ViralHepatitis

Masika M.M.

x Etiology
x AcuteHepatitis

Session
Outline

x ChronicHepatitis
x HBV:Virology,epidemiology,presentation,diagnosis,treatment,prevention
x HAV:Virology,epidemiology,presentation,diagnosis,treatment,prevention
x HCV:Virology,epidemiology,presentation,diagnosis,treatment,prevention

Hepatitisisinflammationoftheliver.
Causes:
x Infectious Viral,Fungal,Bacterial,Parasitic

Hepatitis

x Drugs e.g.antiTBs,ARVs,NSAIDS,etc.
x Alcohol
x Poisoning e.g.aflatoxin
x Metabolicdisorders
x Autoimmunediseases

x HepatitisAvirus(HAV)
x HepatitisBvirus(HBV)
x HepatitisCvirus(HCV)

ViralHepatitis
ETIOLOGY

x HepatitisDvirus(CoinfectionwithHBVonly)
x HepatitisEvirus(HEV)
x Others HepatitisFvirus,HepatitisGvirus
x Infrequent:Adenovirus,EBV,CMV,HSV,

HAV

HBV

HCV

HDV

HEV

Genus

Hepatovirus

Orthohepadnavirus

Hepacivirus

Deltavirus

Hepevirus

(Family)

(Picornaviridae) (Hepadnaviridae)

(Flaviviridae)

(Unassigned)

(Hepeviridae)

Blood/body fluids

Blood/body fluids

Feco-oral

Transmission Feco-oral

Blood/body fluids

Chronic
Infection

No

Yes (sometimes)
Yes (common)
5-90% of infections 70% of infections

Yes

No

Prevention

Immunization

Immunization

Screening blood

Screening blood

Environmental
hygiene

Screening blood

Behavior
modification

Behavior
modification

Safe drinking
water

None

Antivirals

Interferon
Tenofovir
Lamivudine
Adefovir
Entecavir

Interferon
Ribavirin
Sofosbuvir
Boceprevir
Simeprevir

None

None

HepatitisBvirus
HBV

x Family:Hepadnaviridae
x Genus:Orthohepadnavirus

HBV
Virology

x Species:HepatitisBvirus
x 8genotypes:A H
x CircularDNA,partiallydoublestranded
x Enveloped

HBVstructure

x Athirdofglobalpopulationhasbeeninfected
x 5%(400million)areHBVcarriers

HBV
Epidemiology

x Aquarterofchroniccarriersdevelopseriousliver
disease cirrhosis,Hepatocellularcarcinoma(HCC)
x 1milliondeathsp.a.relatedtoHBV
x HBVcauses80%ofallcasesofHCC

HBV
Prevalence

WHO2011

x Sexualcontact

x Predominantmodeamongadults

x Closecontact

x Inchildren&families

x Verticaltransmission

HBV
Transmission

x Duringdelivery,rarelytransplacental
x Noevidenceoftransmissionthroughbreastfeeding

x Blood

x Unscreenedbloodtransfusions,serumproducts
x Sharingofneedles,razors
x Tattooing,acupuncture
x Renaldialysis
x Organtransplant

1. Multiplesexualpartners
2. IntravenousDrugUse(PWIDs)

HBV
RiskFactors

3. MSM
4. Householdmembersofaninfectedperson
5. Crowding/Institutionalization
6. Occupationalrisk Healthworkers

x Parenterally transmitted
x ReplicatesinHepatocytes

HBV
Pathogenesis

x Virusparticles &surfaceproteinreleasedintoblood
x Viremia isprolongedandbloodofinfected
individualsishighlyinfectious
x Hostimmuneresponsetotheviruscauses
hepatocellulardamage

Acute Hepatitis B

90%

9%

Resolution

HBsAg + for > 6 months

1%
Fulminant
Hepatitis

50%
Resolution

HBV
Clinicaloutcomes

Asymptomatic
carrier state

Chronic Persistent
Hepatitis

Extra-hepatic
manifestations:
Glomerulonephritis
Arteritis
Myocarditis

Chronic Active
Hepatitis

Cirrhosis

Hepatocellular
Carcinoma

1. Immunetolerancephase

HBV Infection
Disease Phases

2. Immuneactive/immuneclearancephase
3. Inactivechronicinfection
4. Chronicdisease
5. Recovery

x Longincubationperiod120days(16months)
x Insidiousonsetofsymptoms.

HBV
ClinicalFeatures

x Oftenasymptomatic,esp.intheveryyoung,(dueto
aweakimmuneresponsetothevirus)
x Resultsindecreasedinflammationintheliver
&ahigherrateofchronicity.
x 90% ofinfectedinfantsdevelopchronicinfection
x Approx.5%ofadultsdevelop chronicinfection,

x Variablepresentation

HBV
AcutePhase

x Subclinical
x Icteric
x Fulminanthepatitis(1%ofHBVinfections)

Symptoms
x Malaise
x Myalgia/Athralgia
x Fever

Acute
Hepatitis

x Fatigability
x Nauseaorvomiting
x Lossofapetite
x Abdominalpain Rightupperquadrant
x Darkurine
x Jaundice

x Hepaticencephalopathy
x Somnolence/alteredsleeppattern
x Confusion

HBV
FulminantHepatitis

x Coma
x Ascites
x GITbleeding
x Coagulopathy

x PossibleoutcomesofChronicHBVinfection:
x AsymptomaticChronicInfection(carrier)

HBV
ChronicPhase

x ChronicPersistentHepatitis
x ChronicActiveHepatitis
x Cirrhosis
x HepatocellularCarcinoma

Symptoms
x Malaise,fatigue,weakness

Chronic
Hepatitis

x Weightloss
x Peripheraledema
x Ascites
x Extrahepaticmanifestations

Extrahepaticmanifestations:
x Resp:Pleuraleffusions/hepatopulmonary syndrome

HBVInfection
Complications

x CVS:arrhythmias,pericarditis,myocarditis,arteritis
x CNS:encephalopathy,somnolence,confusion
x MSS:arthralgia,Serumsickness
x Renal:Glomerulonephritis,
x Hematological:bonemarrowaplasia

Serology:
x Antigens:
HBsAg,eAg,

HBV
Diagnosis

x Antibodies:
antiHBs,eAb,coreAb
PCR:
x HBVDNA/Viralload

HBV
Acuteinfection

HBV
Persistentinfection

SurfaceAntigen(sAg)
x Surface(envelope)protein
x Secretedinexcessintotheblood(spheres&tubules)
x Presenceinserumindicatesvirusreplication

HBV
Viralantigens

eantigen(eAg)
x Secretedprotein,shedinsmallamountsintoblood
x Presenceindicatesthatahighlevelofviralreplication
x MaybefalselynegativeincarrierssomemutationsineAg gene

CoreAntigen(cAg)
x Coreprotein
x Presentininfectedlivercells,notfoundinblood

Surfaceantibody(sAb,antiHBs)
x Detectablelateinconvalescenceafterresolutionofinfection,
x Remainsdetectableforlife
x Notfoundinchroniccarriers
x Indicatesimmunity

HBV
AntibodyResponse

eantibody(eAb,antiHBe)
x Becomesdetectableasviralreplicationfalls
x Inacarrier,itindicateslowinfectivity
CoreIgM
x Risesearlyininfection
x Indicatesrecentinfection
CoreIgG
x Risesearly
x Presentforlifeinbothcarriers&thosewhocleartheinfection
x IndicatesexposuretoHBV

x HBVviralloadmeasureslevelofHBVDNAinblood

HBV
ViralLoad

x Themostreliable markerofinfectivity.
x MorereliablethaneAg whichcanbenegativein
somecarriersduetomutationsintheeAg gene

HepatitisBserology
HBsAg

Anti-HBs Anti-HBc

Anti-HBc
(IgM)

(-)

(-)

(-)

Susceptible

(-)

(+)

(+)

Immune after infection

(-)

(+)

(-)

Immune after vaccine

(+)

(+)

(+)

(+)

Acute Infection

(+)

(-)

(+)

(-)

Chronic Infection

(-)

(-)

(+)

Resolved infection,
Low level chronic infection,
False positive (Anti-HBc)

1. LiverFunctionTests:
x ALT,AST,ALP,GGT,Bilirubin

HBV
OtherInvestigations

2. CoagulationProfile
x INR(Internationalnormalizedratio)
3. RenalFunctionTests
4. Fullbloodcount
5. Radiology:Ultrasound/CTscan/MRI
6. Liverbiopsy&histology

1. Interferons(6months)
x INF2a
x Pegylated INF 2a
Bestoutcomeisinfectionclearance(25%ofalltreatedcases)

HBV
Treatment

2. DNApolymeraseinhibitors(Lifelong)
x Entecavir
x Tenofovir
x Lamivudine
x Adefovir
x Telbivudine

x Vaccine
x Postexposureprophylaxis
x Vaccine&HBIG givenwithin48hrs ofexposure

HBV
Prevention

x Safesexpractices
x Safeinjectionpractices
x Screeningblood/bloodproducts
x Healtheducation

Fourtypesofvaccinesareavailable
1. Serumderived sAgpurifiedfromtheserumofHBVcarriers
2. RecombinantsAg madebygeneticengineeringinyeast

HBV
Activeimmunization

3. 3rd Generation Geneticallyengineeredvaccines

4. Combination vaccines vaccinesagainstHBVvaccine+
otherorganismse.g.HepatitisA+B
x 3dosesinduceimmunityin95%ofrecipients
x Infantsreceivethreedoses:at6,10and14weeks

PassiveAntibody

HBV
Passiveimmunization

x HBIG(HepatitisBsurfaceImmunoglobulin)
x BothHBIGandvaccineshouldbeadministeredto
nonimmuneindividualsfollowingexposureto

x HBV/HCVCoinfection
x IncreasesrateofHepatocellularcarcinoma

HBV
Coinfection

x HBVHDVCoinfection
x IncreasesrateofHCC
x HBVHIVCoinfection
x Lowerincidenceofictericillness
x Higherratesofchronicity
x Higherriskofcirrhosis&endstageLiverDisease

HepatitisAVirus
HAV

x Order:Picornavirales
x Family:Picornavirus
x Genus: Hepatovirus

HepatitisAvirus
(HAV)

x 7genotypes, 1 serotype
x (+)ssRNA virus,naked,icosahedral
x Withstandsacid,dessication,temp(20to560C)
x Destroyedbyboiling,chlorine&iodine
x Transmissionisfecooral

x Worldwidedistribution
x Commonestcauseofacutehepatitis

HAV
Epidemiology

x Highestindevelopingcountries
x Nearlyuniversal inUrbancentres inAfrica&Asia
x Factors:Overcrowding&poorsanitation
x Mostareinfectedby2yrs ofage

x Fecooraltransmission,
x Replicatesinenterocytes,

HAV
Pathogenesis

x Spreadstoliver&multipliesinhepatocytes,
x Excretedinfeces
x Causestransientviremia

x Incubation 28days(26weeks)
x Relatedtothedoseoftheinoculum

HAV
ClinicalFeatures

x Preictericprodrome 1week
x Flulikeillness:anorexia,nausea,vomiting,fatigue,fever,
myalgia,headache

x IctericPhase upto12weeks
x Darkurine,palestool,jaundice,abdominalpain,pruritus

x FulminantHepatitis 1%ofallHAVinfections
x RelapsingHAVinfection (usuallyintheelderly)
x AutoimmuneHepatitis

HAV
Complications

x Extrahepaticmanifestations rare
x RenalFailure
x Arrythmias
x Bonemarrowaplasia
x SLE
x Guillan Barre Syndrome

HAV
Diagnosis

x Serology:IgM/IgG
x HAVcannotbeculturedinvitro
x RNAPCR(blood&stool) forresearchpurposes

HAVInfection
TimeCourse

x Supportive

HAV
Treatment

x Analgesia/antypyretics
x Antiemesis
x Rehydration
x Livertransplant maybeneededinfulminantHF

x Vaccination:

HAV
Prevention

x Liveattenuatedvaccine(IM,2doses)
x Passiveimmunizationwithimmunoglobulins
x Environmentalsanitation,cleandrinkingwater

HepatitisCvirus
HCV

x Family:Flaviviridae
x Genus:Hepacivirus

HCV
Virology

x (+)ssRNA,enveloped
x 6genotypes,numeroussubtypes
x Infectsmanandchimpanzees
x Transmittedviabloodorbodyfluids:
x Transfusions,PWIDs,tattoing,needlestickinjuries

x 170millioncasesWorldwide.

HCV
Epidemiology

x Highestburden:SEAsia,EasternMediterranean,
NorthAfrica
x Africa prevalenceof5%,highestinEgypt~20%
x Kenya<2%
x Prevalencehigherinolderpopulation>20years

x Perenteral transmission
x Multipliesinhepatocytes

HCV
Pathogenesis

x ViralclearancewithlongtermCMimmunity(25%)
x Usuallycauseschronicinfection(75%ofinfections)
x Persistentviremia&hepaticinflammation/fibrosis
x HCVpolymerasegeneratesmutants(quasispecies)
x ChallengesinCMI&vaccinedevelopment

x 6070%ofcasesareasymptomatic
x Incubationperiodis15150days

HCV
ClinicalFeatures

x Commonestsymptomsarefatigue&jaundice
x 70 80%ofnewlyinfectedindividualsdevelop
chronicinfection

x ChronicHCVinfection (75%)
x Cirrhosis(1020%ofchronicinfections)

HCV
Complications

x Hepatocellularcarcinoma(HCC)(15%)
x HCVisresponsibleforabout25%ofHCCcases.
x Immunecomplexdisorderscommonincarriers
x CoinfectionwithHIV isassociatedwithmore
aggressiveliverdisease.

x Serology:IgG

HCV
Diagnosis

x PCR
HCVcannotbecultured

AimsofTreatment:

HCV
Treatment

1. SustainedViralResponse(SVR)
AbsenceofHCVRNAinserum6monthsafter
completingtreatment
2. Preventprogression
Tocirrhosis,hepatocellularcarcinomaor
decompensatedliverdisease
Rxincludessupportiveandantiviraltherapy

Antiviralagents
1. Interferon2a&2b

HCV
Treatment

2. Polymeraseinhibitors:
x Ribavirin
x Sofosbuvir
3. Proteaseinhibitors:
x Boceprevir,
x Simeprevir

HCV
Prevention

x Novaccine
x Screeningblood&bloodprojects
x Avoidinjectiondruguse/sharingneedles

HIV/HCV
Coinfection

x Increasesliverscarringandlongterm
complicationse.g.cirrhosis
x Increasesviralreplication
x IncreasedperinatalHCVtransmission

TheEnd