Hepatitis B Infection (HBV)

Hepatitis B InfectionHepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus, which infects the liver of hominoidea, including humans. It can cause chronic infection and puts people at high risk of death from cirrhosis and liver cancer.

Epidemiology

• >200 million carriers worldwide• 1 million people die each year from hepatitis B

and its complications• Established cause of chronic hepatitis and

cirrhosis• Human carcinogen - cause of up to 80% of

hepatocellular carcinomas

Prevalence of Chronic HBV Infection, Worldwide, 2006

HBsAg Prevalence

>8% = High

2-7% = Intermediate

< 2% = Low

Global HBV: Major Genotypes

A, B, C, D, G

F

A, D, E

B, CD G

A, B, C, D

D

A

Hepatitis B Virus

• Hepatitis B virus is an hepadnavirus • Has a circular genome composed of partially

double-stranded DNA • The viruses replicate through an RNA

intermediate form by reverse transcription• Replication takes place in the liver• Retains infectivity for at least 1 month at

room temperature

Structure

Characteristics • Lipid envelope • Icosahedral nucleocapsid • Core composed of proteins• Nucleocapsid enclosed viral

DNA • DNA polymerase • Outer envelope containing

embedded proteins• Enveloped 42 nm virus

Morphology

Hepatitis B may exist in 3 different forms:• Spherical 22nm• Tubular 22 nm varying length• Double walled spherical 42 nm (Dane particle)

no DNA in these forms so they are not infectious

Dane Particle

HBV virion is also referred to as Dane particle.Core antigens are located in its center:• HBsAg = surface (coat) protein ( 4

phenotypes : adw, adr, ayw and ayr)• HBcAg = inner core protein (a single serotype) • HBeAg = secreted protein; function unknown• HBxAg

8 genotypes (A-H) according to overall nucleotide sequence variation of the genome

Dane Particle

Replication Reverse transcription: one

of the mRNAs is replicated with a reverse transcriptase making the DNA that will eventually be the core of the progeny virion

RNA intermediate: HBV replicates through an RNA intermediate and produces and release antigenic decoy particles.

Integration: Some DNA integrates into host genome causing carrier state

Resistance

• HBV is a relatively heat stable virus (viable room temperature for long periods)

• 60° C for 10 hours (reduce infectivity 100-1000 times)

• Susceptible to chemical agents(hypochlorine, gluteraldehyde)

Modes of Transmission

• Parenteral: IV drug abusers, health workers are at increased risk

• Sexual: sex workers and homosexuals are at particular risk

• Perinatal (vertical): from mother (HBeAg+) to infantThough not transmissible by holding hands, sharing eating utensils or drinking glasses, kissing, hugging, coughing, sneezing, or breastfeeding

Concentration of HBV in Various Body Fluids

High Moderate Low

Blood Semen Urines

Serum Vaginal fluid Feces

Wound exudates Saliva Tears

Breast milk

Pathogenesis• The incubation period is from 6 weeks to 6 months after artificial

inoculation of infected blood and blood products• HBV interferes with the functions of the liver by replicating in

hepatocytes • HBV virions bind to the host cell via the preS domain of the viral

surface antigen and are subsequently internalized by endocytosis• PreS and IgA receptors interact with each other• HBV-preS specific receptors are primarily expressed on

hepatocyte• During HBV infection, the host immune response causes both

hepatocellular damage and viral clearance• Adaptive immune response, particularly virus-specific CTLs,

contributes to most of the liver injury associated with HBV infection

Symptomso Loss of appetite, nausea, vomiting, headache, myalgia,

body aches, mild fever, dark urine, and then progresses to development of jaundice

o Itchy skin is a possible indication of all HV typeso At least 50% of infections are asymptomatico Tends to cause a more severe disease than Hepatitis Ao Extrahepatic manifestations of hepatitis B are present

in 1–10% of HBV-infected patients and include serum-sickness–like syndrome, acute necrotizing vasculitis (polyarteritis nodosa), membranous glomerulonephritis, and papular acrodermatitis of childhood (Gianotti-Crosti syndrome)

Possible Outcomes

Laboratory Diagnosis• Serum or blood tests (detect either viral antigens or antibodies)• Hepatitis B surface antigen (HBsAg) is most frequently detected• Hepatitis B core antigen (HBcAg)• IgM antibodies to the hepatitis B core antigen anti-HBc IgM• HBeAg in a host's serum means higher rates of viral replication and enhanced

infectivity • A person negative for HBsAg but positive for anti-HBs has either cleared an

infection or has been vaccinated previously• Individuals who remain HBsAg positive for at least six months are considered

to be hepatitis B carriers• Carriers of the virus may have chronic hepatitis B, which would be reflected

by elevated serum alanine aminotransferase (ALT)• PCR tests have been developed to detect and measure the amount of HBV

DNA

Serologic Markers for Phases of Acute and Chronic HBV InfectionHBsAg HBeAg IgM 

anti-HBc

IgG anti-HBc

Anti-HBs

Anti-HBe

HBV DNA

Interpretation

Acute HBV Infection

+ + + + Early phase

+ ± Window phase

+ + + - Recovery phase

Chronic HBV Infection

+ + + + Replicative phase

+ + + - Low, nonreplicative phase

+ ± + + Flare-up

+ + + Precore/core promoter mutants

Treatment • Acute hepatitis B infection does not usually require treatment because

most adults clear the infection spontaneously• Treatment of chronic infection may be necessary to reduce the risk of

cirrhosis and liver cancer• Although none of the available drugs can clear the infection, they can

stop the virus from replicating, thus minimizing liver damage• Antiviral drugs:

• lamivudine (Epivir)• adefovir (Hepsera)• tenofovir (Viread)• telbivudine (Tyzeka)• entecavir (Baraclude)

• Immune system modulators: interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys)

Prevention

• Vaccination - highly effective recombinant vaccines

• Hepatitis B Immunoglobulin (HBIg) - WHO recommends joint immunoprophylaxis for the newborn, multiple injections of small doses of hepatitis B immune globulin (HBIg, 200–400 IU per month) and oral lamivudine (100 mg per day) for HBV carrier mothers with a high degree of infectiousness in late pregnancy

• Other measures - screening of blood donors, blood and body fluid precautions

Hepatitis B Vaccine

• CompositionRecombinant HBsAg

• Efficacy 95% (Range, 80%-100%)

• Duration ofImmunity >15 years

• Schedule 3 Doses

• Booster doses not routinely recommended

Hepatitis B Vaccine Routine Infant Schedule

Dose Usual Age Minimum Interval

Primary 1 0-2 months ------

Primary 2 1-4 months 1 month

Primary 3 6-18 months 2 months