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Hepatitis B. Steve Hart. Electron micrograph of serum containing hepatitis B virus after negative staining . . Overview. Discussion Hepatitis B Epidemiology Serologies Clinical course Prevention Treatment options Herbs. Hepatitis B. Hepadnaviridae family DNA virus

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hepatitis b

Hepatitis B

Steve Hart

Electron micrograph of serum containing hepatitis B virus after negative staining.

overview
Overview
  • Discussion Hepatitis B
    • Epidemiology
    • Serologies
    • Clinical course
    • Prevention
    • Treatment options
    • Herbs
hepatitis b3
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

hep b epidemiology
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

hepatitis b transmission
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
hepatitis b primary infection
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
hepatitis b primary infection7
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
hepatitis b primary infection8
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
hep b persistent infection
Hep B - Persistent Infection
  • Definition:
    • Persistence of HBsAg for greater than 6 months
hepatitis b persistent infection
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
persistent hepatitis b
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
persistent hepatitis b12
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
hepatocellular carcinoma
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
who gets chronic disease
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
hepatitis b serology
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
hep b e antigen
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.
hep b serology interpretation
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
screening who
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.
hepatitis b treatments
Hepatitis B Treatments
  • Prevention
    • Neonates
    • Vaccine
  • Prophylaxis
    • Possible exposure
  • Chronic infection
prevention
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
prophylaxis
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
treatment of persistent infection who to treat
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

treatment options
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
interferon alfa
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
interferon alfa25
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
lamivudine
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
lamivudine27
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.
lamivudine28
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.
lamivudine29
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
adefovir
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
adefovir31
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
approach to treatment
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.
hepatitis b c alternative therapy what your patient might read about on the internet
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.

hepatitis b and herbs cochrane review
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
hepatitis b alternative therapies
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
slide36

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
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