Hepatitis B & C for the Generalist

Ravi Jhaveri M.D.

Division of Infectious Diseases
Duke Children’s Hospital
 Learning Objectives
• Understand the changing epidemiology
of Hepatitis B virus
• Understand the current methods for
treatment and prevention of chronic
HBV infection
• Understand the risk factors for
transmission of Hepatitis C virus
• Understand the current methods for
screening infants exposed to HCV
 Hepatitis B-introduction
• Classic case:
– 12 y.o male, son of Chinese immigrant with
persistently elevated LFTs, mild symptoms
of fatigue
OR
– 16 y.o. female, sexual contact of IVDU, with
acute onset of jaundice
 Hepatitis B-introduction
• Hepatitis B virus (HBV) is a member of the
Hepadnavirus family-”hepatotropic dna
viruses”
• large DNA virus with a circular chromosome
with an RNA stage in the host cell during its
replicative cycle
• Replicative RNA subsequently produces viral
DNA that leads to synthesis of the viral
proteins. (retrovirus-like reverse transcription)
Hepatitis B-life cycle
 Hepatitis B-introduction

• The major proteins involved in HBV infection

are the surface antigen (HBsAg), core
antigen (HBcAg) and the e antigen (HBeAg).
– HBsAg is an element of the outer surface of the
virus
– HBcAg and HBeAg are different forms of the same
polyprotein
– HBcAg is made up of subunit proteins to form the
genomic core of the full virus
– HBeAg is a truncated form thought to play a role in
signaling for viral replication
 Hepatitis B-introduction

• HBV infection is only seen in humans

• passed from person to person:

– sexual contact
– Blood borne contact
– vertical transmission
 Hepatitis B-introduction

• HBV is a worldwide public health concern

– It is estimated that 350 million people are carriers

of the virus
– prevalence rates in Africa and Asia of greater than
8%
– In developing nations, the major route of
acquisition of HBV is vertical transmission
– in the Western Hemisphere, most acquire HBV in
adolescence and adulthood via sexual or
parenteral routes
 Hepatitis B-clinical manifestations

• Incubation of HBV after exposure

averages 70 days before the onset of
symptoms

• Acute HBV infection is subtle in most

cases
– may be symptomatic in about 30% of
patients.
 Hepatitis B-clinical manifestations

• Symptoms include:
– Fever
– Jaundice
– Malaise
– abdominal pain
– clinical course identical to HAV.

• Symptoms appear after the peak period of

Hepatitis B surface antigen (HBsAg) levels
have peaked in the bloodstream
 Hepatitis B-pregnancy
• HBV can infect pregnant women but does not
cause more severe disease than seen in the
general population
• Chronic carriers should have uncomplicated
pregnancies unless liver failure is present.

• significance of HBV infection during

pregnancy lies in risk of transmission to the
infant-90% of infants develop chronic HBV
 Hepatitis B-clinical manifestations
• 90% of patients with acute HBV infection will
resolve their illness spontaneously

• very small percentage of patients develop

fulminant hepatic failure

• 2-6% of older children and adults develop a

chronic carrier state where the virus remains
active at a low level-30% of 1-5 yr olds
 Hepatitis B-clinical manifestations
• HBV carriers are at high risk for end stage
liver disease and ultimately hepatocellular
carcinoma-25% mortality in children who
acquire chronic infection at birth
• Patients with chronic HBV infection may also
present with glomerulonephritis secondary to
immune complex deposition.
• In addition to their own morbidity and
mortality, HBV carriers represent the
largest reservoir for transmission of HBV
 Hepatitis B-laboratory diagnosis
• Detection of HBV infection involves
detecting the presence of:

– Viral genetic material

– Viral proteins (antigens)
– Antibody response to viral antigens
Hepatitis B-laboratory diagnosis
 Hepatitis B Virus (HBV) Serologic Markers

Stage of Infection HBsAg Anti-HBs Anti-HBc HBe Ag Anti-HBe

IgG IgM
Late incubation period of hepatitis B + - - - + or - -

Acute hepatitis B + - + + + -

HBsAg-negative acute hepatitis B - - + - - -

Healthy HBsAg carrier + - +++ + or - - +

Chronic hepatitis B + - +++ + or - + -

HBV infection in recent past - ++ ++ + or - - +

HBV infection in distant past - + or - + or - - - -

Recent HBV vaccination - ++ - - - -

 Hepatitis B-treatment
• No need to treat acute HBV infection

• Chronic HBV can be treated because of

high risk of progression to:
– Cirrhosis
– Hepatocellular carcinoma
 Hepatitis B-treatment
• Options are 4:
– Interferon-α-response rate of around 30% after 4-6
months of therapy, most durable of available
therapies because lower relapse rate
– Lamivudine(3TC)-arrests viral replication
temporarily, however mutation renders virus
resistant, viral load rises again but lower
– Adefovir-former HIV agent that is active against
HBV at lower concentrations, active against
lamivudine resistant virus as well with no new
resistance mutations detected after 1 year
– Tenofovir-HIV agent that has activity against HBV,
good for treating dual infected patients, less
experience overall
 Hepatitis B-prevention

• Pillars of prevention are:

– Recombinant vaccine

– Hepatitis B Immune Globulin

 Hepatitis B-prevention
• Vaccine:
– Recombinant protein (HBsAg) purified and
combined with adjuvant
– 3 doses given routinely to infants OR to
adolescents and high risk adults as catch
up program
– Prevents 90-95% protection that is durable
Acute cases of HBV
Acute cases of HBV
 Hepatitis B-prevention

• HBIG:
– Concentrated IVIG with high anti-HBV titer
– Used primarily for high risk post-exposure
prophylaxis
• Needlestick exposure
• Infant born to mother with known chronic infection or
unknown status-dose in first 12 hours if known HBsAg+
mom, up to 7th day if mom is determined later to be
HBsAg+ >>90-95% efficacy in preventing transmission
• Household contact with blood exposure
• Sexual contact with person with chronic HBV
 Hepatitis B-take home points
• Emphasize use of vaccine for everyone!

• Follow up on those exposed at birth-

confirm they were protected and refer
those who were breakthroughs

• Screen ALL international adoptees

regardless of what their records say!
 Hepatitis C-Introduction
• Classic cases:
– 17 y.o. with cirrhosis, liver failure after
having transfusion with HCV infected blood
at age 2 as part of chemotherapy
OR
– 28 y.o. mother just delivered healthy boy.
She has chronic HCV viremia and asks
what should she/we do for the baby?
 Hepatitis C-Background
• Virology of HCV
– Hepatitis C virus (HCV) is a flavivirus-remotely
related to Yellow Fever, West Nile
– single stranded, plus sense RNA virus
– genome size of approximately 9500 base pairs
– encodes for single large polyprotein that is
cleaved to form individual viral proteins
– virus displays marked heterogeneity
• six distinct genotypes
• numerous quasispecies attributable to “hypervariable”
regions of the two envelope proteins that readily mutate
 Hepatitis C-Background
• First discovered in 1989 to be the major
cause of transfusion related “non-A, non-B”
hepatitis
– Chiron corporation still holds patent to HCV
genome

• Currently, there is no established cell culture

system for HCV
• chimpanzees are the only available
laboratory animal model, so little is still known
about the mechanisms of infection
 Hepatitis C-Transmission

• HCV is transmitted by contact with

contaminated blood or blood containing body
fluids:
– intravenous drug use
– blood transfusion or transplantation prior to
1992
– Vertical transmission
 Hepatitis C-Transmission

• HCV is possibly transmitted by other routes, but

substantial proof is lacking:
– Breastfeeding-not likely and not contraindicated by
CDC
– Sexual transmission-not likely, but if so, VERY
inefficient means of transmission
– Sharing razors and toothbrushes-more likely than
others, actually contraindicated by CDC in
guidelines
– Tattooing-unlikely and not an indication for testing
according to CDC
 Hepatitis C- The Burden

• Epidemiology-
– Approximately 2% of US is HCV antibody positive-
4 million people
– 350 million people worldwide
– 0.2 to 0.4% of children are HCV antibody positive

– Leading indication for adult liver transplant in US

– Projected burden of $20-50 billion for years 2010-
9 in adults
 Hepatitis C- Symptoms
• Clinical manifestations:
– Acute subclinical hepatitis is most common after
blood borne exposure
– chronic hepatitis is also relatively asymptomatic.
– Symptoms are indolent when they do occur,
sometimes months to years later and include:
• Fever
• Fatigue
• jaundice.
– Patients may only present with signs of end stage
liver disease.
 Hepatitis C- Symptoms
• Clinical manifestations:

– 60-70% of adults progress to chronic infection,

men>women
– Only about 50% of children, increases with age

– Acute Fulminant hepatic failure with HCV is

exceedingly rare
 Hepatitis C-Pregnancy
• Acute HCV infection can and does occur
during pregnancy
• more common to see a pregnant patient who
either has known chronic HCV infection or has
chronic infection diagnosed during her
prenatal evaluation
• HCV infection has not been shown to be more
severe during pregnancy
• HCV has not been shown to more rapidly
progress during pregnancy
 Hepatitis C-Pregnancy

• HCV is vertically transmitted

– 5-10% overall transmission, but only 3-5% go on to

chronic infection
– Jumps to 20-25% in setting of HIV-HCV co-
infection (pre-HAART era)
– Infants do have a high rate of resolution of
seemingly high levels of viremia-not clear why
 Hepatitis C-Laboratory Diagnosis
• HCV infection can be detected by:
– Presence of antibody response-indicated
infected with HCV currently or at some
point previously
– HCV RNA
• Qualitative testing indicates viremia, which is
sign of chronic infection, has place in diagnosis
early after exposure and in infants
• Quantitative testing used for following therapy-
indications still not clear for when necessary
Hepatitis C- Vertical Transmission

Ceci et al, JPGN 33:570-5, Nov 2001

Hepatitis C- Vertical Transmission

Ceci et al, JPGN 33:570-5, Nov 2001

 Hepatitis C-Therapy
• Initial therapy of interferon-α was poor-
less than 40% cure rate
• Always better in non-genotype 1
infections

• Addition of Ribavirin increased overall

efficacy to 40% across the board-48
weeks of therapy
 Hepatitis C-Therapy
• Addition of polyethylene glycol moiety to
interferon molecule to increase serum levels
and prolong half life was breakthrough
• Peg-IFN monotherapy was equivalent to old
IFN-Ribavirin combination

• Peg-IFN and Ribavirin pushed cure rates to

50-60%, in some cases >80% (genotypes 2
and 3) and also only 24 weeks of therapy
 Hepatitis C-Therapy

• Therapy in adults is now recommended for

those with chronic infection (viremia) and
histology score that is moderate or worse

• No recommendations in children for therapy

– I hope to help change that someday
– School age may be an ideal time to maximize the
advantages of childhood (better SVR, less drug
needed, hopefully prior to high risk behavior, more
compliant patients)
 Hepatitis C-Prevention
• No means of prevention currently
• Attempt at hyper anti-HCV IVIG-not
efficacious since antibody not
neutralizing
• Vaccine is still under development-long
way from patients-may only be adjuvant
therapy
• Screen those at risk-may help
 Hepatitis C- Take Home Points

• Hepatitis C does cause symptoms in

children
• We have not yet worked out the best
methods to screen infants exposed at
birth for infection
– Combination of antibody and RNA testing
• Treatment for infected children is on the
horizon