Hepatitis B

1. Hepatitis B Steve Hart Electron micrograph of serum containing hepatitis B virus after negative staining.

2. Overview • Discussion Hepatitis B • Epidemiology • Serologies • Clinical course • Prevention • Treatment options • Herbs

3. Hepatitis B • Hepadnaviridae family • DNA virus • Double-shelled particles • Outer lipoprotein envelope (surface Ag) • Inner viral nucleocapsid (core) • seven genotypes • four major subtypes. • All HBV subtypes share one common antigenic determinant - "a.“ • Thus, antibodies to the "a" determinant confer protection to all HBV subtypes Diagrammatic representation of the hepatitis B virion and the surface antigen components EM of Hepatitis B viron

4. Hep B epidemiology • 1/3 of world’s population has been infected • 350 million with chronic disease • 15-25% of these die due to liver related diseases • 1 million deaths annually • United States • 1.25 million chronic carriers • 5000 deaths annually Hep B surface Ag prevalence, 2002 Source: CDC website

5. Hepatitis B transmission • Dominant mode of transmission related to prevalence • Low prevalence (.1 to <2%) –adults • unprotected sexual intercourse • intravenous drug use • Moderate (3-5%) - children • Horizontal transmission • High prevalence (>10-20%) - infants • Maternal infant • Percutaneous • Other • Occupational exposure • Blood transfusions • Increasingly rare

6. Symptoms Malaise, fatigue, anorexia, nausea, low grade fever after 45-160 day incubation Can be asymptomatic More common in children Usually self limited – in adults Viral clearance from blood and liver Lasting immunity Can result in fulminate hepatic failure Hepatitis B primary infection

7. Hepatitis B primary infection • HBsAg 4-10 wks • Anti-HBc antibody follows • +/- HBeAg • Viral load very high • 109 to 1010 • Highly contagious at this time

8. Hepatitis B primary infection • Decrease in HBsAg correlates with onset of T-cell mediated immune response • Also, when present, correlates with onset of elevated liver enzymes • Traditionally, conversion to anti-HBs antibodies signals cure • Viral DNA may persist for years to lifetime • Significance unknown

9. Hep B - Persistent Infection • Definition: • Persistence of HBsAg for greater than 6 months

10. Hepatitis B persistent infection • Persistent viral load that declines over time • HBeAg declines overtime, converting eventually to anti-HBe antibody • Seroconversion correlates with rise in LFTs and 5 order of magnitude decline in viral load. • Classically, to Anti-HBe antibody = no viral DNA circulating, which is incorrect • 0.5% clear HBsAg annually

11. Persistent Hepatitis B • Two clinical patterns • Chronic liver disease • Elevated LFTS • Abnormal hepatic histology • 20% develop cirrhosis • Asymptomatic carrier • Normal LFTs • Asymptomatic • Near normal liver histology • Both risk development of Hepatocellular Carcinoma

12. Persistent Hepatitis B • HBV replication extensive and continuous in chronic carriers • Replication is not cytotoxic • Host immune response to viral antigens expressed on infected hepatocytes

13. Hepatocellular carcinoma • 100 times the risk in persistently infected patients • Risk is greater if HBeAg positive • Twice a year screening is recommended in persistent carriers • Alpha fetoprotein and/or hepatic U/S • When to start screening is unclear

14. Who gets chronic disease? • Rule of thumb, the younger the age, the more likely to become chronic • Neonates – 95% chronic, most asymptomatic • Infant to 6 yo – 30% chronic • Older children to adults 3-5% chronic

15. Hepatitis B - Serology • Surface Antigen (HBsAg) • Hep B surface antigen Outer surface lipoprotein, appears early • Hallmark of infection • Surface antigen antibody (anti-HBs) signifies cure • Hep B core antigen (HBcAg) • intracellular antigen • expressed in infected hepatocytes • not detectable in serum • Core antibody appear early in infection (Anti-HBc) • Predominately IGM early in infection • detection of IgM anti-HBc usually regarded as an indication of acute HBV infection • Traditionally, the sole marker of HBV infection during the window period between the disappearance of HBsAg and the appearance of anti-HBs

16. Hep B – e antigen • secretory protein that is processed from the precore protein • Elevated early in infection and usually coverts to antibody early on. • Traditionally used as a marker for viral load as viral load was undetectable with early assays when Ag was absent. • However, certain variants of the Hep B virus do not create the HBeAg as it has no known function. • When present, it does correlate with elevated viral load and seroconversion the antibody usually correlates with a decrease in viral load by a magnitude of 4-5.

17. Hep B – serology interpretation • Acute infection • HBsAg positive and anti-HBcAg IGM • Rarely, IgM anti-HBc only marker • Usually seen in acute fulminate Hep B • Chronic infection • HBsAg positive and anti-HBcAg • Previous Infection • HBsAg negative • anti-HBs positive • IgG anti-HBc positive

18. Screening – Who? • Who • Persons born in hyperendemic areas • Men who have sex with men • Injection drug users • Patients on dialysis • HIV infected patients • Pregnant women • Family and household contacts and sexual contacts of HBV-infected persons. • Testing should be performed by obtaining an HBsAg and anti-HBs.

19. Hepatitis B Treatments • Prevention • Neonates • Vaccine • Prophylaxis • Possible exposure • Chronic infection

20. Prevention • In 1991, US started routine vaccination • Since then incidence of acute HBV infection has declined by 67% • However, incidence has continued to increase in adults • Offer vaccine to high risk individuals

21. Prophylaxis • Hepatitis B immune globulin (HBIG) and vaccine • Indications • Patients with no history of vaccine and • Percutaneous exposure (needle sticks) • Household contacts exposed to blood • Perinatal exposure – prevents transmission in 95% of mothers HBsAg positive when given within 12 hours of birth • Breast feeding ok if baby received prophylaxis

22. Treatment of persistent infection-Who to treat? • Treat: • HBeAgpositive with persistent infection • No treatment: • HBeAg negative and carrier (nl LFTs, viral load less than 105 and asymptomatic) • Probably treat: • HBeAg negative with chronic infection (high viral load, abnormal LFTs) HBeAg Pos Neg Chronic dz Probably treat treat Probably not treat Carrier treat

23. Treatment options • FDA approved • Interferon Alfa • Lamivudine – reverse transcriptase inhibitor • Adefovir – nucleotide analogue that inhibits viral polymerase • Investigational • Tenofovir – adenine nucleotide analogue • Approved for HIV • Entecavir – guanosine analogue, highly selective for the HBV polymerase

24. Interferon alfa • Had been mainstay for therapy • Subcutaneous injection three times per week for 3 months or longer • 30% of patients who could tolerated regime had a successful response • Seroconverted to HBe antibodies • Normalization of LFTs • Multiple side effects • Fever, myalgia, thrombocytopenia, depression

25. Interferon alfa • Contraindicated in very advanced liver disease • ‘Flairs’ or bump in LFTs occur at time of seroconversion to anti-Hbe due to increased immune response • may precipiate overt liver failure

26. Lamivudine • Oral medication • Usually given for year or longer • Found to inhibit HIV reverse transcriptase. • Noted that patients with both HIV and chronic Hep B had large declines in Hep B viral load • This phenomenon was then noted in patients with only chronic Hep B • By itself, results in a 3 to 4 log decrease serum viral load • Increased rate of seroconversion to HBe-antibodies and normalization of LFTs

27. Lamivudine • Those who respond best are those with elevated LFTs • >5 times normal -> 65% response rate • 2-5 times normal -> 26% response • <2 times normal -> 5% response • Remember, liver damage is caused by immune response • So higher LFTs likely correlates to a most robust host immune response • By inhibiting viral reproduction, the immune system is able to clear the virus more effectively.

28. Lamivudine • Use limited by resistance • At one year of treatment 15-20% of patients develop resistance • 40% at two years • 67% at four years • However, the resistant virus is less hearty than the native virus resulting is lower replication rates than pretreatment • Resistant variants also convert to anti-HBe antibodies at higher rates.

29. Lamivudine • Resistance • No clear evidence regarding continuation of treatment • Prior to new meds, many continued. • Discontinuing medication is associated with flairs • Overlapping with another medication recommended

30. Adefovir • Initially, devoloped for HIV • Nucleotide analogue • Prodrug phosphorylated intracellularly to yield active drug • Inhibits viral polymerase • Has been evaluated for primary monotherapy and in patients with resistance to Lamivudine

31. Adefovir • Efficacy • Reduces viral load by 3 to 4 log • Enhances HBeAg seroconversion • Results in histological improvement of liver • Improved LFTs • Effective even in Lamivudine resistant patients • Much lower rate of resistance than Lamivudine

32. Approach to treatment • Unfortunately, studies are lacking to define what is the best approach • Presently, alpa interferon, Adefovir and Lamivudine are all considered first line therapy • Considerations • Adefovir – less resistance, possibly nephrotoxic • Lamivudine – good side effect profile • Interferon – difficult course • All provided about the same results • Unknown if benefit to using combination therapy.

33. Hepatitis B/C Alternative Therapy:What your patient might read about on the internet • MTH-68/B. vaccine strain of Newcastle disease, virus that causes a bird infection • Controlled study - conventional tx’ment vs vaccine in acute phase n=42, showed more progressed to chronic infection with conventional tx’mt. • Case reports of benefit to pts given this vaccines after progressing to decompensated liver failure. Both studies investigated the use in both Hepatitis B and C.

34. Hepatitis B and Herbs – Cochrane review • Asymptomatic carries • Very few quality studies • Three randomised clinical trials of carriers (307 patients) three months or more of follow identified. • The methodological quality was poor overall, only one significant trial • 'Jianpi Wenshen recipe' • significant effects on viral markers compared to interferon serum: • HBsAg,HBeAg, and seroconversion of HBeAg to anti-HBe. • Poor long term f/u • Chronic carriers • Fuzheng Jiedu Tang (compound of herbs) • positive effects on clearance of serum HBsAg, HBeAg, and HBV DNA • Polyporus umbellatus polysaccharide vs interferon • Positive effects on serum HBeAg and HBV DNA • Phyllanthus amarus vs interferon • Improvement in serum HBeAg

35. Hepatitis B Alternative Therapies • One small retrospective study showed patients in fulminent hepatic failure who took dietary or herbal supplements often did worse than those who did not. Arch Surg. 2003 Aug;138(8):852-8. • Thought to be due to heptotoxic effects of componds in these supplements. • Basically – • No firm evidence supporting medicinal herbs • follow-up randomized trials seem justified for some • Would not recommend due to potential hepatotoxic effects

36. References • Images: • http://www.cdc.gov/ncidod/diseases/hepatitis/ • http://gsbs.utmb.edu/microbook/ch070.htm • http://web.uct.ac.za/depts/mmi/jmoodie/dihep.html • http://www.aids-hepatitisc.org/healthinsurance/maps-graphs/figure7-infectious-hepatitis.gif • Am J Gastroenterol. 2003 Mar;98(3):538-44 • Arch Surg. 2003 Aug;138(8):852-8 • N Engl J Med Mar 11,2004; • Pediatrics in Review, Vol 24, No.12 Dec 2003