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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

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Hepatitis b l.jpg

Hepatitis B

Steve Hart

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


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Overview

  • Discussion Hepatitis B

    • Epidemiology

    • Serologies

    • Clinical course

    • Prevention

    • Treatment options

    • Herbs


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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


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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


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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


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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


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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


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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


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Hep B - Persistent Infection

  • Definition:

    • Persistence of HBsAg for greater than 6 months


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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


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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


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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


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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


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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


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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


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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.


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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


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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.


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Hepatitis B Treatments

  • Prevention

    • Neonates

    • Vaccine

  • Prophylaxis

    • Possible exposure

  • Chronic infection


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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


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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


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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


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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


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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


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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


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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


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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.


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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.


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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


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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


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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


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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.


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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.


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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


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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


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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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