Viral Hepatitis: A, B, C, D, E

1
Viral Hepatitis A, B, C, D, E
Wayne A. Duffus, MD, PhD November 2nd, 2009
2
Viral Hepatitis - Historical Perspective
Enterically transmitted
Infectious
A
E
NANB
Viral hepatitis
Parenterally transmitted
B
D
C
Serum
F, G, ? other
3
Viral Hepatitis
A
B
C
D
E
Source of
feces
blood/
blood/
blood/
feces
virus
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
permucosal
permucosal
permucosal
Chronic
no
yes
yes
yes
no
infection
Prevention
pre/post-
pre/post-
blood donor
pre/post-
ensure safe
exposure
exposure
screening
exposure
drinking
immunization
immunization
risk behavior
immunization
water
modification
risk behavior
modification
4
Viral Hepatitis 1982-1993
34
42
16
3
Source CDC Sentinel Counties Study on Viral
Hepatitis
5
Estimates of Acute and Chronic DiseaseBurden for
Viral Hepatitis, United States
HAV
HBV
HCV
HDV
Acute infections
(x 1000)/year
125-200
140-320
35-180
6-13
Fulminant
deaths/year
100
150
?
35
Chronic
0
1-1.25
3.5
infections
million
million
70,000
Chronic liver disease
deaths/year
0
5,000
8-10,000
1,000
Source CDC -Range based on estimated annual
incidence, 1984-1994.
6
Hepatitis A Virus (HAV)
7
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

8
Hepatitis A - Clinical Features

• Incubation period Mean 30 days Range 15-50
  days
• Jaundice by lt6 yrs, lt10 age group 6-14
  yrs 40-50 gt14 yrs 70-80
• Complications Fulminant hepatitis Cholestati
  c hepatitis Relapsing hepatitis
• Chronic sequelae None

9
HAV - Typical Serologic Course
Symptoms
Total anti-HAV
ALT
Titer
Fecal HAV
IgM anti-HAV
4
5
6
12
24
0
1
2
3
Months after Exposure
10
Serological Testing

• HAV total Ab appears 4-5 weeks after infection
  and remains positive for the patients 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

11
HAV Immune Globulin

• IM administration within 2 weeks after HAV
  exposure is gt85 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.

12
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.

13
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.

14
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) Positive
• HAV IgM Negative

Does he have HAV infection?
15
CDC RecommendationsTesting and Vaccination
16
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)

17
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

18
ACIP RECOMMENDATIONSPERSONS 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

19
STD Treatment GuidelinesMMWR August 4, 2006 55
(RR11)
Vaccination against hepatitis is the most
effective means of preventing sexual
transmission of hepatitis A and B.
20
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.

21
Indications for IG for Post-Exposure Prophylaxis

• Person exposed to contaminated food/water.
• Persons who ate food prepared by HAV food
  handler.

22
Hepatitis A Surveillance and Response
23
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.

24
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

25
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.

26
Hepatitis E Virus
27

• 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?

28
Hepatitis E Virus

• Most outbreaks associated withfecally
  contaminated drinking water
• Minimal person-to-person transmission
• U.S. cases usually have history of travelto
  HEV-endemic areas

29
Geographic Distribution of Hepatitis E
Outbreaks or Confirmed Infection in gt25 of
Sporadic Non-ABC Hepatitis
Source CDC
30
Hepatitis E Virus

• Incubation period Average 40 days Range
  15-60 days
• Case-fatality rate 1-3 overall 15-25
  in pregnancy
• Illness severity Increased with age
• Chronic sequelae None identified

31
Typical Serological Course - HEV
Symptoms
anti-HEV
ALT
IgM anti-HEV
Titer
Virus in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Weeks after Exposure
32
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 patients lifetime

33
CDC Criteria for Testing Acute Phase Sera

• Discrete onset of illness with jaundice or
• Serum ALT gt2.5 times the upper limit of normal
  and
• HAV IgM negative
• HBV Core IgM negative
• HCV Ab negative

34
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

35

• Steps to prevent HEV transmission in home
  setting?
• Safe sex practices
• Do not share eating/grooming utensils.
• Respiratory precautions
• Vigorous hand washing
• No special requirements needed

36
Hepatitis C Virus
37

• 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?

38
What is Claudias Risk of Infection?

• High risk HCV can be transmitted sexually.
• Low risk The efficiency of sexual transmission
  is low.

39
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
40
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

41
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

42
Hepatitis C Genotypes

• Genotype Countries Where Prevalent
• 1a USA, England, Europe
• 1b USA, Japan, Europe
• 2a, 2b, 2c, 2d Japan, China
• 3a, 3b, 3c, 3d, 3e, 3f Scotland, England
• 4a, 4b, 4c, 4d, 4e, 4f,
• 4g, 4h, 4i, 4j Middle East, Africa
• 5a Canada, South Africa
• 6a Hong Kong, Macau

43
Genotype Distribution
44
Hepatitis C A Global Health Problem
170 Million Carriers Worldwide, 3-4 MM new
cases/year
EAST MEDITERRANEAN 20M
WEST EUROPE 9 M
FAR EAST ASIA 60 M
U.S.A. 4 M
SOUTH EAST ASIA 30 M
AFRICA 32 M
SOUTH AMERICA 10 M
AUSTRALIA 0.2 M
SOURCE, WHO 1999
45
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. 199726 (suppl 1) 15S-20S NIH
Consensus Development Conference Panel Statement
Management of Hepatitis C, 2002
46
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

47
Natural History of Hepatitis C
Acute Hepatitis C
10-20 years
Chronic Hepatitis 75-85
Cirrhosis 20
Hoofnagle JH Hepatology. 199726 (suppl 1)
15S-20S Di Bisceglie, Hepatology, 2000
48
Natural History of Hepatitis C
Annual rate
Hoofnagle JH Hepatology. 199726 (suppl 1)
15S-20S Di Bisceglie, Hepatology, 2000
49
Acute HCV Infection with Recovery
HCV Ab
Symptoms /-
HCV RNA
Titer
ALT
Normal
2
3
4
5
6
1
2
3
4
0
1
Years
Months
Time after Exposure
50
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
51
Acute HCV Infection with Progression to Chronic
Infection
HCV Ab
Symptoms /-
HCV RNA
Titer
ALT
Normal
0
1
2
3
4
5
6
1
2
3
4
Years
Months
Time after Exposure
52
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

53
Extrahepatic Manifestations of Hepatitis C

• Hematologic Mixed cryoglobulinemia
• (1025 of HCV patients)
• Renal Glomerulonephritis
• Dermatologic
• Porphyria cutanea tarda
• Cutaneous necrotizing vasculitis
• Lichen planus

Management of Hepatitis C. NIH Consensus
Statement, 2002.
54
Chronic Hepatitis C Factors Promoting
Progression or Severity

• Increased alcohol intake
• Age gt 40 years at time of infection
• HIV co-infection
• Other
• Male gender
• Chronic HBV co-infection

55

• Claudia needs to see her family physician.
• She wants to be tested for HCV.
• What test do you recommend?

56
Diagnostic Tests for HCV

• Anti-HCV
• RIBA (supplemental assay)
• Qualitative PCR
• Quantitative PCR
• Genotyping assays

57
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

58
Hepatitis C Antibody TestSignal to Cut Off
(S/CO) Ratio

• S/CO ratio is a comparison of the pts positive
  EIA result with the labs 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).

59
HCV RIBA Tests

• Used to resolve possible false positive anti-HCV,
  particularly in low-risk patients (blood donors)
• Use is analogous to HIV western blot

Core
E1
E2/NS1
NS2
NS3
NS4
NS5
5 UTR
60
HCV Screening Algorithm
Negative (non-reactive)
STOP
EIA for Anti-HCV
Positive (repeat reactive)
OR
Negative
RT-PCR for HCV RNA
RIBA for Anti-HCV
Negative
Positive
Positive
Indeterminate
STOP
Additional Laboratory Tests (e.g. PCR, ALT)
Medical Evaluation
Negative PCR, Normal ALT
Positive PCR, Abnormal ALT
Source MMWR 199847 (No. RR 19)
61
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

62
Diagnosis of Chronic Viral HepatitisSerologic
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.
63
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

64
Histologic Staging
65
Diagnostic Evaluation of HCV Infection
66
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

67
Treatment
68
Treatment for Hepatitis C

• Interferon Ribavirin x 6-12 months about 40
  - 50 sustain viral clearance gt 3 years.
• Predictive Factors for Treatment Response
• Genotype 2 and 3
• Low initial viral load levels
• Young age
• Low Fibrosis Score (Liver Biopsy)
• Female

69
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

70
Rationale for the development of a once-weekly
pegylated interferon ?-2b

71
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.
2002899.Harris JM, et al. Clin Pharmacokinet.
200140539.
72
Why PEG as a Protein-Modifying Agent?

• Inert
• Water soluble
• Can be made any size and shape

Bailon et al., Bioconjugate Chemistry, 2001 Wyss
et al., Current Pharmaceutical Design, 2002
73
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, 82139-215
74
Pegylation Antiviral Activity
More Less
PEG Molecular Weight (PEG size)
Adapted from Grace M et al., AASLD 2003,
Abstract 1928
The clinical relevance of this in vitro data has
not been established.
75
Relationship between PEG size and Renal Clearance
Wyss et al., Current Pharmaceutical Design,
2002 Xian-Hui He et al., Life Sciences, 1999
76
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

77
Predicting Response to Treatment
78
Response Rate to Treatment Based on Genotype

• Genotype Response Rate
• 1a/1b 41 of patients
• 2-6 75 of patients
• Overall Response 52 of patients

79
HCV Kinetics
80
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

81
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.

• The Second aim is to prevent relapse in patients
  who cleared HCV RNA during induction, in order to
  achieve a sustained virological response

Adapted from Pawlotsky JM, Hepatology vol. 32,
5, 2000
82
Patterns of Response to InitialAntiviral Therapy
83
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 2007357124-134
84
Resources

• S.C. Hepatitis C Coalition
• SC DHEC Hepatitis Nurse Consultant
• Elona Rhame, RN
• Pharmaceutical Companies
• Physician Referral List

85
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

86
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.

87
Hepatitis B
88
Clinical Features

• Incubation period Mean 60-90 days
• Range 45-180 days
• Clinical illness (jaundice) lt5 yrs, lt10
  ?5 yrs, 30-50
• Acute case-fatality rate 0.5-1
• Chronic infection lt5 yrs, 30-90 ?
  5 yrs, 2-10
• Premature mortality fromchronic liver disease
  15-25

89
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
?8 - High
2-7 - Intermediate
lt2 - Low
Source Centers for Disease Control and
Prevention
90
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

91
Antibody to HBsAg

• Anti-HBsAg
• Identification of individuals who have resolved
  HBV infections.
• Determination of immunity after immunization.

92
Hepatitis B Envelope Antigen

• HBeAg
• Identification of infected individuals at
  increased risk for transmitting HBV

93
Antibody to HBe

• HBeAb or anti-HBe
• Identification of infected individuals with lower
  risk for transmitting HBV

94
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.

95
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)

96
Acute HBV Infection with Recovery
Symptoms
anti-HBe
HBeAg
Total anti-HBc
Titer
anti-HBs
IgM anti-HBc
HBsAg
0
4
8
12
16
20
24
28
32
36
52
100
Weeks after Exposure
97
Progression to Chronic HBV Infection
Acute (6 months)
Chronic (Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
IgM anti-HBc
Years
0
4
8
12
16
20
24
28
32
36
52
Weeks after Exposure
98
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

99
35 year old Medical Technologist who cut her
hand. She was removing the top from a Vacutainer
tube when the tube broke.

• Test Result
• HBsAg Negative
• Anti-HBc Negative
• Anti-HBc-IgM Negative
• Anti-HBs Positive
• Anti-HBs Ratio 23.1

100
29 year old automotive engineer who
presented with fatigue x 2 weeks and mild
jaundice. Liver enzyme levels were significantly
elevated.

• Test Result
• HBsAg Positive
• Anti-HBc Positive
• Anti-HBc-IgM Positive
• Anti-HBs Negative
• Anti-HBs Ratio lt2.1

101
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.

• HBsAg Positive
• Anti-HBc Positive
• Anti-HBc-IgM Negative
• Anti-HBs Negative
• HBe Ag Positive
• Anti-Hbe Negative

What is his HBV Status?
102
Chronic Active Hepatitis

• High levels of HBV in blood
• Increased risk of cirrhosis
• Increased risk of liver cancer

103
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.

• High viral load
• Increased risk of virus transmission

Can he work as a food handler in your hospital?
104
HBV Transmission

• Parenteral
• Sexual
• Perinatal
• Risk of transmission increases with the level of
  HBV DNA in serum and HBeAg positive

105
HBV Concentrations in Various Body Fluids
Low/Not
High
Moderate
Detectable
blood
semen
urine
serum
vaginal fluid
feces
wound exudates
saliva
sweat
tears
breast milk
106
Outcome of HBV Infection
107
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 gt 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

108
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 ltltlt 20,000 copies/mL
• HBeAg negative and HBeAb positive
• Normal ALT

109
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

110
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

111
Indications for Pre-Exposure Vaccination

• Children lt 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

112
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

113
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

114
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)

115
Indications for Post-Vaccination Serologic
Testing

• Persons at occupational risk
• Infants born to HBsAg mothers
• Immunocompromised persons

116
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.

117
Household Contacts to Acute Cases

• Children (gt12 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.

118
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.

119
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.

120
Healthcare Worker Pre-Exposure Vaccination

• Administer vaccination series.
• Obtain postvaccination serology at 1-2 months
  after completion of series.
• If anti-HBs levels are gt 10 mIU/mL, employee is a
  responder.
• If anti-HBs levels are lt 10 mIU/mL, employee is a
  non-responder. Revaccinate and repeat serology.

121
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.

122
Postvaccination Testing

• Persons who were tested 1-2 months after
  completion of series and had anti-HBs levels gt 10
  mIU/mL should not receive any further testing.

123
Approved Therapies for HBV Infection

• Interferons
• 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)
• Nucleoside analogues
• Lamivudine (100 mg qd)
• Entecavir (0.5 mg qd 1 mg if lamivudine
  resistance)
• Nucleotide analogues
• Adefovir (10 mg qd)

124
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.

125
Hepatitis D Virus
126
HDV Transmission

• Percutanous exposures
• injecting drug use
• Permucosal exposures
• sex contact

127
Geographic Distribution of HDV Infection
Taiwan
Pacific Islands
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
Source Centers for Disease Control and Prevention
128
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

129
HBV - HDV Coinfection
Symptoms
ALT Elevated
anti-HBs
Titer
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure
130
HBV - HDV Superinfection
Jaundice
Symptoms
Total anti-HDV
ALT
Titer
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure