Presentation on theme: "Hepatitis B Steve Hart Electron micrograph of serum containing hepatitis B virus after negative staining."— Presentation transcript:
1Hepatitis BSteve HartElectron micrograph of serum containing hepatitis B virus after negative staining.
2Overview Discussion Hepatitis B Epidemiology Serologies Clinical coursePreventionTreatment optionsHerbs
3Hepatitis B Hepadnaviridae family DNA virus Double-shelled particles Outer lipoprotein envelope (surface Ag)Inner viral nucleocapsid (core)seven genotypesfour major subtypes.All HBV subtypes share one common antigenic determinant - "a.“Thus, antibodies to the "a" determinant confer protection to all HBV subtypesDiagrammatic representation of the hepatitis B virion and the surface antigen componentsEM of Hepatitis B viron
4Hep B epidemiology 1/3 of world’s population has been infected 350 million with chronic disease15-25% of these die due to liver related diseases1 million deaths annuallyUnited States1.25 million chronic carriers5000 deaths annuallyHep B surface Ag prevalence, Source: CDC website
5Hepatitis B transmission Dominant mode of transmission related to prevalenceLow prevalence (.1 to <2%) –adultsunprotected sexual intercourseintravenous drug useModerate (3-5%) - childrenHorizontal transmissionHigh prevalence (>10-20%) - infantsMaternal infantPercutaneousOtherOccupational exposureBlood transfusionsIncreasingly rare
6Hepatitis B primary infection SymptomsMalaise, fatigue, anorexia, nausea, low grade fever after day incubationCan be asymptomaticMore common in childrenUsually self limited – in adultsViral clearance from blood and liverLasting immunityCan result in fulminate hepatic failure
7Hepatitis B primary infection HBsAg 4-10 wksAnti-HBc antibody follows+/- HBeAgViral load very high109 to 1010Highly contagious at this time
8Hepatitis B primary infection Decrease in HBsAg correlates with onset of T-cell mediated immune responseAlso, when present, correlates with onset of elevated liver enzymesTraditionally, conversion to anti-HBs antibodies signals cureViral DNA may persist for years to lifetimeSignificance unknown
9Hep B - Persistent Infection Definition:Persistence of HBsAg for greater than 6 months
10Hepatitis B persistent infection Persistent viral load that declines over timeHBeAg declines overtime, converting eventually to anti-HBe antibodySeroconversion 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 incorrect0.5% clear HBsAg annually
11Persistent Hepatitis B Two clinical patternsChronic liver diseaseElevated LFTSAbnormal hepatic histology20% develop cirrhosisAsymptomatic carrierNormal LFTsAsymptomaticNear normal liver histologyBoth risk development of Hepatocellular Carcinoma
12Persistent Hepatitis B HBV replication extensive and continuous in chronic carriersReplication is not cytotoxicHost immune response to viral antigens expressed on infected hepatocytes
13Hepatocellular carcinoma 100 times the risk in persistently infected patientsRisk is greater if HBeAg positiveTwice a year screening is recommended in persistent carriersAlpha fetoprotein and/or hepatic U/SWhen to start screening is unclear
14Who gets chronic disease? Rule of thumb, the younger the age, the more likely to become chronicNeonates – 95% chronic, most asymptomaticInfant to 6 yo – 30% chronicOlder children to adults 3-5% chronic
15Hepatitis B - Serology Surface Antigen (HBsAg) Hep B surface antigen Outer surface lipoprotein, appears earlyHallmark of infectionSurface antigen antibody (anti-HBs) signifies cureHep B core antigen (HBcAg)intracellular antigenexpressed in infected hepatocytesnot detectable in serumCore antibody appear early in infection (Anti-HBc)Predominately IGM early in infectiondetection of IgM anti-HBc usually regarded as an indication of acute HBV infectionTraditionally, the sole marker of HBV infection during the window period between the disappearance of HBsAg and the appearance of anti-HBs
16Hep B – e antigensecretory protein that is processed from the precore proteinElevated 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.
17Hep B – serology interpretation Acute infectionHBsAg positive and anti-HBcAg IGMRarely, IgM anti-HBc only markerUsually seen in acute fulminate Hep BChronic infectionHBsAg positive and anti-HBcAgPrevious InfectionHBsAg negativeanti-HBs positiveIgG anti-HBc positive
18Screening – Who?WhoPersons born in hyperendemic areasMen who have sex with menInjection drug usersPatients on dialysisHIV infected patientsPregnant womenFamily and household contacts and sexual contacts of HBV-infected persons.Testing should be performed by obtaining an HBsAg and anti-HBs.
19Hepatitis B Treatments PreventionNeonatesVaccineProphylaxisPossible exposureChronic infection
20Prevention In 1991, US started routine vaccination Since then incidence of acute HBV infection has declined by 67%However, incidence has continued to increase in adultsOffer vaccine to high risk individuals
21Prophylaxis Hepatitis B immune globulin (HBIG) and vaccine Indications Patients with no history of vaccine andPercutaneous exposure (needle sticks)Household contacts exposed to bloodPerinatal exposure – prevents transmission in 95% of mothers HBsAg positive when given within 12 hours of birthBreast feeding ok if baby received prophylaxis
22Treatment of persistent infection- Who to treat? HBeAg positive with persistent infectionNo 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)HBeAgPosNegChronic dzProbably treattreatProbably not treatCarriertreat
23Treatment options FDA approved Investigational Interferon Alfa Lamivudine – reverse transcriptase inhibitorAdefovir – nucleotide analogue that inhibits viral polymeraseInvestigationalTenofovir – adenine nucleotide analogueApproved for HIVEntecavir – guanosine analogue, highly selective for the HBV polymerase
24Interferon alfa Had been mainstay for therapy Subcutaneous injection three times per week for 3 months or longer30% of patients who could tolerated regime had a successful responseSeroconverted to HBe antibodiesNormalization of LFTsMultiple side effectsFever, myalgia, thrombocytopenia, depression
25Interferon alfa Contraindicated in very advanced liver disease ‘Flairs’ or bump in LFTs occur at time of seroconversion to anti-Hbe due to increased immune responsemay precipiate overt liver failure
26Lamivudine 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 loadThis phenomenon was then noted in patients with only chronic Hep BBy itself, results in a 3 to 4 log decrease serum viral loadIncreased rate of seroconversion to HBe-antibodies and normalization of LFTs
27Lamivudine Those who respond best are those with elevated LFTs >5 times normal -> 65% response rate2-5 times normal -> 26% response<2 times normal -> 5% responseRemember, liver damage is caused by immune responseSo higher LFTs likely correlates to a most robust host immune responseBy inhibiting viral reproduction, the immune system is able to clear the virus more effectively.
28Lamivudine Use limited by resistance At one year of treatment 15-20% of patients develop resistance40% at two years67% at four yearsHowever, the resistant virus is less hearty than the native virus resulting is lower replication rates than pretreatmentResistant variants also convert to anti-HBe antibodies at higher rates.
29Lamivudine Resistance No clear evidence regarding continuation of treatmentPrior to new meds, many continued.Discontinuing medication is associated with flairsOverlapping with another medication recommended
30Adefovir Initially, devoloped for HIV Nucleotide analogue Prodrug phosphorylated intracellularly to yield active drugInhibits viral polymeraseHas been evaluated for primary monotherapy and in patients with resistance to Lamivudine
31Adefovir Efficacy Much lower rate of resistance than Lamivudine Reduces viral load by 3 to 4 logEnhances HBeAg seroconversionResults in histological improvement of liverImproved LFTsEffective even in Lamivudine resistant patientsMuch lower rate of resistance than Lamivudine
32Approach to treatmentUnfortunately, studies are lacking to define what is the best approachPresently, alpa interferon, Adefovir and Lamivudine are all considered first line therapyConsiderationsAdefovir – less resistance, possibly nephrotoxicLamivudine – good side effect profileInterferon – difficult courseAll provided about the same resultsUnknown if benefit to using combination therapy.
33Hepatitis 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 infectionControlled 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.
34Hepatitis B and Herbs – Cochrane review Asymptomatic carriesVery few quality studiesThree 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/uChronic carriersFuzheng Jiedu Tang (compound of herbs)positive effects on clearance of serum HBsAg, HBeAg, and HBV DNAPolyporus umbellatus polysaccharide vs interferonPositive effects on serum HBeAg and HBV DNAPhyllanthus amarus vs interferonImprovement in serum HBeAg
35Hepatitis 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 herbsfollow-up randomized trials seem justified for someWould not recommend due to potential hepatotoxic effects
36References Images: Am J Gastroenterol. 2003 Mar;98(3):538-44 Am J Gastroenterol Mar;98(3):538-44Arch Surg Aug;138(8):852-8N Engl J Med Mar 11,2004;Pediatrics in Review, Vol 24, No.12 Dec 2003