Hepatitis B virusHepatitis B virus

Hepatitis viruses:Hepatitis viruses:AAB B formerly serum hepatitisformerly serum hepatitis

DD non A nonB non A nonB EE

GG

One of the most prevalent infectionsOne of the most prevalent infections

Worldwide:2 out of 6 billion encountered with HBV350–400 million CHB cases - 4 million new cases/year- >1 million deaths/year

HBV HBV

Hepadnavirus semi (relaxed) circular 3.2 semi (relaxed) circular 3.2

kb ds DNAkb ds DNA Encodes 7 polypeptidesEncodes 7 polypeptides Large amounts of of HBs Large amounts of of HBs

is released from infected is released from infected cellscells

HBV genome integrates HBV genome integrates to host cell chromosometo host cell chromosome

Proteins: 4 ORFProteins: 4 ORF- Two structural proteins: HBs and HBc/HBeTwo structural proteins: HBs and HBc/HBe- PolymerasePolymerase- X proteinX protein

- 3 initiation codons for S: L, M, S3 initiation codons for S: L, M, S- 2 inititions codons for C: HBc+e2 inititions codons for C: HBc+e

S protein contains common antigenic S protein contains common antigenic determinan “a”determinan “a”

Phenotypes of HBs: 4 major serotypes Phenotypes of HBs: 4 major serotypes adw, ayw*, adr and ayr – 9 subtypesadw, ayw*, adr and ayr – 9 subtypes

Genotypes A-H Genotypes A-H

In serum with EM:In serum with EM:- Spherical particles 22 Spherical particles 22

nmnm- Tubuler of Tubuler of

filamentous 200 nm filamentous 200 nm longlong

- Spherical virions 42 Spherical virions 42 nm (Dane particle)nm (Dane particle)

ReplicationReplication

Attachment and uncoatingAttachment and uncoating cccDNA formation in nucleuscccDNA formation in nucleus cccDNA cccDNA 3.5 kb pregenomic RNA 3.5 kb pregenomic RNA Pregenomic RNA is encapsidated with Pregenomic RNA is encapsidated with

new HBc and + sense DNA is produced by new HBc and + sense DNA is produced by reverse transcription in Golgireverse transcription in Golgi

Transmission: Through blood and body Transmission: Through blood and body fluids (semen, saliva, milk, vagina, fluids (semen, saliva, milk, vagina, menstruel secretions and amniotic fluidsmenstruel secretions and amniotic fluids

Vertical transmissionVertical transmission Incubation period min 6 weeksIncubation period min 6 weeks

1/3 of world pop. Has serologic evidence1/3 of world pop. Has serologic evidence350 M chronically infected350 M chronically infected

HBV related HCCHBV related HCC >1 M deaths and 5-10 >1 M deaths and 5-10 % liver transplantations% liver transplantations

High-Risk Groups for Hepatitis B VirusHigh-Risk Groups for Hepatitis B Virus People from endemic regions (i.e., China, parts of Africa, Alaska, People from endemic regions (i.e., China, parts of Africa, Alaska,

Pacific Islands) Pacific Islands)

Babies of mothers with chronic hepatitis B virus Babies of mothers with chronic hepatitis B virus

Intravenous drug abusers Intravenous drug abusers

People with multiple sex partners, homosexual and heterosexual People with multiple sex partners, homosexual and heterosexual

Hemophiliacs and other patients requiring blood and blood product Hemophiliacs and other patients requiring blood and blood product treatmentstreatments

Health care personnel who have contact with bloodHealth care personnel who have contact with blood Residents and staff members of institutions for the mentally retardedResidents and staff members of institutions for the mentally retarded Hemodialysis patients and blood and organ recipientsHemodialysis patients and blood and organ recipients

95% of neonates95% of neonates30% of children under 6 years of age30% of children under 6 years of ageless than 5% of adults less than 5% of adults become chronic carriersbecome chronic carriers

5 phases of chronic HBV 5 phases of chronic HBV infectionsinfections

Immune tolerant phaseImmune tolerant phase: HBeAg +, high : HBeAg +, high replication, normal ALT,AST levels, mild-replication, normal ALT,AST levels, mild-no necroinflammation, no or slow no necroinflammation, no or slow progression to fibrosisprogression to fibrosis

Spontaneous HBeAg loss is very low.Spontaneous HBeAg loss is very low.More frequent more prolonged among More frequent more prolonged among

subjects infected vertically or in the first subjects infected vertically or in the first year of lifeyear of life

Highly contagiousHighly contagious

Immune reactive phaseImmune reactive phase: HBeAg +, lower : HBeAg +, lower replication, more fluctuations in ALT, AST levels, replication, more fluctuations in ALT, AST levels, Moderate-severe necroinlammation, more rapid Moderate-severe necroinlammation, more rapid progression of fibrosisprogression of fibrosis

May take from several weeks to several yearsMay take from several weeks to several years

Spontan HBeAg loss is more frequentSpontan HBeAg loss is more frequent

More frequent among subjects infected during More frequent among subjects infected during adulthoodadulthood

IInactive HBV carrier statenactive HBV carrier state: HBeAg+ : HBeAg+ AntiHBeAntiHBe Low or undetectable HBV levelsLow or undetectable HBV levels ALT, AST normal, low fibrosis or HCC riskALT, AST normal, low fibrosis or HCC risk HBsAG+HBsAG+ Anti-HBs 1-2% per year Anti-HBs 1-2% per year

HBeAg negative CHBHBeAg negative CHB: A later phase in : A later phase in the natural course of CHB following the the natural course of CHB following the HBeAg + HBeAg + Anti-HBe cenversion Anti-HBe cenversion

Periodic reactivation Periodic reactivation HBV variants with alterations in precore HBV variants with alterations in precore

and/or basal core promoter regionsand/or basal core promoter regions

HBsAg negative phaseHBsAg negative phase: Phase after loss : Phase after loss of AHBsAgof AHBsAg

Chronic hepatitis B

1. HBsAg-positive 6 months2. Serum HBV DNA 20,000 IU/mL (10 5copies/mL), lower values 2,000-20,000 IU/mL (10 4-10 5 copies/mL) are often seen in HBeAg-negativechronic hepatitis B3. Persistent or intermittent elevation in ALT/AST levels4. Liver biopsy showing chronic hepatitis with moderate or severenecroinflammation

Resolved hepatitis B1. Previous known history of acute or chronic hepatitis B or the presenceof anti-HBc anti-HBs2. HBsAg3. Undetectable serum HBV DNA*4. Normal ALT levels*Very low levels may be detectable using sensitive PCR assays

Serologic markers of HBVSerologic markers of HBV

IFN-alphaIFN-alpha

LAmivudinLAmivudin EntacavirEntacavir AdefovirAdefovir TenofovirTenofovir TelbivudinTelbivudin

Hepatitis DHepatitis D

HDV prevalence in TurkeyHDV prevalence in Turkey

CHB n = 5961 20 % 1980-1990 31 % 1991-2000 19.4 % 2001-2005 11 %

Cirrhosis n= 264 32.5 % 1980-1990 43.5 % 1991-2000 26.1 % 2001-2005 24 %

(

ViroidViroid HBV dependentHBV dependent 1700 bp ss RNA 1700 bp ss RNA HBsAg envelopeHBsAg envelope Cellular RNA pol II copies genomik RNACellular RNA pol II copies genomik RNA

Ribozyme Ribozyme cleaves circular RNA into cleaves circular RNA into mRNA for small delta agmRNA for small delta ag

Delta ag gene is mutated by celular ds Delta ag gene is mutated by celular ds RNA activated adenosine deaminase RNA activated adenosine deaminase enzyme which allows large delta ag enzyme which allows large delta ag production.production.

PercutaneousPercutaneous Blood and blood product transfusion kan Blood and blood product transfusion kan

ve faktörve faktör Person-personPerson-person Open lesions of the skinOpen lesions of the skin

HCVHCV

FlaviviridaeFlaviviridae

+ sense ssRNA+ sense ssRNA

About 9000 bp, envelopedAbout 9000 bp, enveloped

Milestones in HCVMilestones in HCV

1989 1989 cloning of hepatitis C (HCV) genomecloning of hepatitis C (HCV) genome 1989 1989 developement ofdevelopement of HCV antibody test HCV antibody test

(ELISA)(ELISA) 1990 1990 HCV viral load test (HCV RNAHCV viral load test (HCV RNA test)test) 1998 1998 approval ofapproval of Interferon + ribavirin Interferon + ribavirin

combination therapycombination therapy

2001 FDA 2001 FDA approval of pegylated IFNapproval of pegylated IFN

Worldwide 210 million HCV infectionWorldwide 210 million HCV infection Annual 35.000 new casesAnnual 35.000 new cases 10000-12000 deaths per year10000-12000 deaths per year Anti-HCV seropositivity rate in Turkey Anti-HCV seropositivity rate in Turkey

0.5 % - 1.8 %0.5 % - 1.8 %

Anti-HCV seroprevalence by age groupsAnti-HCV seroprevalence by age groups

DiagnosisDiagnosis

Anti-HCV antibodiesAnti-HCV antibodies

ELISAELISA

RIBA (recombinant immunoblot RIBA (recombinant immunoblot assay)assay)

HCV RNAHCV RNA

Fecal-oral transmission HAV (+++) HEV (+++)

Parenteral transmission HBV (+++) HCV (+++) HDV (++) HGV (++) HAV (+)

Sexual transmission HBV (+++) HDV (++) HCV (+)

Perinatal transmission HBV (+++)

HCV (+) HDV (+)

Sporadic (unknown) transmission HBV (+) HCV (+)