Hepatitis AE

1
Hepatitis A-E

• Rohit Talwani MD
• Assistant Professor of Medicine
• Division of Infectious Diseases
• USC School of Medicine

2
Overview

• Virology
• Transmission
• Epidemiology
• Pathogenesis
• Symptoms
• Diagnosis
• Management
• Prevention

3
HEPATITIS A VIRUS
4
Hepatitis A Structure
5
Hepatitis A Virus Structure and Classification

• RNA Picornavirus
• Separate genus because of differences with other
  enteroviruses
• Naked icosahedral capsid
• SS RNA (740 nucleotides)
• Single serotype worldwide
• Humans only reservoir

6
HEPATITIS A VIRUS TRANSMISSION

• Fecal-oral transmission
• Close personal contact(e.g., household contact,
  sex contact, child day-care centers)
• Contaminated food, water(e.g., infected food
  handlers, contaminated raw oysters)
• Blood exposure (rare use, rarely by transfusion)

7
HEPATITIS A, UNITED STATES

• Most disease occurs in the context of
  community-wide outbreaks
• Infection transmitted from person to person in
  households and extended family settings
• - facilitated by asymptomatic infection among
  children
• Some groups at increased risk
• specific factor varies
• do not account for majority of cases
• Children are the most frequently infected group
• No risk factor identified for 40-50 of cases

8
DISEASE BURDEN FROM HEPATITIS AUNITED STATES,
2001
9
GEOGRAPHIC DISTRIBUTION OF HEPATITIS A VIRUS
INFECTION
10
Hepatitis A Pathogenesis

• Incubation 4 weeks (range 2-6 weeks)
• Oral cavity?GI tract?liver via blood
• Replicates in hepatocytes (little damage to
  cells) released via bile to intestines 7-10 days
  prior to clinical symptoms
• Liver damage and clinical syndrome result of
  immune response and not direct effect of virus

11
Hepatitis A Clinical Features

• An acute illness with
• discrete onset of symptoms (e.g. fatigue,
  abdominal pain, loss of appetite, intermittent
  nausea, vomiting)
• jaundice or elevated serum aminotransferase
  levels, dark urine, light stool
• Adults usually more symptomatic
• Patients are infective while they are shedding
  the virus in the stool- usually before the onset
  of symptoms
• Most cases resolve spontaneously in 2-4 weeks
• Complete recovery 99

12

• HEPATITIS A - CLINICAL FEATURES

• Jaundice by 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
• Chronic sequelae None

13
EVENTS IN HEPATITIS A VIRUS INFECTION
Clinical illness
Infection
ALT
IgM
IgG
Viremia
Response
HAV in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Week
14
Hepatitis A Diagnosis

• Detection of IgM antibody
• IgG positive 1-3 weeks later suggests prior
  infection or vaccination.

15
Hepatitis A Treatment

• Supportive- no specific role of antiviral therapy
• Lifelong immunity likely after infection or
  vaccination

16
PREVENTING HEPATITIS A

• Hygiene (e.g., hand washing)
• Sanitation (e.g., clean water sources)
• Hepatitis A vaccine (pre-exposure)
• Immune globulin (pre- and post-exposure)

17
HEPATITIS A VACCINES

• Inactivated vaccine
• Highly immunogenic
• 97-100 of children, adolescents, and adults
  have protective levels of antibody within 1 month
  of receiving first dose essentially 100 have
  protective levels after second dose
• Highly efficacious
• In published studies, 94-100 of children
  protected against clinical hepatitis A after
  equivalent of one dose

18
HEPATITIS A VACCINES
1st dose at time 0 2nd dose 6-12 months
afterwards
19
DURATION OF PROTECTION AFTER HEPATITIS A
VACCINATION

• Protection begins 4 weeks after vaccine
• Persistence of antibody
• At least 5-8 years among adults and children
• Efficacy
• No cases in vaccinated children at 5-6 years of
  follow-up
• Mathematical models of antibody decline suggest
  protective antibody levels persist for at least
  20 years
• Other mechanisms, such as cellular memory, may
  contribute

20
Hepatitis A Vaccine Recs

• Vaccine is recommended for the following persons
  2 years of age and older
• Travelers to areas with increased rates of
  hepatitis A
• Men who have sex with men
• Injecting and non-injecting drug users
• Persons with clotting-factor disorders (e.g.
  hemophilia)
• Persons with chronic liver disease
• Children living in areas with increased rates of
  hepatitis A during the baseline period from
  1987-1997- mainly West Coast.

21
Hep A Passive Immunization

• Hepatitis A immune globulin can be given up to 2
  weeks after an exposure
• Immunity temporary (4-5 months)
• Also given in travelers leaving for endemic area
  on short notice (ie not enough time for the
  vaccine to be effective)

22
Hepatitis B Virus
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Hepatitis B Structure

• Member of the hepadnavirus group
• Virion also referred to as Dane particle
• 42nm enveloped virus
• Core antigens located in the center
  (nucleocapsid)
• Core antigen (HbcAg)
• e antigen (HBeAg)- an indicator of
  transmissibility (minor component of the core-
  antigenically distinct from HBcAg)
• 22nm spheres and filaments other forms- no DNA in
  these forms so they are not infectious (composed
  of surface antigen)- these forms outnumber the
  actual virions

25
Structure and Replication

• Circular partially double stranded DNA of virus
• Initial replication to complete circular DNA with
  subsequent transcription to make several mRNAs
  some of which are translated into viral proteins
• One of the mRNAs is replicated with a reverse
  transcriptase making the DNA that will eventually
  be the core of the progeny virion
• Some DNA integrates into host genome causing
  carrier state
• Virus stable and resist many stresses making them
  more infectious

26
Hepatitis B virus particles
27
Epidemiology - United States1

• 100,000 new infections per year
• 8,000 - 32,000 chronic infections/year
• 5,000 - 6,000 deaths/year
• 1.25 million Americans with chronic HBV infection
• 15 to 25 of chronically infected patients will
  die from chronic liver disease

1. Center for Disease Control
28
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
³8 - High
2-7 - Intermediate
29
High Prevalence of CHBV in Asian American
Communities is Often Overlooked1

• US prevalence for chronic HBV is
• However, chronic HBV prevalence of 10-15 in
  Asian American communities has been reported
• In Asian American men living in California, HCC
  ranks as a leading cause death
• 2 in Vietnamese and Cambodian Americans
• 4 in Chinese and Korean Americans
• 50 of children born to mothers with chronic HBV
  in the US are Asian American

1. www.liver.stanford.edu
30
Hepatitis B Virus Modes of Transmission

• Sexual
• Parenteral
• Perinatal

31
Concentration of Hepatitis B Virus in Various
Body Fluids

Low/Not
High
Moderate
Detectable
blood
semen
urine
serum
vaginal fluid
feces
wound exudates
saliva
sweat
tears
breastmilk
32
Risk Factors for Acute Hepatitis B United States,
1992-1993
Heterosexual (41)
Injecting Drug Use (15)
Homosexual Activity (9)
Household Contact (2)
Health Care Employment (1)
Unknown (31)
Other (1)
Includes sexual contact with acute cases,
carriers, and multiple partners. Source CDC
Sentinel Counties Study of Viral Hepatitis
33
HBV Pathogenesis

• Virus enters hepatocytes via blood
• Immune response (cytotoxic T cell) to viral
  antigens expressed on hepatocyte cell surface
  responsible for clinical syndrome
• 5 become chronic carriers (HBsAg 6 months)
• Higher rate of hepatocellular ca in chronic
  carriers, especially those who are e antigen
  positive
• Hepatitis B surface antibody likely confers
  lifelong immunity
• Hepatitis B e Ab indicates low transmissibility

34
Hepatitis B - Clinical Features

• Incubation period Average 60-90 days
• Range 45-180 days
• Clinical illness (jaundice)
• 1/3
  adults-no symptoms
• Acute case-fatality rate 0.5-1
• Chronic infection yrs, 2-10
• More likely in ansymptomatic
  infections
• Premature mortality fromchronic liver
  disease 15-25

35
Outcome of Hepatitis B Virus Infection by Age at
Infection
100
100
80
80
60
60
Chronic Infection
Chronic Infection ()
Symptomatic Infection ()
40
40
20
20
Symptomatic Infection
0
0
1-6 months
7-12 months
Older Children and Adults
Birth
1-4 years
Age at Infection
36
Possible Outcomes of HBV Infection
Acute hepatitis B infection
3-5 of adult-acquired infections
95 of infant-acquired infections
Chronic HBV infection
Chronic hepatitis
12-25 in 5 years
Cirrhosis
20-23 in 5 years
6-15 in 5 years
Hepatocellular carcinoma
Liver failure
Liver transplant
Death
Death
37
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titer
anti-HBs
IgM anti-HBc
HBsAg
0
4
8
12
16
24
28
32
52
100
20
36
Weeks after Exposure
38
Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
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
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Current Treatment Options for HBV

• Interferon alfa (Intron A)
• Lamivudine (Epivir HBV)
• Adefovir dipivoxil (Hepsera)

41

Elimination of Hepatitis B Virus Transmission
United States
Strategy

• Prevent perinatal HBV transmission
• Routine vaccination of all infants
• Vaccination of children in high-risk groups
• Vaccination of adolescents
• all unvaccinated children at 11-12 years of age
• high-risk adolescents at all ages
• Vaccination of adults in high-risk groups

42
Hepatitis B Vaccine

• Infants several options that depend on status of
  the mother
• If mother HepBsAg negative birth, 1-2m,6-18m
• If mother HepBsAg positive vaccine and Hep B
  immune globulin within 12 hours of birth, 1-2m,
  
• Adults
• 0,1, 6 months
• Vaccine recommended in
• All those aged 0-18
• Those at high risk

43
Hepatitis B High Risk Groups

• Persons with multiple sex partners or diagnosis
  of a sexually transmitted disease
• Men who have sex with men
• Sex contacts of infected persons
• Injection drug users
• Household contacts of chronically infected
  persons
• Infants born to infected mothers
• Infants/children of immigrants from areas with
  high rates of HBV infection
• Health care and public safety workers
• Hemodialysis patients

44
Estimated Incidence of Acute Hepatitis B United
States, 1978-1995
HBsAg screening of pregnant women recommended
80
Infant immunization recommended
Vaccine licensed
70
60
OSHA Rule enacted
50
Cases per 100,000 Population
Adolescent immunization recommended
40
30
20

Decline among homosexual men HCWs
Decline among injecting drug users
10
0
78
79
81
82
83
84
85
87
88
89
90
91
92
93
94
95
80
86
Year
Provisional date
45
Hepatitis B Passive Immunization

• Infants of surface antigen positive mothers
• Exposures to infected blood or infected body
  fluids in individuals who are unvaccinated,
  unknown vaccination, or known non-responders.
• Ideally within 24 hours
• Probably not effective 7days post exposure

46
Hepatitis D (Delta) Virus
d antigen
HBsAg
RNA
47
Hepatitis D Structure

• Defective virus that requires co-infection with
  hepatitis B for replication
• Enveloped with SS RNA genome
• Only antigen encoded in the delta antigen

48
Hepatitis D virus genome
49
Hepatitis D Virus Modes of Transmission

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

50
Geographic Distribution of HDV Infection
Taiwan
Pacific Islands
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
51
Hepatitis DPathogenesis

• Pathogenesis
• Immune mediated
• Co-infection- infection with B at the same time
  (more severe)
• Superinfection acquisition of Hep D in
  chronically Hep B

52
Sequelae of hepatitis D virus
53

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

54
HBV - HDV Coinfection
Typical Serologic Course
Symptoms
ALT Elevated
anti-HBs
Titer
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure
55
HBV - HDV Superinfection
Typical Serologic Course
Jaundice
Symptoms
Total anti-HDV
ALT
Titer
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure
56

Hepatitis D - Prevention

• 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
• Alpha interferon may help reduce hepatocellular
  damage

57
Hepatitis C viruses particles and genome
58
Hepatitis C Structure and Classification

• Member of the flavivirus family (other members
  yellow fever and dengue)
• Enveloped single stranded RNA virus
• Humans and chimpanzees only known reservoirs
• 6 serotypes (genotypes) and multiple subtypes
  based on high variability of envelope
  glycoproteins

59
Hepatitis C Virus Infection, United States

• New infections per year 1985-89 242,000
• 2001 25,000
• Deaths from acute liver failure Rare
• Persons ever infected (1.8) 3.9 million
  (3.1-4.8)
• Persons with chronic infection 2.7 million
  (2.4-3.0)
• HCV-related chronic liver disease 40 - 60
• Deaths from chronic disease/year 8,000-10,000
• 95 Confidence Interval

60
Estimated Incidence of Acute HCV InfectionUnited
States, 1960-2001
Decline in injection drug users
Decline in transfusion recipients
Source Hepatology 200031777-82 Hepatology
19972662S-65S CDC, unpublished data
61
Exposures Known to Be Associated With HCV
Infection in the United States

• Injecting drug use
• Transfusion, transplant from infected donor
• Occupational exposure to blood
• Mostly needle sticks
• Iatrogenic (unsafe injections)
• Birth to HCV-infected mother
• Sex with infected partner
• Multiple sex partners

62
Sources of Infection forPersons With Hepatitis C
Injecting drug use 60
Sexual 15
Transfusion 10 (before screening)
Occupational 4
Other 1
Unknown 10
Nosocomial iatrogenic perinatal
Source Centers for Disease Control and Prevention
63
Posttransfusion Hepatitis C
All volunteer donors
HBsAg
Donor Screening for HIV Risk Factors
Anti-HIV
ALT/Anti-HBc
Anti-HCV
Improved HCV Tests
Adapted from HJ Alter and Tobler and Busch, Clin
Chem 1997
64
Injecting Drug Use and HCV Transmission

• Highly efficient
• Contamination of drug paraphernalia, not just
  needles and syringes
• Rapidly acquired after initiation
• 30 prevalence after 3 years
• 50 after 5 years
• Four times more common than HIV

65
Occupational Transmission of HCV

• Inefficient by occupational exposures
• Average incidence 1.8 following needle stick
  from HCV-positive source
• Associated with hollow-bore needles
• Case reports of transmission from blood splash to
  eye one from exposure to non-intact skin
• Prevalence 1-2 among health care workers
• Lower than adults in the general population
• 10 times lower than for HBV infection

66
Perinatal Transmission of HCV

• Transmission only from women HCV-RNA positive at
  delivery
• Average rate of infection 6
• Higher (17) if woman co-infected with HIV
• Role of viral titer unclear
• No association with
• Delivery method
• Breastfeeding
• Infected infants do well
• Severe hepatitis is rare

67
Sexual Transmission of HCV

• Occurs, but efficiency is low
• Rare between long-term steady partners
• Factors that facilitate transmission between
  partners unknown (e.g., viral titer)
• Accounts for 15-20 of acute and chronic
  infections in the United States Partner studies
• Low prevalence (1.5) among long-term partners
• infections might be due to common percutaneous
  exposures (e.g., drug use), BUT
• Male to female transmission more efficient
• more indicative of sexual transmission

68
Household Transmission of HCV

• Rare but not absent
• Could occur through percutaneous/mucosal
  exposures to blood
• Contaminated equipment used for home therapies
• IV therapy, injections
• Theoretically through sharing of contaminated
  personal articles (razors, toothbrushes)

69
Other Potential Exposures to Blood

• No or insufficient data showing increased risk
• intranasal cocaine use, tattooing, body piercing,
  acupuncture, military service
• No associations in acute case-control or
  population-based studies
• Cross-sectional studies in highly selected groups
  with inconsistent results
• Temporal relationship between exposure and
  infection usually unknown
• Biologically plausible, but association or causal
  relationship not established

70
Hep C Pathogenesis

• Blood-borne pathogen that infects hepatocytes
• Much like Hep A and B, liver damage and clinical
  illness due more to elicited immune response as
  opposed to direct cytopathic effect of the virus
• Likely cytotoxic T cells that mediate most of the
  damage
• Like other chronic liver diseases (Hep B and
  chronic alcoholism), can cause hepatocellular ca
  (HCC)
• Some genotypes more amenable to therapy- i.e. 3a

71
Features of Hepatitis C Virus Infection

Incubation period Average 6-7 weeks Range 2-26
weeks Acute illness (jaundice) Mild (fatality rate Low Chronic infection 60-85 Chroni
c hepatitis 10-70 (most asx) Cirrhosis ortality from CLD 1-5
Age- related
72
Hepatitis C Clinical Features

• Acute infection asymptomatic in over 80 of
  patients, when present, acute illness usually
  mild
• Acute symptoms include jaundice, nausea,
  abdominal pain, loss of appetite, dark urine

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Hepatitis C Extrahepatic Manifestations

• Seen with chronic infection
• ? Due to immune complexes
• Extrahepatic manifestations
• Essential mixed cryoglobulinemia (vasculitis,
  skin rash, fatigue)
• Porphyria cutanea tarda
• Membranoproliferative glomerulonephritis
• ?Diabetes mellitus
• Other autoimmune disease
• ?Lymphoma

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Porphyria cutanea tarda
76
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

77
Serologic Pattern of Acute HCV Infection with
Recovery
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
78
Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Years
Months
Time after Exposure
79
Hepatitis C Diagnosis

• ELISA-a serological test which is usually.
  positive within 2-5 months after infection
• 3rd generation assays now 99 specific and
  sensitive
• Confirmatory testing
• PCR (positive 1-2 weeks post infection) both
  quantitative and qualitative (I.e. ye/no)
  available
• RIBA (recombinant immunoblot assay)- looks for 2
  or more antibodies to HCV viral antigens
• Genotype testing done when treatment anticipated

80
HCV Testing Routinely Recommended
Based on increased risk for infection

• Ever injected illegal drugs
• Received clotting factors made before 1987
• Received blood/organs before July 1992
• Ever on chronic hemodialysis
• Evidence of liver disease
• Healthcare, emergency, public safety workers
  after needle stick/mucosal exposures to
  HCV-positive blood
• Children born to HCV-positive women

Based on need for exposure management
81
HCV Infection Testing Algorithmfor Diagnosis of
Asymptomatic Persons
STOP
Negative
Screening Test for Anti-HCV
Positive
OR
Negative
NAT for HCV RNA
RIBA for Anti-HCV
Negative
Positive
Positive
Indeterminate
STOP
Additional Laboratory Evaluation (e.g. PCR, ALT)
Medical Evaluation
Negative PCR, Normal ALT
Positive PCR, Abnormal ALT
Source MMWR 199847 (No. RR 19)
82
Medical Evaluation and Managementfor Chronic HCV
Infection

• Assess for biochemical evidence of CLD
• Assess for severity of disease and possible
  treatment, according to current practice
  guidelines
• 40-50 sustained response to antiviral
  combination therapy (peg interferon, ribavirin)
• Vaccinate against hepatitis A
• Counsel to reduce further harm to liver
• Limit or abstain from alcohol

83
Hepatitis C Therapy

• Standard of care is pegylated interferon alpha
  and ribavirin
• Many barriers to treatment as the above regimen
  is difficult to take and has many systemic side
  effects (fatigue, myalgias, depression, anemia to
  name a few)
• Overall response rate to treatment is 40-50
  (higher for non 1 genotypes)

84
Postexposure Management for HCV

• IG, antivirals not recommended for prophylaxis
• Follow-up after needlesticks, sharps, or mucosal
  exposures to HCV-positive blood
• Test source for anti-HCV
• Test worker if source anti-HCV positive
• Anti-HCV and ALT at baseline and 4-6 months later
• For earlier diagnosis, HCV RNA at 4-6 weeks
• Confirm all anti-HCV results with RIBA
• Refer infected worker to specialist for medical
  evaluation and management

85
Hepatitis E Virus
86
Hepatitis E

• Non-enveloped single stranded RNA virus
• Resembles calicivirus or Norwalk agent
• Similar illness to Hep A except high mortality in
  pregnant women

87
Geographic Distribution of Hepatitis E
Outbreaks or Confirmed Infection in 25 of
Sporadic Non-ABC Hepatitis
88
Hepatitis E - Epidemiologic Features

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

89
Hepatitis E - Clinical Features

• Incubation period Average 40 days
• Range 15-60 days
• Case-fatality rate Overall, 1-3 Pregnant
  women, 15-25
• Illness severity Increased with age
• Chronic sequelae None identified

90
Hepatitis E Virus Infection
Typical Serologic Course
Symptoms
ALT
IgG anti-HEV
IgM anti-HEV
Titer
Virus in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Weeks after Exposure
91
Prevention and Control Measures for Travelers to
HEV-Endemic Regions

• 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?

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