Table 300-4 Recommendations for Treatment of Chronic Hepatitis B HBeAg StatusClinicalHBV DNA (copies/mL) ALTRecommendation Harrison’s Principles of Internal Medicine, 17 edition