Introduction to hepatitis B and C for healthcare workers

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Introduction to hepatitis B and C for healthcare
workers

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• 1910.1030(f)
• Hepatitis B Vaccination and Post-exposure
  Evaluation and Follow-up --
• ..1910.1030(f)(1)
• 1910.1030(f)(1)
• General.
• 1910.1030(f)(1)(i)
• The employer shall make available the hepatitis B
  vaccine and vaccination series to all employees
  who have occupational exposure, and post-exposure
  evaluation and follow-up to all employees who
  have had an exposure incident.

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• 1910.1030(f)(2)
• Hepatitis B Vaccination.
• 1910.1030(f)(2)(i)
• Hepatitis B vaccination shall be made available
  after the employee has received the training
  required in paragraph (g)(2)(vii)(I) and within
  10 working days of initial assignment to all
  employees who have occupational exposure unless
  the employee has previously received the complete
  hepatitis B vaccination series, antibody testing
  has revealed that the employee is immune, or the
  vaccine is contraindicated for medical reasons.

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Acute hepatitis
Resolution
Chronic hepatitis
cirrhosis
Hepatocellular carcinoma
Death
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Prevalence among blood donors in Chiang Mai
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Hepatitis B

• Incomplete circular DNA virus
• Four overlapping genes S, C,P and X
• Family Hepadna virus
• Human, woodchuck, squirrel, Peking duck
• Replicate as the retrovirus

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Hepatitis B
A. The HBV invades the cell by binding to surface
receptors B. the virus is taken up by the cell C.
enzymes extend the S() strand to form a
covalently closed circular double-stranded DNA
(CCC-DNA) D. The HBV genome in its core migrates
to the nucleus E. F. Additional viral structural
protein messenger RNAs pass into the cytoplasm
and are translated G. The pregenome and viral
DNA polymerase are packaged into new capsids H.
I. The pregenome is then destroyed. The L(-)
strand (H) is then used as a template for
formation of the S() strand J. the mature cores
(I) are packaged into HBsAg particles, which
accumulate in the endoplasmic reticulum and exit
the cell
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Hepatitis B acute infection and resolution
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Hepatitis B acute infection turn into chronicity
Weeks after Exposure
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Hepatitis B

• Incubation period 30-180 days, mean 60-90
• Perinatal transmission and intimate contact
  between toddlers are the important transmission
  routes
• 350 million HBsAg carriers worldwide

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Prevalence of chronic hepatitis B
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Chronic HBV
Asymptomatic with normal ALT HBe , HBV DNA
Spontaneous HBe to Anti-HBe rare
Immune tolerance
15-35 yr.
Adult acquired
Symptoms Increase ALT with active histology HBV
DNA but usually low HBe to Anti-HBe 2.7-25
/year
Immune clearance
rapid silence
prolonged fluctuating
No symptom with normal ALT HBeAg -, HBsAg
(cytoplasm), HBV DNA (host DNA)
Nonreplicative
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Natural History of Chronic HBV Infection
CompensatedCirrhosis
90-95 Resolution
Stabilisation
15-25
Liver Cancer
AcuteInfection
ChronicHepatitis
Cirrhosis
Death
5-10 Chronic Carrier
Progression
DecompensatedCirrhosis (Death)
3050 Years
Adapted from Feitelson, Lab Invest 1994
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The new concept of carrier

• All with HBsAg-positive should be called chronic
  hepatitis B (CHB), with consideration of
• Virologic (HBeAg status, viral load)
• Biochemical (ALT level)
• Histological status
• Then consider as active or inactive carrier
  state
• Inactive carrier state is
• HBeAg-negative
• Normal ALT, viral load lt 105
• Very mild necroinflammation (HAI score lt 3), no
  fibrosis

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Carrier vs chronic hepatitis

• Depends on ALT
• Carrier has normal ALT at every 6 months for at
  least 3 years (6 tests)
• Chronic hepatitis
• HBsAg-positive for more than 6 months
• High ALT (preferably gt1.5x) two times six months
  apart
• Biopsy reveals moderate necroinflammation

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Whom should we treat?

• Chronic hepatitis
• Documented HBsAg gt6 month
• Either HBeAg , (antiHBe -) or HBeAg - (precore
  mutant)
• HBV-DNA , but not very high
• Moderately increased ALT, gt2x but lt10x
• Documented necroinflammation and fibrosis by
  biopsy

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Why biopsy needed?

• Confirm the need to be treated
• No ideal treatment exists
• Treatments are with certain risks, including
  resistance and flares both during and after
  treatment failure
• Uncontrolled treatment means uncontrolled
  infection

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Should we treat the CARRIERS?

• Carriers also carry the certain risk of
  developing cirrhosis and hepatocellularcarcinoma
• No study on the incidence risk, but very low
• Surveillance is not recommended, but may be
  considered if affordable
• Treatment for carrier (eradication of the virus)
  is not available now
• Current treatment relies on activated immune
  status
• No treatment that can eradicate the virus
• Carriers should have regular follow up, avoid
  alcohol and other liver injury

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Current treatment

• Interferon alpha
• 5-10 million units qd or tiw for 16-24 weeks
• Pegylated interferon
• Only pegylated interferon alpha-2a
• 180 mcg qw for 48 weeks
• Antivirals
• Lamivudine
• Adefovir dipivoxil

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Response to lamivudine treatment
Guan R . J. Gast. Hep. 2001 16 Suppl. Abs 160
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Emerging of YMDD resistance
Incidence of YMDD mutant HBV
69 - 75
47 - 56
16 - 32
2 year
1 year
3 year
At year of Lamivudine therapy
Atkins M. et al. Hepatology. 1998.
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Hepatitis flare from YMDD resistance
Liaw YF. et al. Hepatology. 1999.
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Treatment of chronic disease

• Long term treatment
• Increasing cost in progressing disease
• Even sky high cost for end stage
• Supportive treatment
• Organ replacement therapy
• Transplantation
• Cancer prevention and treatment

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What do we expect from chronic hepatitis B?

• Cirrhosis
• Compensated
• Decompensated
• Complication of cirrhosis
• Ascites
• Variceal bleeding
• Hepatic encephalopathy
• Hepatocellular carcinoma

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Is treatment of chronic hepatitis B
cost-effective?

• Relatively low effectiveness as compared to
  hepatitis C (20-40 vs. 80-90)
• Treatment is considerably expensive
• Undesirable side effects with high dose
  interferon
• Treatment with antiviral may result in flare or
  resistance
• No firm data on prevention of cirrhosis and HCC

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Role of oral antivirals
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Hepatitis B vaccination

• First anti-cancer Vaccine
• Hepatitis B vaccine prevents hepatitis B disease
  and its serious consequences like hepatocellular
  carcinoma. Therefore, this is the first
  anti-cancer vaccine.
• Safe and effective
• Medical, scientific and public health communities
  strongly endorse using hepatitis B vaccine as a
  safe and effective way to prevent disease and
  death.
• Scientific data show that hepatitis B vaccines
  are very safe for infants, children, and adults.
• There is no confirmed evidence indicating that
  hepatitis B vaccine can cause chronic illnesses.

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The schedule for hepatitis B vaccination is
flexible and varies. Consult the ACIP statement
on hepatitis B (11/91), AAP's 2003 Red Book, or
the package insert for details.Note For adult
dialysis patients, the Engerix-B dose required is
40µg/2.0ml (use the adult 20µg/ml formulation) on
a schedule of 0, 1, 2, and 6 months. For
Recombivax HB, a special formulation for dialysis
patients is available. The dose is 40µg/1.0ml and
it is given on a schedule of 0, 1, and 6 months.
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• Vaccine interruption
• If the vaccination series is interrupted after
  the first dose, the second dose should be
  administered as soon as possible. The second and
  third doses should be separated by an interval of
  at least 2 months. If only the third dose is
  delayed, it should be administered when
  convenient.
• Booster doses
• Current data show that vaccine-induced hepatitis
  B surface antibody (anti-HBs) levels may decline
  overtime however, immune memory (anamnestic
  anti-HBs response) remains intact indefinitely
  following immunization. Persons with declining
  antibody levels are still protected against
  clinical illness and chronic disease.
• For health care workers with normal immune status
  who have demonstrated an anti-HBs response
  following vaccination, booster doses of vaccine
  are not recommended nor is periodic anti-HBs
  testing.

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• Post-vaccination Testing
• After routine vaccination of infants, children,
  adolescents, or adults post-vaccination testing
  for adequate antibody response is not necessary.
• Post-vaccination testing IS recommended for
  persons whose medical management will depend on
  knowledge of their immune status.
• This includes persons who
• are immunocompromised (e.g., hemodialysis
  patients)
• received the vaccine in the buttock
• are infants born to HBsAg (hepatitis B surface
  antigen)-positive mothers
• are healthcare workers who have contact with
  blood
• are sex partners of persons with chronic
  hepatitis B virus infection
• Post-vaccination testing should be completed 1-2
  months after the third vaccine dose for results
  to be meaningful. A protective antibody response
  is 10 or more milliinternational units
  (gt10mIU/mL).

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Hepatitis C

• Linear single -stranded RNA virus
• Family Flaviviridae
• Anti-HCV is not neutralizing antibody
• Neutralizing antibody can be demonstrated but
  short-lived

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Hepatitis C

• HCV is a positive sense, single-stranded RNA
  virus, with an estimated diameter of 36 to 72 nm.
• HCV is believed to represent a distinct genus in
  the Flaviviridae family
• A viral envelope comprising a lipid layer and
  envelope proteins, surrounds a core (capsid)
  structure enclosing the viral nucleic acid
• HCV RNA is 9.4 kb in length and consists of a
  5'nontranslated region, followed by core (C),
  envelope (E), and nonstructural (NS) protein
  encoding regions

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Hepatitis C

• Incubation period 15-160 days,mean 50
• Transmitted mostly by blood and blood products
• The second generation test in 1992 reduced the
  infection to near zero
• Perinatal and sexual transmission is also
  possible but with rather low incidence

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HCV infection
2-20 wks
All abnormal ALT 1/3 jaundice
15 Resolved
85 chronic
1/3
2/3
All abnormal pathology
normal ALT
Abnormal ALT
cirrhosis
20-30 in 10-20 yr.
HCC
3/yr.
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Different in Disease Progression of HCV
100
Medium rate 0.133 /y
Very rapid fibrosis 0.36/y
30 years to cirrhosis
cirrhosis
11 years to cirrhosis
50
Very slow fibrosis 0.04/y
100 years to cirrhosis
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HCV genotypes and subtypes
P. Simmonds, Philos Trans R Soc Lond B Biol Sci
20013561013-26
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Geographic distribution of hepatitis C genotypes
1b 2a, 2b, 2c, 3a
1b
1a, 1b 2a, 2b, 3a
2a
4
1b, 3, 6
1b, 3a
4
3b
1b, 3a
5a
Adapted from Fang J Clin Liver Dis 19971503.
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Current treatment

• Pegylated-interferon alfa ribavirin
• Pegylated interferon qw, 24-48 weeks
• Ribavirin according to body weight and genotypes
• lt70 kg, or genotypes non-1, 800 mg/day
• gt70 kg, 1,000-1,200 mg/day

• All cases that have undetectable HCV-RNA at the
  end of treatment need to have it checked again 6
  months later
• Undetectable HCV-RNA at 6 months after completion
  of treatment means complete eradication

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Benefit from treatment

• Eradication, 60-90Termination of disease course
  and even with regression of fibrosis
• Non sustained remission, 20Retardation of
  disease progression
• Less than 10 will not benefit from treatment

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Fibrosis regression or retardation in CH-C
patients treated with interferon (IFN)
IFN
Fibrosis stage
Fn1
untreated (0.10 unit/year)
Fibrosis progression
Fn
non-SR (0.024 unit/year)
Fn-1
Fibrosis resolution
SR (-0.28 unit/year)
0
10
5
-10
-5
(Years)
After IFN treatment
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Screening for HCC