Update on Hepatitis C
Hepatitis B Revised
Recommendations
Authors: Mark D.
Hennessy, M.D.
Objectives: Upon the completion of
this CNE article, the reader will be able to:
1. Discuss the impact of Hepatitis B
infections on healthcare and the diagnostic work-up of the patient infected
with this virus.
2. Describe the different ways in which
the Hepatitis B virus can be transmitted between adults and to children through
perinatal transmission and breastfeeding.
3. Discuss the effectiveness of and
recommendations for immunoprophylaxis against Hepatitis B and the potential
treatment options for chronic infections.
4. Explain future concerns regarding the
emergence of mutant strains of the hepatitis B virus.
Background and Healthcare Impact:
Hepatitis
B was the first primary hepatitis virus discovered and reported upon in JAMA by
Blumberg et al in 1965. Because the spread of this virus is primarily by a
percutaneous or permucosal pathway, it was originally called serum
hepatitis. Hepatitis B (HBV) is a
circular DNA virus that is 42 nanometers in size. It is unique in that it is
double stranded for two-thirds of its length and single stranded for the
remaining third. It also contains its own DNA polymerase enzyme. None distinct
subtypes exist. These are primarily important when performing epidemiology
studies. All HBV particles contain a group-reactive determinant labeled “a”
along with 2 sets of sub-determinants designated “d” or “y” and “w” or “r”. The
“w” was then found to have 4 different variants w1, w2, w3,
and w4. Thus, eight distinct subtypes have been identified, which
are ayw1, ayw2, ayw3, ayw4, ayr,
adw2, adw3, adw4 and adr. With the boom of
genetics in the past 10 to 20 years, hepatitis B has now been sequenced and
there are 10 genotypes labeled A to J. Genotype A is the most prevalent in
North America and Europe along with Genotype G; Genotypes B & C are
dominant in Asia and Southeast Asia; Genotype D is more predominant in the Middle
East; Genotype E is in Sub-Saharan Africa; Genotypes F & H are Central and South America;
Genotype I is Southeast Asia; and Genotype J is mostly in Japan. It is
important to know, however, that several Genotypes can be found in any given
region around the world.
Many patients are at increased risk for being a chronic
carrier of Hepatitis B. These include the ethnic groups of Asians, Eskimos,
Pacific Islanders, Haitians, and Sub-Saharan Africans. Other risk factors
include male homosexual activity, prostitution, intravenous drug usage,
patients with multiple tattoos, prior blood transfusion recipients,
hemodialysis patients, hemophiliacs or other patients with bleeding disorders,
and individuals who work in hospitals or chronic care facilities.
At the present time, there are 350 to 400 million carriers
worldwide. The carrier rate in the United States ranges between 0.1% and 1%
depending upon the population tested (or from 1 in 100 to 1 in 1000 persons).
Individuals who become chronically infected have a 10% to 25% chance of
progressing to cirrhosis and a 200-fold increased risk for developing
hepatocellular carcinoma.
If an adult becomes acutely infected, there is about a 10%
chance of becoming a chronic carrier. This chronic carrier state can lead to
the development of chronic persistent hepatitis, chronic active hepatitis,
cirrhosis, or hepatocellular carcinoma, as stated above. Table 1 puts this information into better
perspective.
Table 1: Significance of an acute HBV infection in the
adult population
(Assuming
1000 Adults are infected)
·
Number with symptoms 250
·
Number asymptomatic 750
·
Number of fulminant cases (liver failure, DIC,
etc.) 1 to 5
·
Number who become chronic carriers 100
·
Number who develop cirrhosis / hepatocellular
carcinoma 15 to 25
Diagnosis:
The laboratory testing involved with Hepatitis B is one of
the more difficult areas in understanding this infection. In the general laboratory evaluation, 6
distinct blood tests are available, which are:
1. Hepatitis B
surface antigen (HBsAg) (originally called the Australia Antigen)
2. Antibody to
hepatitis B surface antigen (anti-HBsAg)
3. Antibody to
hepatitis B core antigen (anti-HBcAg)
4. Hepatitis B e
antigen (HBeAg) and
5. Antibody to
hepatitis B e antigen (anti-HBeAg).
6. Hepatitis B
DNA viral load
The IgG antibody to the hepatitis B
core antigen develops shortly after infection and usually remains positive for
life. Some laboratories also offer an IgM antibody to the core antigen and this
in conjunction with a positive HBsAg is more indicative of an acute HBV
infection. The hepatitis B core antigen
itself (HBcAg) is not available as a blood test. It is demonstrated primarily in liver biopsy
specimens.
The other marker that develops shortly after infection is the
presence of hepatitis B surface antigen or HBsAg and this remains positive until
the patient becomes immune. If immunity occurs, then the antibody to the
hepatitis B surface antigen or anti-HBsAg develops. There is a subset of the
population that never produces an antibody to the surface antigen and these
patients are considered to be chronically infected or are chronic
carriers. The presence of an e antigen
only signifies active viral replication and a more infectious disease state.
The presence of antibody to the e antigen implies that the patient has a lower
infectivity capability but does not exclude the possibility of transmission.
A patient who becomes immune to a hepatitis B infection will
be positive for anti-HBcAg as well as anti-HBsAg. Over a long period of time,
the antibody to the surface antigen may become non-detectable; whereas, the
presence of the anti-HBcAg usually remains positive.
Patients who become chronic carriers will also have a
positive anti-HBcAg, however, they never produce the anti-HBsAg. Instead,
chronic carriers will continue to be HBsAg positive. Therefore, a positive IgG
anti-HBcAg only denotes that an HBV infection occurred sometime in the past.
The anti-HBcAg antibody is not protective and does not kill the virus. On the other hand, the anti-HBsAg antibody is
protective and does result in immunity. A breakdown of the potential laboratory
results is seen in Table 2 along with an explanation for the laboratory
findings.
Table 2: The potential meaning of various Hepatitis B
blood test results.
Possible
Results
|
HBsAg
|
Anti-HBsAg
|
Anti-HBcAg
|
HBeAg
|
Anti-HBeAg
|
1.
|
+
|
–
|
–
|
–
|
–
|
2.
|
+
|
–
|
+
|
+
|
–
|
3.
|
+
|
–
|
+
|
–
|
+
|
4.
|
+
|
–
|
+
|
–
|
–
|
5.
|
–
|
–
|
+
|
–
|
+/–
|
6.
|
–
|
+
|
+
|
–
|
+/–
|
7.
|
–
|
+
|
–
|
–
|
–
|
8.
|
+
|
+
|
+
|
+/–
|
+/– *
|
1. Acute HBV infection (very early
stages)** or chronic HBV carrier state (with low levels of non-detected
anti-HBcAg).
2. Acute
HBV infection** or chronic HBV carrier state (that is highly infectious).
3. Acute HBV infection** (later stages) or
chronic HBV infection (lower infectious status, but still infectious).
4. Acute HBV infection** or chronic HBV
infection (without HBeAg or Anti-HBeAg).***
5. Window state between the disappearance
of HBsAg prior to the development of anti-HBsAg** or evidence of past HBV
infection with a low level undetected anti-HBsAg.
6. Recovery
from acute infection or infection in the remote past (now immune).
7. Infection in the remote past with a low
level undetected anti-HBcAg or a person who is status post hepatitis B
vaccination.
8. Late acute infection with early
detection of antibodies (anti-HBsAg and anti-HBeAg) prior to the disappearance
of the antigens, HBsAg and HBeAg, or a very rare unusual entity where the HBsAg
is one serotype of the anti-HBsAg is for a different serotype.
* HBeAg and anti-HBeAg essentially never
exist at the same time. However, the ability to detect antibodies has improved so
much that this may occur transiently when a patient is developing anti-HBeAg as
the HBeAg is disappearing.
** In this setting, an anti-HBcAg IgM
antibody test might be helpful since a positive IgM denotes recent infection.
*** In
some patients, HBeAg and anti-HBeAg never develop.
Transmission of HBV:
The transmission of hepatitis B is through a percutaneous or
permucosal route. Therefore,
transmission from person to person primarily occurs in the following ways:
·
Through Blood or Blood Products
·
Through IV Drug abuse
·
Through contaminated or unsterilized needles
(i.e. tattooing, ear-piercing, acupuncture, and needle sticks in the healthcare
setting)
·
Sexually
·
Perinatal Transmission
·
Contact through breaks in the skin or through
mucus membranes (i.e. a splash in the eyes with contaminated fluid)
Hepatitis B surface antigen has been detected in all body
fluids with the highest concentrations found in blood, saliva, and semen. Transmission
of HBV through blood products at one time was a significant problem; however,
now through the advent of testing donated blood, this risk is down to
approximately 1 in 200,000 units transfused. The percutaneous spread is still
significant in the IV drug abuse population and other exposures to potentially
infected needles. This is due to the very high viral loads that are seen with
this infection. For example, a high viral load for someone infected with HIV or
Hepatitis C (HCV) is at concentrations of 104 to 106
viral particles per ml of blood. In comparison, viral loads for Hepatitis B can
reach levels of 1013 viral particles per ml of blood. Therefore, the
risk of becoming infected following a needle stick exposure to HBV is much
greater than the risk of becoming infected with HIV or HCV.
Sexual transmission is also significant when compared to
other viral infections. Up to 40% of spouses will become infected after contact
with a partner who has an acute infection.
This rate is lower per contact if the partner is a chronic carrier;
however, it increases based on the number of exposures. Perinatal transmission
is a significant problem in parts of Asia and Sub-Saharan Africa and is a major
concern because of the high rate of chronic carriers that develop. This is
discussed further below.
With
Hepatitis B, once infected the disease onset is slow and insidious. The first
thing to appear (usually within 1 to 4 weeks) is the presence of HBsAg. This is
followed by the development of anti-HBcAg. The elevation in liver function
tests and the occurrence of clinical symptoms (including jaundice, dark urine,
light colored stools, and right upper quadrant pain) can take 1 to 6 months to
develop with an average of 2 to 3 months. The majority of patients
(approximately 75%), however, do not have clinical symptoms that result in a
diagnosis of hepatitis. Many of these will be asymptomatic or only have
prodromal symptoms similar to that of the flu.
Vertical Transmission of HBV:
Vertical transmission of the hepatitis B virus from the
mother to the neonate is a major concern. Studies have shown that up to 70% to
90% of neonates can become chronic carriers of the disease if they do not
receive appropriate immunoprophylaxis following delivery, especially if the
mother is HBeAg positive or has an acute infection in the third trimester. It
is important to note that even if the HBsAg positive mother is HBeAg negative
or even if she has a positive anti-HBeAg antibody, transmission to the neonate
can still occur and immunoprophylaxis is indicated. A similar significance
table is presented in Table 3. Note the differences in potential long-term
outcome of a neonate infected with hepatitis B compared to that of an
adult.
Table 3: Significance of an acute
HBV infection in the newborn population
(Assuming
1000 Neonates are infected)
(Assuming
an equal distribution of patients – HBeAg positive & negative)
·
Number with symptoms 250
·
Number asymptomatic 750
·
Number of fulminant cases (liver failure, DIC,
etc.) 1 to 5
·
Number who become chronic carriers 600
·
Number who develop cirrhosis / hepatocellular
carcinoma 150
The transmission from the mother to the infant primarily
occurs at the time of birth due to exposure to infected maternal blood or
vaginal secretions. The recommended treatment of the newborn that is delivered
of an HBsAg positive mother involves a dose of hepatitis B immune globulin
(HBIG) followed by the hepatitis B vaccine series (given at birth, one month,
and six months). If an infant receives this prophylaxis following delivery, the
risk that the child will become a chronic carrier falls to about 5% to
10%.
Breastfeeding in a patient who is HBsAg positive is
controversial. HBsAg has been found in breast milk in several studies; however,
most of these have not shown an increase in the neonatal infection rate. It is
of utmost importance, however, that these infants are adequately treated with
both HBIG and the full vaccine protocol.
Several studies evaluated populations of pregnant women to
determine the incidence of a positive HBsAg result. These studies found that
only 50% of hepatitis B surface antigen positive mothers would be identified if
screening were only performed for risk factors. Due to these studies, the
Centers for Disease Control and the American College of Obstetricians and
Gynecologists, recommended that routine prenatal blood test screening include
the hepatitis B surface antigen blood test.
Since the development of the hepatitis B vaccine in 1982, the
rate of acute hepatitis B viral infections in the United States has not
changed. Epidemiology studies revealed that approximately 200,000 to 300,000
acute HBV infections occur in the United States each year. Perinatal hepatitis
B infections only accounted for a small proportion of the total picture
(approximately 20,000 cases). Research has shown that there is a significant
incidence of child-to-child transmission of this virus. Therefore, the American
Academy of Pediatrics and the Centers for Disease Control now recommend that
all children receive the hepatitis B vaccine series in a hope that this will prevent
future child-to-child transmissions and sexual transmissions and eventually
decrease the rate of new cases in the United States.
Treatment:
Unfortunately, there is no certain cure for hepatitis B once
a person becomes infected. The treatment of chronic carriers of Hepatitis B
primarily consisted of interferon alpha-2b alone or in combination with other
treatment modalities. This treatment was similar to the treatment of chronic
Hepatitis C infected individuals. However, long-term effectiveness is seen in
less than 50% of treated individuals. More recently, several new drugs (that
are related to the research on HIV) have been developed and marketed. These are
Lamivudine, Entecavir, Adefovir, Telbivudine, and Tenofovir. Many of these have
been reported to drop a patient’s DNA viral load to undetectable; however,
resistance has developed along with reactivations (patients with a negative
viral load that then turns positive again).
Overall, the best treatment approach for HBV is to prevent
infection through the use of immunization. If a person is exposed to the virus
through blood or sexual transmission, the treatment requires both hepatitis B
immune globulin (HBIG) in conjunction with the hepatitis B vaccine. If a person
wants to prevent a future risk of infection, the treatment primarily involves
the hepatitis B vaccine series. One recent concern that has developed is the
potential that some of the current testing for hepatitis B infection may not
identify all of the mutant strains of hepatitis B that beginning to develop.
Likewise, there is a concern that the vaccine might not cover all strains
(mutants) in the future. However, for now, Table
4 below depicts one approach to managing HBV immunoprophylaxis.
Because the risk of becoming infected and developing a
chronic care status is much higher for a newborn exposed at the time of
delivery, recent studies have looked at treating women prior to birth to lower
the DNA viral load. These studies have involved small numbers and have usually
used lamivudine, tenofovir, and telbivudine. Most recommend using a viral load
cutoff value of a million (106); however, some have suggested a
value of 200,000 IU/mL. In addition, no specific drug has been recommended as
first line other than a suggestion of using tenofovir first, due to a lower
rate of postpartum flare.
The immunogenicity of the hepatitis B vaccine is excellent
with over 90% to 95% of the vaccinated population developing antibody to the
hepatitis B surface antigen following the third injection. It is important to note that the site of
vaccine injection is important. Adults
should receive an intramuscular injection (IM) in the deltoid region.
Intradermal injections and gluteal injections have resulted in lower response rates.
For infants, an injection in the anterolateral thigh is preferable due to the
smaller deltoid muscles.
The original vaccine, Heptavax, was created by purifying
HBsAg from the blood of carriers. When a person is infected with HBV and is a
chronic carrier, their blood contains the full virion, which consists of the
core DNA encapsulated by the HBsAg surface protein material. In addition, their
blood will contain millions of tubules and 22 nanometer spheres that consist of
only the HBsAg protein. These spheres of HBsAg were purified to create the
original vaccine. The vaccine was extremely safe because it went through a
3-step purification process of pepsin, urea, and formalin. However, the vaccine
today is created in the laboratory through recombinant DNA in yeast, and
therefore does not carry any risk for transmitting infection. The most common vaccines
are Recombivax and Engerix-B, but others are Elovav B, Genevac B, and Shanvac
B. There is a Twinrix vaccine that immunizes for both Hepatitis A and Hepatitis
B.
Table 4: Recommendations for Immunoprophylaxis of
Hepatitis B
I. Perinatal
Exposure:
Give 0.5 cc of HBIG
at birth followed by 0.5 cc of the hepatitis B vaccine* within 7 days of birth
(most now give the vaccine at the same time as HBIG in opposite anterolateral
thighs). The vaccine is repeated at one
month of age and at 6 months of age.
Then check for HBsAg and anti-HBsAg at 12 to 15 months of age (the
presence of HBsAg signifies treatment failure whereas the presence of
anti-HBsAg signifies treatment success).
If both are negative, a vaccine booster should be given.
II. Postexposure prophylaxis against a
known HBV carrier – but the exposed individual has been vaccinated:
Check for the
presence of anti-HBsAg and if positive, no treatment is indicated. If negative, give 0.06 cc/kg of HBIG single
injection ASAP (but within 14 days) of contact along with a booster injection
of the vaccine.
III. Postexposure prophylaxis from a known
HBV carrier – but the exposed individual has not been vaccinated:
Give 0.06 cc/kg of
HBIG single injection ASAP (but within 14 days) of contact and administer the
vaccine series. Another option is to
first draw blood from the exposed person for anti-HBcAg/anti-HBsAg and then
give 0.06 cc/kg of HBIG single injection.
If the test results are negative then administer the vaccine series, if
positive, the exposed person was already previously infected, and the vaccine
is not indicated.
IV. Postexposure prophylaxis from a known
source with unknown HBsAg testing status – but the exposed individual has been
vaccinated:
Test the source for
HBsAg and the exposed person for anti-HBsAg.
If the exposed individual is positive for anti-HBsAg, then no treatment
is indicated. If the source is positive
and the exposed person is negative for the antibody, give 0.06 cc/kg of HBIG
single injection and administer a vaccine booster. If the source is HBsAg negative but the
exposed individual is also negative for the antibody, only administer the
vaccine booster.
V. Postexposure prophylaxis from a known
source with unknown HBsAg testing status – and the exposed individual has not
been vaccinated:
Test the source for
HBsAg and the exposed person for anti-HBcAg/anti-HBsAg. If the source is HBsAg positive and the
exposed individual is negative for the antibodies, give the exposed person 0.06
cc/kg of HBIG single injection and administer the vaccine series. If the source is HBsAg negative and the
exposed individual is negative for the antibodies, then administer the vaccine
series. If the exposed person is
positive for the antibodies, then he or she was already previously infected,
and the vaccine is not indicated.
VI: Postexposure prophylaxis from an
unknown source – but the exposed individual has been vaccinated:
Test the exposed
person for anti-HBsAg. If the test is
positive for the antibody, then no treatment is indicated. If the test is negative for the antibody,
administer a vaccine booster.
VII: Postexposure prophylaxis from an
unknown source – and the exposed individual has not been vaccinated:
Test the exposed
person for anti-HBcAg/anti-HBsAg. If the
exposed individual is negative for the antibodies, administer the vaccine
series. If the exposed individual is
positive for the antibodies, then he or she was already previously infected,
and the vaccine is not indicated.
* Hepatitis B vaccine doses for an
infant and children under the age of 10, is generally 0.5 cc or half the adult
dose. The adult dose and children over
the age of 10 is generally 1.0 cc.
Heptavax comes at a concentration of 20ug of HBsAg per cc, Recombivax HB
is 10ug of HBsAg per cc and Engerix-B is at a concentration of 20ug of HBsAg
per cc.
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Dr. Hennessy is currently an Associate Professor in the Department of Obstetrics & Gynecology at the University of Tennessee Graduate School of Medicine. Dr. Hennessy has multiple publications in peer review medical journals and he has given lectures on a wide variety of medical topics to nurses, medical students, physician assistants, and residents. His medical institution has numerous certified residencies in nearly all fields of medicine and a nationally certified school of nursing.