Hepatitis Infectiosa

Mulyana
Post-graduate Program
Hospital Pharmacy Clinical Pharmacy
Faculty of Pharmcy
Padjadjaran University

Definition

Hepatitis is defined as inflammation of the liver.

Hepatitis may result from any of a number of
infectious and noninfectious causes (NASH, ASH)
Many viral infections can cause liver inflammation,
but the term viral hepatitis is usually reserved for
infections with one of the five hepatotropic viruses
(viruses known to target the human liver);

Hepatitis
Hepatitis
Hepatitis
Hepatitis
Hepatitis

A virus (HAV)
B virus (HBV)
C virus (HCV)
D virus (HDV)
E virus (HEV)

Type of
Hepatitis
A

Source of
virus
Route of
transmission
Chronic
infection
Prevention

feces

blood/
blood/
blood/
blood-derived blood-derived blood-derived
body fluids
body fluids
body fluids

feces

fecal-oral

percutaneous percutaneous percutaneous

permucosal
permucosal
permucosal

fecal-oral

no

yes

pre/postexposure
immunization

pre/postexposure
immunization

yes

yes

blood donor
pre/postscreening;
exposure
risk behavior immunization;
modification risk behavior
modification

no

ensure safe
drinking
water

Hepatitis A

Hepatitis A

Hepatitis A virus (HAV) is an RNA-containing virus of the

Picornaviridae family.
The key feature is that it is a self-limiting disease.
Management of HAV should therefore be supportive. The
average HAV incubation time is 28 days, but it can vary from
15 to 45 days.
HAV infection is self-limiting and does not require treatment;
contacts should be vaccinated (particularly in low incidence
areas). There is no chronic infection; HAV infection induces
lifelong immunity.
Some people with HAV will have relapses after 69 months.
The risk of fulminant hepatic failure is very low (0.01
0.1%), but increases with age and in those with preexisting
liver disease.
In patients over the age of 40, there is a 1% mortality rate
WGO Practice Guidelines. ,2007.

Epidemiology

There are an estimated 1.5 million cases of

acute hepatitis A annually worldwide, or
depending on local endemicity around 150
per 100,000. Most of these occur in areas with
poor hygiene and a poor sanitation
infrastructure

WGO Practice Guidelines. ,2007

WGO Practice Guidelines. ,2007

Transmision

HAV is found in the feces of individuals with

acute HAV in the presymptomatic and early
phases of the disease.
HAV is usually spread between individuals by oral
contact with something that has been contaminated
by fecal matter from an HAV-infected person HAV
transmission is fecaloral.
Most transmission is through contact with a
household member, tourist travel to an endemic
area, contact with a sex partner who has HAV, from
an infection in an individual preparing food, or
contact with babies in nurseries. Poor hygiene and
poor sanitation pose the greatest risks.
WGO Practice Guidelines. ,2007.

Risk groups

Children living in poor sanitation and in areas

with low hygiene
Children living in areas with a high incidence
of HAV
Those participating in anal sex
Users of injected illegal drugs (homeless)
Poor sanitation
Consumers of high-risk foods (e.g., raw
shellfish)
Day-care employees and family of children in
day care
People traveling to endemicWGO
areas
Practice Guidelines. ,2007.

Diagnosis

All forms of acute viral hepatitis have the same initial

presentation. HAV virus is reliably diagnosed by anti-HAV
immunoglobulin M (IgM); the presence of anti-HAV immunoglobulin
G indicates a previous infection).
Persistent anti-HAV IgM can sometimes be detected in patients
with autoimmune hepatitis. In children, the illness is usually
asymptomatic. In adults, HAV infection is usually symptomatic
Symptoms

Jaundice (yellowing of the skin and eyes)

Fatigue
Abdominal pain
Loss of appetite
Nausea
Diarrhea
Fever
Dark urine
Relapse with cholestasis or serum sickness

WGO Practice Guidelines. ,2007.

Management

The subjective impression of the patient should guide the doctors

approach. Neither hospital admission, quarantine or bed rest, or
medication (e.g., vitamin administration, dietary restrictions, blood
transfusions) are necessary.
The treatment should be conservative and supportive.
There is no specific medication for HAV infection.
Hygiene is very important hands should always be washed after
bathroom use.
The management should focus on treating the symptoms and
identifying the small proportion of patients with a particular risk of
developing fulminant hepatic failure.
Patients over the age of 40 and those with underlying chronic
liver disease are most at risk.
Contacts should be vaccinated
Oral contraceptive treatment and hormone replacement therapy
should be stopped to avoid cholestasis. Alcohol consumption is not
advised

WGO Practice Guidelines. ,2007.

Prevention

There are a number of inactivated

vaccines on the market. Vaccination for
preexposure prophylaxis (for example, with
VAQTA or .Havrix) provides long-term
protection for up to 20 years.
Vaccination for postexposure prophylaxis
should be given as early as possible

WGO Practice Guidelines. ,2007.

Hepatitis B

Hepatitis B

In neonates with immature immune systems, 95%

of those infected become asymptomatic chronic
HBV carriers, compared with 30% of children
infected over the age of 6 years
Most (70%) of primary infections with HBV in
adults are asymptomatic and self-limiting, with
clearance of virus from the blood and liver, and
lasting immunity to re-infection.
However, about 30% of adults with acute HBV
may have symptomatic icteric hepatitis
Patients who develop chronic HBV have a 10% to
30% risk of developing cirrhosis, particularly older
patients with high levels of HBV DNA, or patients
with hepatitis C, hepatitis D, or HIV co-infection.

Hepatitis B

Hepatitis B virus (HBV) is a DNA-containing

virus of the Hepadnaviridae family.
The virus is present in most body fluids in
individuals with acute or chronic hepatitis and in
inactive carriers.
It is transmitted parenterally for example, as a
result of sharing needles. Oral transmission is
unlikely.
Sexual contact is a frequent cause.
Unvaccinated health-care workers are a high-risk
group due to the risk of needlestick injury.
In endemic areas, hepatitis B is often
transmitted vertically or horizontally amongst
young children playing together (through biting

Acute hepatitis B

The World Health Organization (WHO) estimates that

over 5 million cases of acute hepatitis B infection
occur annually
The incubation period for HBV is 60 days, and it can
vary from 28 to 160 days.
Approximately 30% of infections among adults
present as icteric hepatitis, and 0.10.5% of
patients develop fulminant hepatitis.
When fulminant hepatitis occurs, the immune
response to infected hepatocytes is overwhelming
and there is often no evidence of viral replication.
Testing for HB s Ag may be negative; there is
therefore a need for further anti-HB c (IgM) testing

WGO Practice Guidelines, 2007

Acute HBV

HBV infection leads to one of four outcomes:

Recovery after acute infection (> 95% in previously healthy adults over
the age of 40)
Fulminant hepatitis
Chronic hepatitis B
Inactive carrier state

Transmission

HBV is transmitted through body fluids such as blood, saliva, and

semen (it is controversial whether there is transmission through
breast milk).
The route may bePerinatal (from mother to baby at birth; vertical)
From child to child (horizontal)
From unsafe injections and transfusions (parenteral)
Nonsterile instruments, tattoo needles, dental equipment, other sharp
objects used, for example, in scarification or female circumcision
Sexual contact Unprotected sex (whether heterosexual or
homosexual)

WGO Practice Guidelines, 2007

HBV antibody development

Serological tests are available commercially

for a variety of antigens and antibodies
associated with HBV infection.
In a suspected acute infection, HB s Ag will be
positive
and should have cleared within 36 months
after the cute onset (a follow-up re-check
should always be carried out).
It is impossible to distinguish acute hepatitis B
from a flare-up of chronic hepatitis B without
follow-up this is essential in all cases.

WGO Practice Guidelines, 2007

Hepatitis B serologic marker interpretation

Symptoms

Principal

Fatigue and tiredness

Malaise
Jaundice
Fever
Muscle and joint aches

Less commons

Weight loss
Depression
Anxiety, irritability
Headaches
Sleep disturbance
Discomfort in the abdomen on the right side
Itching
Nausea and diarrhea
Appetite loss

WGO Practice Guidelines, 2007

Management

Spontaneous recovery occurs after acute infection

with HBV occurs in 9599% of previously healthy
adults.
Antiviral therapy is not therefore likely to improve the
rate of recovery and is not required unless the
disease is accompanied by a nonhepatic
complication such as periarteritis nodosa.
In such cases, and in immunocompromised individuals
(e.g., those with chronic renal failure), antiviral therapy
with lamivudine may be recommended.
In fulminant hepatitis, meticulous intensive care
may improve the survival, but orthotopic liver
transplantation is the only therapy that has been shown
to improve patient outcomes

WGO Practice Guidelines, 2007

Prevention

Recombinant or genetically engineered vaccines

are made using HB s Ag synthesized in yeast
(Saccharomyces cerevisiae) or in mammalian cells
into which the HB s Ag gene has been inserted.
Both consist of a suspension of HB surface
antigen. Each country has different preparations.
Human plasma-derived vaccines (PDVs) are prepared
from purified HB s Ag from the plasma of individuals
with chronic HBV infection. There are more than 15
different PDVs licensed throughout the world
There are no significant differences between the two
types of vaccine with regard to safety,
immunogenicity, or efficacy

WGO Practice Guidelines, 2007

Post exposure vaccination

A combination of hepatitis B immunoglobulin

(HBIg), when available, and HBV vaccine is
recommended. If HBIg is available (in most
countries it is not), it should be given to all
children of HB s -positive mothers at the
time of delivery. This is particularly important
in neonates, in whom an immediate start of
ostexposure immunization will prevent
infection in infants of HBV-infected mothers.
It is important to vaccinate within 24 hours.
There is no evidence of a protective effect if the
vaccine is given more than 7 days after delivery.

WGO Practice Guidelines, 2007

Post exposure vaccination

Direct exposure (percutaneous inoculation or

transmucosal exposure) to HBsAg-positive body
fluid (e.g., needlestick injury):

HBIg single intramuscular dose of 0.06 mL/kg (as soon

as possible)
Followed by a complete course of HBV vaccination
(initiated within 7 days)

Direct exposure following sexual contact with an

individual with HBV:

HBIg single intramuscular dose of 0.06 mL/kg (within 14

days; very expensive and not affordable in most places)
Accompanied by a complete course of HBV vaccination
(do not wait!).

WGO Practice Guidelines, 2007

Chronic HBV

Distribution of hepatitis B virus genotypes

and subgenotypes

Life cycle of hepatitis B virus

Groups That Should Be Routinely Screened

For Hepatitis B

Persons born in regions of the world where hepatitis B prevalence is

2% or higher (including Africa, Asia, Pacifi c Islands,
Middle East, Eastern Europe, Spain, Malta, Mexico, Central America,
the Caribbean, areas of South America, and indigenous
populations in Alaska, Northern Canada, and Greenland)
Injection drug users
Men who have sex with men
Persons with conditions that may require immunosuppressive or
immune-modifying therapy
Persons with elevated liver enzymes of unknown etiology (ALT; AST)
Blood or tissue donors b
Pregnant women b
Infants born to HBV-infected mothers
Hemodialysis patients
Household members or sexual contacts of HBV-infected persons
HIV-positive persons

Hepatitis B

Hepatitis B serologic marker interpretation

HBV screening in pregnancy

Approved Therapies for the Treatment of

Hepatitis B

Algorithm for selection of children for HBV

antiviral treatment

Initial evaluation
1. History and physical examination
2. Family History of liver disease, HCC
3. Laboratory tests to assess liver diseasecomplete blood
counts with platelets, hepatic panel, and prothrombin time
4. Tests for HBV replicationHBeAg/anti-HBe, HBV DNA
5. Tests to rule out viral coinfectionsanti-HCV, anti-HDV (in
persons from countries where HDV infection is common
and in those with history of injection drug use), and antiHIV in those at risk
6. Tests to screen for HCCAFP at baseline and, in high risk
patients, ultrasound
7. Consider liver biopsy to grade and stage liver disease for patients who meet criteria for chronic hepatitis

Suggested follow-up for patients not considered for

treatment HBeAg + , HBV DNA > 20,000 IU/mL and normal
ALT

ALT q 3-6 months, more often if ALT becomes

elevated
If ALT levels are between 1-2 x ULN, recheck
ALT q1-3 months; consider liver biopsy if age
> 40, ALT borderline or mildly elevated on
serial tests. Consider treatment if biopsy
shows moderate/severe inflammation or
significant fibrosis
If ALT > 2 x ULN for 3-6 months and HBeAg + ,
HBV DNA > 20,000 IU/mL, consider liver
biopsy and treatment
Consider screening for HCC in relevant
population

Inactive HBsAg carrier state

ALT q 3 months for 1 year, if persistently

normal, ALT q 6-12 months
If ALT > 1-2 x ULN, check serum HBV DNA
level and exclude other causes of liver
disease. Consider liver biopsy if ALT borderline
or mildly elevated on serial tests or if HBV
DNA persistently 2,000 IU/mL. Consider
treatment if biopsy shows moderate/severe
inflammation or significant fibrosis
Consider screening for HCC in relevant
population

Responses to Approved Antiviral Therapies Among

Treatment-Naive Patients
with HBeAg-Negative Chronic Hepatitis B

Adjustment of Adult Dosage of Nucleosid(t)e

Analogue in Accordance with Creatinine Clearence

Comparison of Approved Treatments of

Chronic Hepatitis B

Recommendations for Treatment of Chronic

Hepatitis B

Recommendations for Treatment of Chronic

Hepatitis B

Management of Antiviral-Resistant HBV

Hepatitis C

Hepatitis C Virus
Genome

resembled
that
of
a
flavivirus
positive stranded RNA genome of around 10,000 bases
1 single reading frame, structural genes at the 5' end, the non-structural
genes
at
the
3'
end.
enveloped virus, virion thought to 30-60nm in diameter
morphological structure remains unknown
HCV

has been classified into a total of six genotypes (type 1 to

6) on the basis of phylogenetic analysis
Genotype 1 and 4 has a poorer prognosis and response to
interferon therapy,
In Hong Kong, genotype 1 accounts for around 67% of cases
and genotype 6 around 25%.

Hepatitis C - Clinical
Features
Incubation period:
Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice):
30%)

30-40% (20-

Chronic hepatitis:

70%

Persistent infection:

85-100%

Immunity:

No protective
antibody
response identified

WHO., 2009

Chronic Hepatitis C Infection

The spectrum of chronic hepatitis C infection is

essentially the same as chronic hepatitis B
infection.

All the manifestations of chronic hepatitis B

infection may be seen, albeit with a lower
frequency i.e. chronic persistent hepatitis, chronic
active hepatitis, cirrhosis, and hepatocellular
carcinoma.

Hepatitis C Virus Infection

Typical Serologic Course
antiHCV

Symptom
s

Titr
e

ALT

Normal
0

3
4
Month
s

2
3
Years

Time after Exposure

Risk Factors Associated

with Transmission of
HCV

Transfusion or transplant from infected

donor
Injecting drug use
Hemodialysis (yrs on treatment)
Accidental injuries with needles/sharps
Sexual/household exposure to anti-HCVpositive contact
Multiple sex partners
Birth to HCV-infected mother

MFMER., 2013

Laboratory Diagnosis

HCV antibody - generally used to diagnose hepatitis C

infection. Not useful in the acute phase as it takes at least 4
weeks after infection before antibody appears.

HCV-RNA - various techniques are available e.g. PCR and

branched DNA. May be used to diagnose HCV infection in
the acute phase. However, its main use is in monitoring the
response to antiviral therapy.

HCV-antigen - an EIA for HCV antigen is available. It is

used in the same capacity as HCV-RNA tests but is much
easier to carry out.

Treatment

Interferon - may be considered for patients with

chronic active hepatitis. The response rate is
around 50% but 50% of responders will relapse
upon withdrawal of treatment.

Ribavirin - there is less experience with ribavirin

than interferon. However, recent studies suggest
that a combination of interferon and ribavirin is
more effective than interferon alone.

Monitoring of on-therapy response during dual or

triple therapy: definitions of virological response levels

Prevention of
Hepatitis C
Screening of blood, organ, tissue
donors
High-risk behavior modification
Blood and body fluid precautions

References

Jonas, M.M., Block, J.M., Haber, B.A., et al. 2010.

Treatment of Children With Chronic Hepatitis B Virus
Infection in the United States: Patient Selectionand
Therapeutic Options. Hepatology. 1-14.
Apuzzio, J., Block, J.M., Cullison, S., et al. 2012. Chronic
Hepatitis B in Pregnancy A Workshop Consensus
Statement on Screening, Evaluation, and Management.
The female patient.com
WGO Practice Guidelines. 2007.
Mayo Foundation for Medical Education and Research
(MFMER). 2013
EASL Clinical Practice Guidelines: Management of
hepatitis C
virus infection. 2014

Hepatitis berlanjut ke serosis berlanjut ke

HCC ( hepatitis cerosis carcinoma)

Hbsag, anti hbc, anti hbc, anti