Hepatitis Viruses Mohammad Reza Fazeli, PharmD, PhD Department of Drug and Food Control Faculty of...

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  • Hepatitis VirusesMohammad Reza Fazeli, PharmD, PhDDepartment of Drug and Food ControlFaculty of PharmacyTehran University of Medical Sciences

  • AInfectiousSerumViral hepatitisEntericallytransmittedParenterallytransmittedF, G, TTV? otherENANBBDCViral Hepatitis - Historical Perspectives

  • Source ofvirusfecesblood/blood-derivedbody fluidsblood/blood-derivedbody fluidsblood/blood-derivedbody fluidsfecesRoute oftransmissionfecal-oralpercutaneouspermucosalpercutaneouspermucosalpercutaneouspermucosalfecal-oralChronicinfectionnoyesyesyesnoPreventionpre/post-exposureimmunizationpre/post-exposureimmunizationblood donorscreening;risk behaviormodificationpre/post-exposureimmunization;risk behaviormodificationensure safedrinkingwaterType of HepatitisABCDE

  • Hepatitis A Virus

  • Hepatitis A VirusFamily: Picornaviridae Genus: Hepatovirus Species: Hepatitis A virus Structure: small; 27 nm in diameter, non-enveloped spherical particle Genome: +ssRNA (positive sense, single stranded RNA)

  • Hepatitis A VirusRelated to enteroviruses, formerly known as enterovirus 72, now put in its own family: heptovirus One stable serotype onlyDifficult to grow in cell culture: primary marmoset cell culture and also in vivo in chimpanzees and marmosets 4 genotypes exist, but in practice most of them are group 1

  • PathogenesisVirus enters via the gut; replicates in the alimentary tract and spreads to infect the liver, where it multiplies in hepatocytes. Viraemia is transient. Virus is excreted in the stools for two weeks preceding the onset of symptoms

  • Incubation period:Average 30 daysRange 15-50 daysJaundice by
  • Hepatitis A - Clinical FeaturesMilder disease than Hepatitis B; Asymptomatic infections are very common, especially in children. Adults, especially pregnant women, may develop more severe disease. Complications: Fulminant hepatitis: rare; 0.3-1.8 % of cases Highest risk: pregnant women, elderly, pre-existing liver disease, other chronic medical conditions

  • FecalHAVSymptoms01234561224Hepatitis A InfectionTotal anti-HAVTitreALTIgM anti-HAVMonths after exposureTypical Serological Course

  • Close personal contact (e.g., household contact, sex contact, child day care centers)Contaminated food, water (e.g., infected food handlers, raw shellfish)Blood exposure (rare) (e.g., injecting drug use, transfusion) Hepatitis A Virus Transmission

  • Laboratory DiagnosisAcute infection is diagnosed by the detection of HAV-IgM in serum by EIA.Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.Cell culture difficult and take up to 4 weeks, not routinely performedDirect Detection EM, RT-PCR of faeces. Can detect illness earlier than serology but rarely performed.

  • Many cases occur in community-wide outbreaksno risk factor identified for most caseshighest attack rates in 5-14 year oldschildren serve as reservoir of infectionPersons at increased risk of infectiontravelershomosexual meninjecting drug users Hepatitis A Vaccination StrategiesEpidemiologic Considerations

  • Pre-exposuretravelers to intermediate and high HAV-endemic regionsPost-exposure (within 14 days)Routinehousehold and other intimate contactsSelected situationsinstitutions (e.g., day care centers)common source exposure (e.g., food prepared by infected food handler)Hepatitis A Prevention - Immune Globulin

  • Hepatitis B Virus

  • Hepatitis B Virus - VirologyFamily: Hepadnaviridae Genus: Orthohepadnavirus Species: Hepatitis B virus Subtypes: A-H Structure: 42 nm in diameter, enveloped spherical particle [also called the Dane particle] Genome: circular DNA, incompletely DS Excess surface antigen is produced, forming spheres and cylinders 22nm in diameterAt least 4 phenotypes of HBsAg are recognized; adw, adr, ayw and ayr.The HBcAg is of a single serotype

  • Viral antigens1) surface antigen (HBsAg) surface (envelope) protein of the dane particle Secreted in excess into the blood as 22 nm spheres and tubules presence in serum indicates that virus replication is occurring in the liver2) e antigen (HBeAg) secreted protein; shed in small amounts into blood presence in serum indicates that a high level of viral replication is occurring in the liver. May be negative in carriers with mutations in the e antigen gene who nonetheless have high level viraemia. 3) core antigen (HBcAg) core protein present in infected liver cells, not found in blood

  • Antibody response1) Surface antibody (antiHBs)) becomes detectable late in convalescence following resolution of infection, remains detectable for life; not found in chronic carriers; indicates immunity2) e antibody (antiHBe) becomes detectable as viral replication falls In a carrier, it indicates low infectivity3) Core IgM rises early in infection, indicates recent infection4) Core IgG Rises early, present for life in both chronic carriers as well as those who clear the infection indicates exposure to HBV Usually tested as total core antibodies, and implies IgG in the absence of IgM

  • HBV viral loadHBV viral load measures level of HBV DNA in blood. This is the most reliable marker of infectivity.It is more reliable than e antigen which can be negative in some carriers due to mutations in the e antigen gene

  • Hepatitis B Virus - VirologyHepatitis B virus (HBV) has been classified into 8 genotypes (A-H). Genotypes A and C predominate in the US. However, genotypes B and D are also present in the US. Genotype F predominates in South America and in Alaska, while A, D and E predominate in Africa. Genotype D predominates in Russia and in all its prior dominions, while in Asia, genotypes B and C predominate.

  • Incubation period:Average 60-90 daysRange 45-180 daysClinical illness (jaundice):
  • Spectrum of Chronic Hepatitis B DiseasesChronic Persistent Hepatitis asymptomaticthe virus persists, but there is minimal liver damageChronic Active Hepatitis - symptomaticthere is aggressive destruction of liver tissue and rapid progression to cirrhosis or liver failure. Hepatocellular carcinoma

  • Spectrum of Chronic Hepatitis B DiseasesApproximately 5% of adults develop a chronic infection, whereas 90% of infants infected vertically go on to chronicity.Co-infection with HBV and HIV results in faster progression towards severe liver damage.

  • SymptomsHBeAganti-HBeTotal anti-HBcIgM anti-HBcanti-HBsHBsAg0481216202428323652100Acute Hepatitis B Virus Infection with RecoveryTypical Serologic CourseWeeks after ExposureTitre

  • Symptomatic InfectionChronic InfectionAge at InfectionChronic Infection (%)Symptomatic Infection (%)Birth1-6 months7-12 months1-4 yearsOlder Childrenand Adults020406080100100806040200Outcome of Hepatitis B Virus Infectionby Age at InfectionChronic Infection (%)

  • High (>8%): 45% of global populationlifetime risk of infection >60%early childhood infections commonIntermediate (2%-7%): 43% of global populationlifetime risk of infection 20%-60%infections occur in all age groupsLow (
  • HighModerateLow/NotDetectablebloodsemenurineserumvaginal fluidfeceswound exudatessalivasweattearsbreastmilkConcentration of Hepatitis B Virus in Various Body Fluids

  • Sexual - sex workers and homosexuals are particular at risk.

    Parenteral - IVDA, Health Workers are at increased risk.

    Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations. Hepatitis B Virus Modes of Transmission

  • DiagnosisA battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.HBsAg - used as a general marker of infection.HBsAb - used to document recovery and/or immunity to HBV infection. anti-HBc IgM - marker of acute infection.anti-HBcIgG - past or chronic infection.HBeAg - indicates active replication of virus and therefore infectiveness.Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV.HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

  • TreatmentInterferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%.alpha-interferon 2b (original)alpha-interferon 2a (newer, claims to be more efficacious and efficient)Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.Adefovir less likely to develop resistance than Lamivudine and may be used to treat Lamivudine resistance HBV. However more expensive and toxicEntecavir most powerful antiviral known, similar to AdefovirSuccessful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

  • PreventionVaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries.Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive. Other measures - screening of blood donors, blood and body fluid precautions.

  • hypervariableregioncapsidenvelopeproteinprotease/helicaseRNA-dependentRNA polymerasec