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, 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. Hepatitis B primary infection
Symptoms
Malaise, fatigue, anorexia, nausea, low grade fever after 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

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?
HBeAg positive 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 Investigational 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 Much lower rate of resistance than Lamivudine
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 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: Am J Gastroenterol. 2003 Mar;98(3):538-44
Am J Gastroenterol Mar;98(3):538-44
Arch Surg Aug;138(8):852-8
N Engl J Med Mar 11,2004;
Pediatrics in Review, Vol 24, No.12 Dec 2003