2. Viral Hepatitis - Historical
Perspective
AA““Infectious”Infectious”
““Serum”Serum”
ViralViral
hepatitishepatitis
EntericallyEnterically
transmittedtransmitted
ParenterallyParenterally
transmittedtransmitted
F, G,F, G,
? other? other
EE
NANBNANB
BB DD CC
3. Viral Hepatitis -
Overview
A B C D E
Source of
virus
feces blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
Route of
transmission
fecal-oral percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
Chronic
infection
no yes yes yes no
Prevention pre/post-
exposure
immunization
pre/post-
exposure
immunization
blood donor
screening;
risk behavior
modification
pre/post-
exposure
immunization;
risk behavior
modification
ensure safe
drinking
water
Type of Hepatitis
5. HEPATITIS A VIRUS
• RNA Picornavirus
• Single serotype worldwide
• Acute disease and asymptomatic infection
• No chronic infection
• Protective antibodies develop in response to
infection - confers lifelong immunity
6. HEPATITIS A - CLINICAL
FEATURES
•Jaundice by <6 yrs <10%
age group: 6-14 yrs 40%-50%
>14 yrs 70%-80%
•Rare complications: Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
•Incubation period: Average 30 days
Range 15-50 days
7. 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Week
Response
Clinical illness
ALT
IgM IgG
HAV in stool
Infection
Viremia
EVENTS IN HEPATITIS A VIRUS INFECTION
8. CONCENTRATION OF HEPATITIS A VIRUS
IN VARIOUS BODY FLUIDS
Feces
Serum
Saliva
Urine
100 102
104
106
108
1010
BodyFluids
Infectious Doses per mL
9. • Close personal contact
(e.g., household contact, sex contact,
child day-care centers)
• Contaminated food, water
(e.g., infected food handlers)
• Blood exposure (rare)
(e.g., injection drug use, rarely by
transfusion)
HEPATITIS A VIRUS TRANSMISSION
10. PREVENTING HEPATITIS A
• Hygiene (e.g., hand washing)
• Sanitation (e.g., clean water sources)
• Hepatitis A vaccine (pre-exposure)
attenuated virus or inactivated virus
• Immune globulin (pre- and post-exposure)
12. •HEV is a 30-32nm non-enveloped particle containing
a s/s (+)sense RNA genome of ~7.5Kb.
•Genetic organization similar (not identical) to
Caliciviruses:
13. Hepatitis E - Clinical
Features
• Incubation period: Average 40 days
Range 15-60 days
• Case-fatality rate: Overall, 1%-3%
Pregnant women, 5%-
25%
• Illness severity: Increased with age
• Chronic sequelae: None identified
14. Hepatitis E Virus Infection
Typical Serologic Course
Weeks after
Exposure
Titer
Symptoms
ALT
IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
15. • Most outbreaks associated with
fecally contaminated drinking water
• Minimal person-to-person
transmission
Hepatitis E -
Epidemiologic Features
16. • Avoid drinking water (and beverages with
ice) of unknown purity, uncooked shellfish,
and uncooked fruit/vegetables not peeled or
prepared by traveler
• IG prepared from donors in Western
countries does not prevent infection
• Unknown efficacy of IG prepared from
donors in endemic areas
• Vaccine?
Prevention and Control Measures
for Travelers to HEV-Endemic
Regions
18. Hepatitis B - Clinical
Features
• Incubation period: Average 60-90 days
Range 45-180 days
• Clinical illness (jaundice): <5 yrs, <10%
³5 yrs, 30%-50%
• Acute case-fatality rate: 0.5%-1%
• Chronic infection: <5 yrs, 30%-90%
³5 yrs, 2%-10%
carrier state (350m )
• Premature mortality from
chronic liver disease: 15%-25%
21. • Baruch Blumberg,
1963: ‘Australian
antigen - Au'.
• 1967: Au was a viral
antigen = HBsAg
(surface antigen)
• Dane, 1970:
Discovered 42nm
'Dane particles‘
HBcAg (core antigen).
• 1973: HBeAg
discovered
(endogenous antigen
= a truncated version
of HBcAg).
secreted filament
secreted sphere
hepatitis B virion
23. • spherical,
• enveloped (? lipid-
containing, detergent
disrupted ?)
• 42-47nm diameter
• d/s DNA
• an RNA-dependent DNA
polymerase (i.e. reverse
transcriptase)
• family
Hepadnaviridae
24. HBV genome organization
two uneven strands
of DNA:
(-)sense strand:
3.0 - 3.3kb
(+)sense strand:
1.7 - 2.8kb
25. (
(
(
ccc-DNA
RNA
Precore, L, M, S + X
proteins
Capsid
protein
P protein
Reverse transcription
ER/IC
Golgi
The HBV infectious cycle
RNA pregenome
cap
ε
26. four open reading
frames (ORFs) :
S,C,P,X
• S – HBsAg
• C – HBcAg
C + preC – HBeAg
• P – polymerase
• X – HBxAg (a
transcriptional
transactivator)
27. HBsAg & anti-HBsHBsAg & anti-HBs
• HBsAg is an envelope protein & an poor
immunogen -------- replicationreplication
• recovery of acute HBV infection is
characterized by HBsAg/anti-HBs
seroconversion
• passively acquired anti-HBs protectsprotects
individuals from infection with HBV
• Anti-HBs is not strictly a ‘neutralizing’
antibody
28. HBcAg & anti-HBcHBcAg & anti-HBc
• HBcAg is not detectable in the sera of
some patients.
• immunogen
• IgM anti-HBc – virus replication, acute
infection, transient response
• IgG anti-HBc – do not protect
individuals, chronic infections, alst for a
long time
29. HBeAg & anti-HBeHBeAg & anti-HBe
• HBeAg is produced when virus isHBeAg is produced when virus is
replicating.replicating.
• HBeAg is correlated strongly with theHBeAg is correlated strongly with the
detection of viral DNA, virons and thedetection of viral DNA, virons and the
viral DNA polymerase in the serum.viral DNA polymerase in the serum.
• The disappearace of HBeAg andThe disappearace of HBeAg and
replacement with anti-Hbe indicates thatreplacement with anti-Hbe indicates that
the patient isthe patient is respondingresponding to the infectionto the infection
and will clear HBsAg.and will clear HBsAg.
30. Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Weeks after
Titer
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
32. Progression to Chronic Hepatitis B Virus
Infection
Typical Serologic Course
Weeks after Exposure
Titer
IgM anti-HBc
Total anti-
HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
34. Hepatitis B Lab Tests (1)
• HBV: Hepatitis B virus.
• HBsAg: Hepatitis B surface antigen. Marker of
infectivity when found in serum.
• anti-HBs: Antibody to HBsAg. Marker of immunity
when found in serum.
• HBcAg: Hepatitis B core antigen. No commercial test
available for this.
• anti-HBc: Antibody HBcAg. Marker of past or current
infection.
35. • IgM anti-HBc: IgM is an antibody subclass of
anti-HBc. Indicates recent infection with HBV
(<4-6 mos.).
• IgG anti-HBc: IgG is a subclass of anti-HBc. Indicates
“older” infection with HBV.
• HBeAg: Hepatitis B “e” antigen. Can only be present if
HBsAg is positive. Marker of high degree of infectivity.
• Anti-HBe: Antibody to “e” antigen. May be present in
infected or immune person.
Hepatitis B Lab Tests (2)
36. HBsAg negative
antiHBc negative susceptible
antiHBs negative
HBsAg negative
antiHBc positive immune due to natural infection
antiHBs positive
HBsAg positive
antiHBc positive acutely infected
IgM antiHBc positive
antiHBs negative
HBsAg positive
antiHBc positive chronically
IgM antiHBc negative infected
antiHBs negative
Interpretation of Hepatitis B Panel
HBsAg negative
antiHBc positive four possible interpretations
antiHBs negative (see next slide)
HBsAg negative
antiHBc negative immune due to vaccine
antiHBs positive
37. Four possible interpretations
of isolated antiHBc positive
1. May be recovering from acute HBV infection.
2. May be distantly immune and test not sensitive
enough to detect very low level of anti-HBs in serum.
3. May be susceptible with a false positive anti-HBc.
4. May be undetectable level of HBsAg present in the
serum and the person is actually a carrier.
39. Concentration of Hepatitis B
Virus
in Various Body Fluids
High Moderate
Low/Not
Detectable
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk
40. Having sex without condoms with someone who
has hepatitis B
Main Ways to Get Hepatitis B
You can pass hepatitis B to others if you have just
gotten the virus (acute hepatitis) or if you are a
carrier of the virus (chronic hepatitis).
Sharing needles and syringes
Being born to a mother who has hepatitis B
Parenteral
Perinatal
Sexual
41. • If you have hepatitis B and a tiny bit of your
blood gets inside your baby at birth.
How does a baby get hepatitis B
from mother?
43. If you have never had hepatitis B,
you can get 3 shots . . .
. . . and get long lasting protection.
321
Hepatitis B can be prevented!
44. 6 months old
Hepatitis B
Vaccine
Baby Shots
for Hepatitis B
if the mother has Hepatitis B
1 - 2 months old
Hepatitis B
Vaccine
+
Birth
H-BIG
Hepatitis B
Vaccine
48. • HBV-HDV Coinfection
Pre or postexposure prophylaxis to
prevent HBV infection
• HBV-HDV Superinfection
Education to reduce risk behaviors
among persons with chronic HBV
infection
Hepatitis D -
Prevention
52. Features of Hepatitis C VirusFeatures of Hepatitis C Virus
InfectionInfection
Incubation periodIncubation period Average 6-7 weeksAverage 6-7 weeks
Range 2-26 weeksRange 2-26 weeks
Acute illness (jaundice)Acute illness (jaundice) Mild (Mild (<<20%)20%)
Case fatality rateCase fatality rate LowLow
Chronic infectionChronic infection 60%-85%60%-85%
Chronic hepatitisChronic hepatitis 10%-70%10%-70%
CirrhosisCirrhosis <5%-20%<5%-20%
Mortality from CLDMortality from CLD 1%-5%1%-5%
Age-
related
53. Serologic Pattern of Acute HCV Infection
with Recovery
Symptoms +/-
Time after
Exposure
Titer anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
54. Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
Symptoms +/-
Time after
Exposure
Titer anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
55. Reduce or Eliminate Risks for
Acquiring HCV Infection
• Screen and test donors
• Virus inactivation of plasma-derived products
• Risk-reduction counseling and services
– Obtain history of high-risk drug and sex behaviors
– Provide information on minimizing risky behavior,
including referral to other services
– Vaccinate against hepatitis A and/or hepatitis B
• Safe injection and infection control practices
HCV Prevention and Control
56. Preventing HCV Transmission to
Others
• Do not donate blood, body organs, other
tissue or semen
• Do not share items that might have blood on
them
– personal care (e.g., razor, toothbrush)
– home therapy (e.g., needles)
• Cover cuts and sores on the skin
Avoid Direct Exposure to Blood
57. Other Transmission Issues
• HCV not spread by kissing, hugging,
sneezing, coughing, food or water, sharing
eating utensils or drinking glasses, or casual
contact
• Do not exclude from work, school, play,
child-care or other settings based on HCV
infection status
HCV Counseling
Notas do Editor
Before the discovery of hepatitis A virus (HAV) and hepatitis B virus (HBV) during the 1960s and 1970s, patients with viral hepatitis were classified based on epidemiological studies as having either infectious (transmitted person to person by the fecal-oral route) or serum (transmitted by transfusion of blood products) hepatitis. When diagnostic tests for HAV and HBV infections were developed, HAV was found to be the major cause of infectious hepatitis and HBV was found to be the major cause of serum hepatitis. Hepatitis delta virus (HDV), discovered in 1977, is a defective virus requiring the presence of HBV in order to replicate. However, some patients with typical signs and symptoms of viral hepatitis did not have serologic markers of HAV, HBV, or HDV infection and were categorized based on epidemiological characteristics as having either parenterally transmitted non-A, non-B (NANB) hepatitis or enterically transmitted NANB hepatitis. Subsequently, two additional viruses were discovered: hepatitis C virus (HCV) and hepatitis E virus (HEV). HCV is the major cause of parenterally transmitted NANB and HEV is the major cause of enterically transmitted NANB hepatitis. In addition, some patients with typical signs and symptoms of acute viral hepatitis do not have serologic markers of any of these types of viral hepatitis and can be classified as having non-ABCDE hepatitis. New viruses might be discovered in patients with non-ABCDE hepatitis.
This is an electron micrograph of HAV that causes hepatitis A. See the next slide for specifics about this virus.
Hepatitis A is caused by HAV, a 27-nm ribonucleic acid (RNA) agent that is classified as a picornavirus. Only one serotype has been observed among HAV isolates collected from various parts of the world. HAV causes both acute disease and asymptomatic infection. HAV does not cause chronic infection. Total antibody to HAV develops in response to infection and confers lifelong immunity from future HAV infection.
The average incubation period for hepatitis A is 30 days, with a range of 15 to 50 days. Patients characteristically have abrupt onset of symptoms which can include fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice. The severity of clinical disease associated with HAV infection increases with increasing age; jaundice occurs among less than 10% of children younger than 6 years of age, 40%-50% of older children, and 70%-80% of adults. Complications of hepatitis A include fulminant hepatitis, in which the case fatality rate can be greater than 50% despite medical interventions such as liver transplantation; cholestatic hepatitis, with very high bilirubin levels that can persist for months; and relapsing hepatitis, in which exacerbations can occur weeks to months after apparent recovery. Chronic infection does not occur following HAV infection.
The diagnosis of acute HAV infection is confirmed during the acute or early convalescent phase of infection by the presence of IgM antibodies to HAV (IgM anti-HAV). IgM anti-HAV is generally present 5-10 days before the onset of symptoms and is no longer detectable in the vast majority of patients 6 months later. IgG anti-HAV, which also appears early in the course of infection, remains detectable for the lifetime of the individual and confers lifelong protection against infection. Commercial tests are available for the detection of IgM and total (IgM and IgG) anti-HAV in serum.
In infected persons, HAV replicates in the liver, is excreted in bile, and is shed in the stool. Peak infectivity occurs during the 2-week period before onset of jaundice or elevation of liver enzymes, when the concentration of virus in stool is highest. The concentration of virus in stool declines after jaundice appears. Children and infants can shed HAV for longer periods than adults, up to several months after the onset of clinical illness. Chronic shedding of HAV in feces does not occur; however, shedding can occur in persons who have relapsing illness. Viremia occurs soon after infection and persists through the period of liver enzyme (alanine aminotransferase [ALT]) elevation.
HAV RNA can be detected in the blood and stool of most persons during the acute phase of infection by using nucleic acid amplification methods, such as PCR, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates. These methods, however, are available in only a limited number of research laboratories and are not used generally for diagnostic purposes.
Feces can contain up to 108 infectious virions per milliliter and are the primary source of HAV. Viremia occurs during the preclinical and clinical phases of illness, and HAV has been transmitted by transfusion (before screening of blood and blood products for HAV was initiated) and by injection drug use. Virus has also been found in saliva and urine during the incubation period in experimentally infected animals, but transmission by saliva or urine has not been reported to occur.
Transmission of HAV generally occurs when susceptible persons put anything in their mouths that has been contaminated with the feces of an infected person. Close personal contact is the most common mode of HAV transmission, as demonstrated by infections among household and sex contacts of persons with hepatitis A and among children in day-care center outbreaks. Contaminated food and water can also serve as vehicles of HAV transmission. HAV transmission can occur when an infected food handler directly handles uncooked or cooked foods. Outbreaks have also been reported in association with foods contaminated before wholesale distribution, such as fresh vegetables contaminated at the time of harvesting or processing. HAV transmission can occur as a result of blood exposures such as injecting drug use or blood transfusion because viremia can occur prior to the onset of illness in infected persons. Screening of blood products for HAV has essentially eliminated the already extremely low risk associated with transfusion.
Good hygienic practices and adequate sanitation are important elements in the prevention of HAV infection, particularly in the developing world. However, hepatitis A vaccine is the key component in the overall strategy to prevent HAV infection in the United States. Immune globulin is also available for pre-exposure and post-exposure prophylaxis.