Viral Hepatitis: A, B, C, D, E
Wayne A. Duffus, MD, PhD
November 2nd, 2009
1
Viral Hepatitis - Historical Perspective
“Infectious”
Viral hepatitis
“Serum”
A
E
Enterically
transmitted
C
Parenterally
transmitted
NANB
B D
F, G,
? other
2
Viral Hepatitis
A
Source of
virus
Route of
transmission
Chronic
infection
Prevention
B
C
D
E
feces
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
fecal-oral
percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
no
pre/postexposure
immunization
yes
pre/postexposure
immunization
yes
blood donor
screening;
risk behavior
modification
yes
pre/postexposure
immunization;
risk behavior
modification
no
ensure safe
drinking
water
3
Viral Hepatitis 1982-1993
Hepatitis B
34%
42%
3%
Hepatitis A
16%
Non-ABC
Hepatitis C
Source: CDC Sentinel
Counties Study on Viral Hepatitis
4
Estimates of Acute and Chronic Disease
Burden for Viral Hepatitis, United States
Acute infections
(x 1000)/year*
Fulminant
deaths/year
Chronic
infections
Chronic liver disease
deaths/year
HAV
HBV
HCV
HDV
125-200
140-320
35-180
6-13
100
150
?
35
0
1-1.25
million
3.5
million
70,000
5,000
8-10,000
1,000
0
* Source: CDC -Range based on estimated annual incidence, 1984-1994.
5
Hepatitis A Virus (HAV)
6
HAV Transmission

Close personal contact
household contact, sex contact, child
day care centers

Contaminated food, water
infected food handlers, raw shellfish

Blood exposure (rare)
injecting drug use, transfusion
7
Hepatitis A - Clinical Features
Incubation period:
Mean 30 days
Range 15-50 days
Jaundice by
age group:
<6 yrs,
6-14 yrs
>14 yrs
Complications:
Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
Chronic sequelae:
None
<10%
40%-50%
70%-80%
8
HAV - Typical Serologic Course
Symptoms
Total anti-HAV
Titer
ALT
Fecal
HAV
0
1
IgM anti-HAV
2
3
4
5
6
Months after Exposure
12
24
9
Serological Testing



HAV total Ab appears 4-5 weeks after
infection and remains positive for the
patient’s lifetime
HAV IgM is present at the onset of symptoms
and usually disappears after 4-6 months.
The presence of total Ig without IgM indicates
past infection
10
HAV Immune Globulin



IM administration within 2 weeks after HAV
exposure is >85% effective in preventing
symptomatic infection.
HAV IG and vaccine does not alter
seroconversion rates but lower serum
antibody concentrations may be obtained.
HAV IG administration will alter normal
serological profiles for 6-12 months.
11
Hepatitis A Virus



Highest virus concentrations occur in stool
1-2 weeks before the onset of illness.
Transmission is most likely at this time.
Minimal virus present in stool 1 week after
the onset of jaundice.
In neonates and young children, virus may
be detected in stool for months.
12
Virus Detection



Culture is worthless except for research
purposes.
PCR detection is available but cannot
distinguish recent from past infection.
Nucleic acid sequencing is useful for
tracking HAV outbreaks.
13
Mitch, a 43 year old salesman, has
increasing fatigue x 5 days and
vague abdominal pain x 3 days. He
ate at the Stage Deli (site of a recent
HAV outbreak) 10 days previously.
His liver enzymes are within normal
limits.
HAV AB (total)
HAV IgM
Positive
Negative
Does he have HAV infection?
CDC Recommendations:
Testing and Vaccination
15
PRE-VACCINATION TESTING

Considerations:





Cost of vaccine
Cost of serologic testing (including visit)
Prevalence of infection
Impact on compliance with vaccination
Likely to be cost-effective for:



Persons born in high endemic areas
Older U.S. born adults
Older adolescents and young adults in certain groups
(e.g., Native Americans, Alaska Natives, Hispanics, IDUs)
16
POST-VACCINATION TESTING
Not recommended:
•
•
High response rate among vaccinees
Commercially available assay not sensitive
enough to detect lower (protective) levels of
vaccine-induced antibody
17
ACIP RECOMMENDATIONS:
PERSONS AT INCREASED
RISK OF INFECTION
•
Men who have sex with men
•
Illegal drug users
•
International travelers
•
Persons who have clotting factor disorders
•
Persons with chronic liver disease
18
STD Treatment Guidelines
MMWR August 4, 2006 55 (RR11)
“Vaccination
against hepatitis is the most
effective means of preventing sexual
transmission
of hepatitis A and B.”
19
Indications for IG for Post-Exposure
Prophylaxis



Household and sexual contacts if exposure is
within 2 weeks.
Childcare center employees and children when
HAV infection is identified in a child or employee.
Close school contacts if transmission within the
school has occurred.
20
Indications for IG for Post-Exposure
Prophylaxis


Person exposed to contaminated
food/water.
Persons who ate food prepared by HAV+
food handler.
21
Hepatitis A Surveillance
and Response
22
Hepatitis A Surveillance & Response



Urgently reportable condition in S.C. – Acute
HAV infection must be reported by phone to
health department within 24 hours.
Investigation of a case of hepatitis A must
be initiated by health department and
district epi staff within 24 hours of
notification.
All cases must be reported to CDC.
23
Important Information





Date of onset of symptoms
Occupation
If child, whether child attends childcare
Names of household/sexual contacts
Restaurants attended 2-6 weeks prior to
symptoms
24
Management of Outbreaks




Initiate enteric precautions during the first 2
weeks of illness.
Refer symptomatic contacts to physician.
Exclude adults/children with HAV infection from
work/school until 1 week after onset of illness or
until IG PEP has been initiated.
Provide education re transmission, prevention, and
hygiene.
25
Hepatitis E Virus
26
Amita, a 23 year old student,
returned from India one month
ago where she spent 3 weeks
visiting her future in-laws. She
presented with fever, jaundice,
malaise, and significantly
elevated ALT levels. Antibody
tests were positive for HEV IgG
and IgM.
How does she prevent the spread of HEV to family and friends?
Hepatitis E Virus



Most outbreaks associated with
fecally contaminated drinking water
Minimal person-to-person transmission
U.S. cases usually have history of travel
to HEV-endemic areas
28
Geographic Distribution of Hepatitis E
Outbreaks or Confirmed Infection in >25% of Sporadic Non-ABC Hepatitis
Source: CDC
Hepatitis E Virus

Incubation period:
Average 40 days
Range 15-60 days
1%-3% overall
15%-25% in pregnancy

Case-fatality rate:

Illness severity:
Increased with age

Chronic sequelae:
None identified
30
Typical Serological Course - HEV
Symptoms
anti-HEV
ALT
Titer
IgM anti-HEV
Virus in stool
0
1
2
3
4
5
6
7
8
Weeks after Exposure
9
10
11
12
13
31
Serological Profile


HEV IgM is usually present at the onset of
symptoms and persists for 3-4 months
HEV IgG is also present at the onset of
symptoms and persists for the patient’s
lifetime
32
CDC Criteria for Testing Acute Phase Sera





Discrete onset of illness with jaundice or
Serum ALT >2.5 times the upper limit of normal
and
HAV IgM negative
HBV Core IgM negative
HCV Ab negative
33
HEV Detection



Culture is worthless
PCR can detect HEV RNA in serum and
stool specimens from 2 weeks before, to 2
weeks after, the onset of symptoms
Nucleic acid sequencing is useful for tracking
HEV outbreaks
34
Steps to prevent HEV
transmission in home setting?
1. Safe sex practices
2. Do not share eating/grooming
utensils.
3. Respiratory precautions
4. Vigorous hand washing
5. No special requirements needed
35
Hepatitis C Virus
36
Claudia is a 46 year old
divorced female.
She has a new man in her life.
She has had unprotected sex
for the past 3 weeks.
She just learned that her new
friend is HCV positive.
What is her HCV risk?
What is Claudia’s Risk of Infection?
1. High risk – HCV can be transmitted
sexually.
2. Low risk – The efficiency of sexual
transmission is low.
38
HCV - Sources of Infection
Injecting drug use 60%
Sexual 15%
Transfusion 10%
(before screening)
Other* 5%
Unknown 10%
*Nosocomial;
Health-care work;
Perinatal
Source: Centers for Disease Control and Prevention
39
Sexual Transmission




Transmission efficiency is low
Rare between long-term steady
partners (1.5%)
Factors that facilitate transmission
between partners (e.g., viral load) are
unknown
Male to female transmission may be
more efficient
40
Other Transmission Issues

HCV is not spread by kissing, hugging,
sneezing, coughing, food or water, sharing
eating utensils or drinking glasses, or
casual contact

HCV infection status should not be used to
exclude patients from work, school, play,
child-care or other settings
41
Hepatitis C Genotypes
Genotype:
1a
1b
2a, 2b, 2c, 2d
3a, 3b, 3c, 3d, 3e, 3f
4a, 4b, 4c, 4d, 4e, 4f,
4g, 4h, 4i, 4j
5a
6a
Countries Where Prevalent:
USA, England, Europe
USA, Japan, Europe
Japan, China
Scotland, England
Middle East, Africa
Canada, South Africa
Hong Kong, Macau
42
Genotype Distribution
Hepatitis C: A Global Health Problem
170 Million Carriers Worldwide, 3-4 MM new cases/year
WEST
EUROPE
9M
U.S.A.
4M
EAST
MEDITERRANEAN
20M
FAR EAST ASIA
60 M
SOUTH EAST ASIA
30 M
AFRICA
32 M
SOUTH
AMERICA
10 M
SOURCE, WHO 1999
AUSTRALIA
0.2 M
44
Acute Hepatitis C Clinical Presentation
and Natural History

HCV RNA can be detected in blood within 1-3 weeks after
exposure

Average time from exposure to seroconversion is 8-9 weeks

Average time from exposure to symptoms period 6-7 weeks

Liver injury (elevations in ALT) with 4-12 weeks

Symptoms develop in only of 20% of patients
 Nonspecific 10%-20%
 Jaundice in only 20%-30%
CDC. MMWR. 1998; 47(No. RR-19):1-39.
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S
NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002
45
Hepatitis C Infection

Incubation period
Average 6-7 weeks
Range 2-26 weeks

Case fatality rate
Low

Chronic infection
75%-85%

Chronic hepatitis
70% (most asx)

Cirrhosis
10%-20%

Mortality from CLD
1%-5%
46
Natural History of Hepatitis C
10-20 years
Acute Hepatitis C
Chronic Hepatitis
75%-85 %
Cirrhosis 20 %
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S
Di Bisceglie, Hepatology, 2000
47
Natural History of Hepatitis C
Annual rate
Cirrhosis 20 %
Decompensation
6%
HCC
4%
Death
4%
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S
Di Bisceglie, Hepatology, 2000
48
Acute HCV Infection with Recovery
HCV Ab
Symptoms +/-
Titer
HCV RNA
ALT
Normal
0
1
2
3
4
5
6
1
Months
Time after Exposure
2
3
4
Years
49
Chronic Hepatitis C

A leading cause of cirrhosis in the US

10,000-20,000 deaths/yr
 This number expected to triple in the next 10 to 20
years (without therapy)

Associated with an increased risk of liver cancer

Most common reason for liver transplantation in the
United States
CDC. MMWR. 1998; 47(No. RR-19):1-39.
NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002
50
Acute HCV Infection with Progression to
Chronic Infection
HCV Ab
Symptoms +/-
Titer
HCV RNA
ALT
Normal
0
1
2
3
4
5
6
1
Months
Time after Exposure
2
3
4
Years
51
Hepatitis C Complications

Hepatitis encephalopathy – if untreated can lead to:










Confusion
Disorientation
Hallucination
Stupor/Coma
Jaundice
Pruritus
Renal damage/failure
Hypo/Hyperthyroidism
Varices of Esophagus, Stomach, Rectum
Muscle Wasting
52
Extrahepatic Manifestations of
Hepatitis C

Hematologic: Mixed
cryoglobulinemia
(10%–25% of HCV patients)*

Renal: Glomerulonephritis

Dermatologic:

Porphyria cutanea tarda

Cutaneous necrotizing vasculitis

Lichen planus
Management of Hepatitis C. NIH Consensus Statement, 2002.
53
Chronic Hepatitis C
Factors Promoting Progression or Severity

Increased alcohol intake

Age > 40 years at time of infection

HIV co-infection

Other


Male gender
Chronic HBV co-infection
54
Claudia needs to see her
family physician.
She wants to be tested for
HCV.
What test do you recommend?
Diagnostic Tests for HCV





Anti-HCV
RIBA (supplemental assay)
Qualitative PCR
Quantitative PCR
Genotyping assays
56
HCV Antibody Tests



Screening tests - total antibody detected
Sensitivity is about 95%
Predictive value



High Risk Population: 90-95%
Low Risk Population: 50-60% (false
positives)
False Negatives due to “window period”
and immunosuppression
57
Hepatitis C Antibody Test:
Signal to Cut Off (S/CO) Ratio


S/CO ratio is a comparison of the pt’s positive
EIA result with the lab’s positive EIA control.
A positive EIA test with a s/co ratio of 3.8 or
higher is indicative that the pt truly has HCV
and that the RIBA test will be positive (95%97% predictive value).
58
HCV RIBA Tests


Used to resolve possible false
positive anti-HCV, particularly in lowrisk patients (blood donors)
Use is analogous to HIV western blot
Core
5’ UTR
E1
E2/NS1
NS
NS
NS
2
3
4
NS5
59
HCV Screening Algorithm
Negative
(non-reactive)
STOP
EIA for Anti-HCV
Positive (repeat reactive)
OR
RIBA for Anti-HCV
Negative
STOP
Negative
Indeterminate
Additional Laboratory
Tests (e.g. PCR, ALT)
Negative PCR,
Normal ALT
RT-PCR for HCV RNA
Positive
Positive
Medical
Evaluation
Positive PCR,
Abnormal ALT
Source: MMWR 1998;47 (No. RR 19)
Diagnosis of Viral Hepatitis in the Primary Care
Setting: Patients Who Have Risk Factors

A single normal ALT level does not rule out
chronic viral hepatitis

ALT levels may be intermittently normal in a
significant number of patients who have
chronic hepatitis C
61
Diagnosis of Chronic Viral Hepatitis
Serologic Testing

Patients should be tested if they:



Have known risk factors for viral hepatitis
Indicate possible risk factors for hepatitis
Have elevated liver enzymes
Management of Hepatitis C. NIH Consensus Statement, 1997.
62
Liver Biopsy

May be guided by CT or ultrasound

Provides information regarding
 Degree of inflammation
 Disease severity
 Tissue damage
 Presence/absence of cirrhosis

Helps determine
 Degree of disease progression
 Cause of liver disease
 Need for treatment
63
Histologic Staging
Stage 0
Stage 1
No Fibrosis
Stage 2
Few septa
Portal Fibrosis
Stage 3
Numerous septa
Stage 4
Cirrhosis
64
Diagnostic Evaluation of HCV Infection
Genotyping
RNA
Qualitative
Quantitation
PCR
Step in Diagnosis
EIA
RIBA
Primary Screening
+
-
-
-
-
Confirmation of
HCV Ab tests
Predicting
Rx Response
Viral response
during Rx
Viral response
after Rx
Determining
Rx Length
-
+
+
-
-
-
-
-
+
+
-
-
+
+
-
-
-
+
-
-
-
-
-
+
+
65
Hepatitis C Screening and Diagnosis
Summary

Suspect disease on the basis of risk factors, not
symptoms

Positive anti-HCV result indicates current infection
until refuted

Measurement of HCV RNA may be required to
establish diagnosis in selected cases
66
Treatment
67
Treatment for Hepatitis C

Interferon + Ribavirin x 6-12 months – about 40% 50% sustain viral clearance > 3 years.

Predictive Factors for Treatment Response:





Genotype 2 and 3
Low initial viral load levels
Young age
Low Fibrosis Score (Liver Biopsy)
Female
68
Treatment Side Effects











Depression
Sleep Disturbances (Insomnia)
Irritability
Anger
Psychosis
Excessive Fatigue
Nausea/Diarrhea/Decreased Appetite/Weight Loss
Anemia/Neutropenia
Autoimmune Disorders, especially Thyroiditis
Decreased Libido
Menstrual Irregularities
69
Rationale for the development of
a once-weekly pegylated
interferon -2b
70
Rationale for Pegylation of Protein
Pharmaceuticals




Pegylation = binding of ethylene oxide polymers to
drug molecule
Decreases clearance
 Prolonged half-life
 Sustained blood levels
Decreases proteolysis
Decreases immunogenicity
Youngster S, et al. Curr Pharm Des. 2002;8:99.
Harris JM, et al. Clin Pharmacokinet. 2001;40:539.
71
Why PEG as a Protein-Modifying Agent?



Inert
Water soluble
Can be made any size and shape
O
CH 3- (OCH 2CH 2) n- O - C- N
H
Bailon et al., Bioconjugate Chemistry, 2001
Wyss et al., Current Pharmaceutical Design, 2002
(protein)
m
72
Pegylation: Effects on Half-life
Longer
Shorter
PEG Molecular Weight (PEG size)
The clinical relevance of this in vitro data has not been established.
Adapted from Youngster et al., Current Pharmaceutical Design, 2002, 8:2139-215
73
Pegylation: Antiviral Activity
More
Less
PEG Molecular Weight (PEG size)
The clinical relevance of this in vitro data has not been established.
Adapted from Grace M et al., AASLD 2003, Abstract #1928
74
Relationship between PEG size and Renal
Clearance
PEG 5,000
Relative clearance (%)
100
80
PEG 12,000
60
(used in PEG-IFN -2b )
40
20
PEG 20,000
0
10
30
80
100
Stokes radius (Angstroms)
Wyss et al., Current Pharmaceutical Design, 2002
Xian-Hui He et al., Life Sciences, 1999
75
HCV-Positive Persons
for Whom Treatment is Recommended

Persistently elevated liver enzyme (ALT) levels

Presence of  HCV RNA (viral load)

A liver biopsy indicating fibrosis or at least moderate
inflammation and necrosis

Cessation of continuing alcohol/substance use
 HCV + HIV coinfection: especially difficult …
Goal: Clear HCV, restore LFT, reverse pathology
76
Predicting Response to Treatment
77
Response Rate to Treatment
Based on Genotype
Genotype:
1a/1b
2-6
Overall Response
Response Rate:
41% of patients
75% of patients
52% of patients
78
HCV Kinetics
79
Goals of HCV Therapy

Primary: HCV RNA below limits of detection
at end of treatment

Secondary:



Inhibition of disease progression
Reduction of incidence of hepatocellular
carcinoma
Reduction in need for liver transplant
80
Treatment Definitions

The First aim is to clear
HCV RNA from
peripheral blood, a
necessary, but not
sufficient condition to
achieve a sustained
virological response.
Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000

The Second aim is to
prevent relapse in
patients who cleared
HCV RNA during
induction, in order to
achieve a sustained
virological response
81
Patterns of Response to Initial
Antiviral Therapy
Serum HCV RNA
7
6
Nonresponder
( < 0.2)
1st Phase
5
Flat-partial responder
(0.0 <  < 0.2)
4
Slow-partial responder
(0.1   < 0.4)
2nd Phase
3
2
detection limit
Rapid responder
(  0.4)
1
0 1 2 3
7
14
21
28
Days
82
Changing Paradigms



Speed of response is an important predictor of sustained
virologic response.
66% of patients with HCV genotypes 2 and 3 had
undetectable HCV levels within 4 weeks of treatment
Sustained virologic response.



90% for 24 week treatment arm
75% for 16 week treatment
Relapse rates


18% for 24 week treatment
31% for 16 week treatment
Shiffman, et al., N. Eng. J. Med 2007;357:124-134
83
Resources


S.C. Hepatitis C Coalition
SC DHEC Hepatitis Nurse Consultant



Elona Rhame, RN
Pharmaceutical Companies
Physician Referral List
84
*
SC Hepatitis C Coalition

803-898-9562
Mick Carnett, CDP, CRPS, D.Div., Executive
Director






Informational & support services to providers & patients
Brochures/literature
Presentations
Annual Statewide Hepatitis C Summit
Statewide Physicians Referral List
ETV program, HCC videos, PSAs
85
Surveillance/Reporting

Hepatitis C is reportable to the health
department within 7 days.

Acute and chronic HCV cases are reported
by health department to CDC via CHESS.
86
Hepatitis B
87
Clinical Features

Incubation period:
Mean: 60-90 days
Range: 45-180 days

Clinical illness (jaundice):
<5 yrs, <10%
5 yrs, 30%-50%

Acute case-fatality rate:
Chronic infection:
0.5%-1%
<5 yrs, 30%-90%
 5 yrs, 2%-10%


Premature mortality from
chronic liver disease:
15%-25%
88
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
Source: Centers for Disease Control and Prevention
89
Hepatitis B Surface Antigen
HBsAg
Detection of acutely or chronically infected
individuals. Antigen components used in HBV
vaccine
Should undergo testing to assess the status of
their liver disease
Assess hepatic synthetic function: serum albumin, prothrombin time
Assess for hypersplenism: CBC (plts, wbc decreased)
Assess for viral replication status: HBeAg and HBV DNA
90
Antibody to HBsAg
Anti-HBsAg
Identification of individuals who have resolved
HBV infections.
Determination of immunity after immunization.
91
Hepatitis B Envelope Antigen
HBeAg
Identification of infected individuals at
increased risk for transmitting HBV
92
Antibody to HBe
HBeAb or anti-HBe
Identification of infected individuals with lower
risk for transmitting HBV
93
Antibody to HBV Core Antigens
Anti-HBc or HBcAb
Identification of persons with acute, resolved,
or chronic HBV infection.
Anti-HBc is not present after immunization.
94
IgM Antibody to HBcAg
IgM anti-HBc or HBc IgM
Identification of acute or recent HBV infections
(including those in HBsAg-negative persons
during the “window” phase of infection)
95
Acute HBV Infection with Recovery
Symptoms
anti-HBe
HBeAg
Total anti-HBc
Titer
0
4
anti-HBs
IgM anti-HBc
HBsAg
8
12
16
20
24
28
32
Weeks after Exposure
36
52
100
96
Progression to Chronic HBV Infection
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
IgM anti-HBc
0
4
8 12 16 20 24 28 32 36
Weeks after Exposure
52
Years
97
Chronic Hepatitis B Infection


Defined as testing positive for the HBsAg for
more than 6 months
Patients are at increased risk for progressive
liver disease and hepatocellular carcinoma
98
35 year old Medical Technologist who cut her hand.
She was removing the top from a Vacutainer tube
when the tube broke.
Test
HBsAg
Anti-HBc
Anti-HBc-IgM
Anti-HBs
Anti-HBs Ratio
Result
Negative
Negative
Negative
Positive
23.1
29 year old automotive engineer who presented
with fatigue x 2 weeks and mild jaundice. Liver
enzyme levels were significantly elevated.
Test
Result
HBsAg
Anti-HBc
Anti-HBc-IgM
Anti-HBs
Anti-HBs Ratio
Positive
Positive
Positive
Negative
<2.1
James is a 23 year old food
service employee. He was tested
as part of his pre-employment
physical examination. He was
diagnosed with HBV infection one
year ago.
What is his
HBV Status?
HBsAg
Anti-HBc
Anti-HBc-IgM
Anti-HBs
HBe Ag
Anti-Hbe
Positive
Positive
Negative
Negative
Positive
Negative
Chronic Active Hepatitis



High levels of HBV in blood
Increased risk of cirrhosis
Increased risk of liver cancer
102
James, a 23 year old food service
employee. He was tested as part
of his pre-employment physical
examination. He was diagnosed
with HBV infection one year ago.
Can he work as a
food handler in
your hospital?
• High viral load
• Increased risk of virus
transmission
HBV Transmission




Parenteral
Sexual
Perinatal
Risk of transmission increases
with the level of HBV DNA in
serum and HBeAg positive
104
HBV Concentrations in Various Body Fluids
High
Moderate
blood
serum
wound exudates
semen
vaginal fluid
saliva
Low/Not
Detectable
urine
feces
sweat
tears
breast milk
105
Outcome of HBV Infection
Infection
Symptomatic
acute hepatitis B
Asymptomatic
Resolved
Immune
Chronic infection
Asymptomatic
Cirrhosis
Liver cancer
Resolved
Immune
Chronic
infection
Asymptomatic
Cirrhosis
Liver cancer
106
Chronic HBV Infection

Immune tolerant patient





HBeAg positive and HBeAb negative
Viral load 100,000 to 1 billion copies/mL
Normal ALT
No necroinflammation in the liver
Chronic Active Hepatitis B (Viral Load > 100,000
cy/mL)




HBeAg positive (wild type virus)
HBeAg negative (pre core or core promoter mutants)
Elevated ALT and/or active liver biopsy
Increased risk for progression to cirrhosis and ESL
disease and candidates for therapy
Chronic HBV Infection

Inactive HBsAg Carrier






HBeAg negative and HBeAb positive
Viral load 100 to 10,000 copies/mL
Normal ALT
Resolution of necroinflammation in the liver
Reduced risk of progressive liver disease
Resolution




HBsAg negative, HBsAb positive
Viral load <<< 20,000 copies/mL
HBeAg negative and HBeAb positive
Normal ALT
108
HBV DNA Testing




Assess of viral replication in chronic HBsAg carriers.
Assess the risk of progression toward cirrhosis and
hepatocellular carcinoma.
Decision to treat.
Assess treatment efficacy and failure
109
Hepatitis B Vaccine
• Licensed in 1982; currently recombinant (in US)
• 3 dose series, typical schedule 0, 1-2, 4-6 months - no
maximum time between doses (no need to repeat
missed doses or restart)
• 2 dose series (adult dose) licensed by FDA for 11-15
year olds (Merck)
• Protection ~30-50% dose 1; 75% - 2; 96% - 3; lower in
older, immunosuppressive illnesses (e.g., HIV, chronic
liver diseases, diabetes), obese, smokers
110
Indications for Pre-Exposure Vaccination

Children < 19 yrs of age

Persons at risk for sexual transmission.

MSM

Current/past IDU

Family member of HBsAg + adoptees

Persons at occupational risk

Hemodialysis patients
111
Indications for Pre-Exposure Vaccination

Clients/staff of institutions for developmentally
disabled

Persons receiving clotting factors

International travelers in high/intermediate areas

Inmates

Adults 19 years of age & older desiring protection
112
Indications for Post-Exposure Prophylaxis







Infants born to HBsAg + mothers
Persons who have percutaneous or permucosal
exposure to blood
Sex partners of persons with acute HBV
Household contacts of persons with acute HBV if
blood exposure or if unimmunized infant
Sex partners of persons with chronic HBV
Household contacts of persons with chronic HBV
Victims of sexual assault
113
Indications for Pre-Vaccination
Serologic Testing:
•
Unimmunized sexual contacts of persons with acute
and chronic Hepatitis.
•
Unimmunized household contacts of persons with
acute HBV if there has been a blood exposure.
•
Unimmunized household contacts of person with
chronic HBV.
•
Unimmunized persons in populations with high rates
of HBV (IDU, inmates)
114
Indications for
Post-Vaccination Serologic Testing

Persons at occupational risk

Infants born to HBsAg+ mothers

Immunocompromised persons
115
Sexual Contacts to Acute HBV

Sexual contacts of persons with acute HBV
regardless of age:



Test if unimmunized
Administer HBIG and first hep B dose at time test is
obtained.
If negative, continue hepatitis vaccination series.
116
Household Contacts to Acute Cases

Children (>12 months of age), Adolescents, and
Adult Household Contacts to Acute Cases:



Not at increased risk unless blood exposure.
Only if blood exposure has occurred in past 14 days, test
and give HBIG and first dose of hepatitis B vaccine.
If negative, continue vaccination series.
117
Sexual and Household Contacts
to Chronic Cases

Sexual Contacts (regardless of age):



If unimmunized, test and give first dose of vaccine.
If test is negative, continue series.
Household Contacts (regardless of age):


If unimmunized, test and give first dose of vaccine.
If test is negative, continue series.
118
Victims of Sexual Assault

If offender is HBsAg positive or status is unknown
and victim is unimmunized:


If offender has acute HBV infection - give HBIG and
hepatitis B vaccine.
If offender has chronic HBV infection – give vaccine.
119
Healthcare Worker – Pre-Exposure Vaccination




Administer vaccination series.
Obtain postvaccination serology at 1-2 months after
completion of series.
If anti-HBs levels are > 10 mIU/mL, employee is a
responder.
If anti-HBs levels are < 10 mIU/mL, employee is a
non-responder. Revaccinate and repeat serology.
120
Postvaccination Serology Testing



Infants born to HBsAg positive mothers.
Persons at high risk of occupational exposure.
Persons who are immunocompromised and at
continued risk of infection.
Persons receiving clotting factors.
121
Postvaccination Testing

Persons who were tested 1-2 months after
completion of series and had anti-HBs levels > 10
mIU/mL should not receive any further testing.
122
Approved Therapies for HBV Infection

Interferons



Nucleoside analogues



Interferon alpha 2b (5 million units qd or 10 million units
TIW for 12-24 weeks)
Pegylated interferon alpha 2a (180 ug once/week for 48
weeks)
Lamivudine (100 mg qd)
Entecavir (0.5 mg qd; 1 mg if lamivudine resistance)
Nucleotide analogues

Adefovir (10 mg qd)
123
Hepatitis B Surveillance

Acute Hepatitis B is an urgently reportable condition.
It must be reported by phone to the health department
within 24 hours.

Chronic Hepatitis B is a reportable condition and must
be reported to health department within 7 days.

Perinatal Hepatitis B is a reportable condition and
must be reported to health department within 7 days.
124
Hepatitis D Virus
125
HDV Transmission


Percutanous exposures
injecting drug use
Permucosal exposures
sex contact
126
Geographic Distribution of HDV Infection
Taiwan
Pacific Islands
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
Source: Centers for Disease Control and Prevention
Hepatitis D - Clinical Features


Coinfection
severe acute disease
low risk of chronic infection
Superinfection
usually develop chronic HDV infection
high risk of severe chronic liver disease
128
HBV - HDV Coinfection
Symptoms
Titer
ALT Elevated
anti-HBs
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure
HBV - HDV Superinfection
Jaundice
Symptoms
Total anti-HDV
Titer
ALT
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure