KEY FACTS ABOUT
HEPATITIS B
The hepatitis B virus is 100 times more contagious than HIV, the virus that causes AIDS. Hepatitis B is spread through blood and other bodily fluids. Common modes of transmission include sexual contact; maternal-fetal transmission at birth; sharing toothbrushes or razors; using unsterilized needles for injection drug use, body or earpiercing, tattooing, and acupuncture. Unlike the HIV virus, hepatitis B viral transmission can also occur in settings of continuous close personal contact, such as among family members living together. In approximately 30 to 40 percent of hepatitis B cases, patients cannot determine how or when they acquired the infection.
Hepatitis A -- FA CT SHEET
Hepatitis A, which infects up to 200,000 Americans each year, is a highly contagious virus that attacks the liver. It is spread by the fecal-oral route through close person-to-person contact, or by ingesting contaminated food or water. Symptoms can be debilitating and include fever, fatigue, loss of appetite, nausea, abdominal discomfort, jaundice and dark urine. Infected individuals can unknowingly infect others 2 weeks prior to feeling ill themselves. Up to 22 percent of adult hepatitis A patients require hospitalization and approximately 100 people in this country die every year from the disease.Source: Cohn &
Wolfe Healthcare
The Facts about Hepatitis
A
· Hepatitis A is a
viral infection of the liver spread by
the fecal-oral route through close person-to-person contact or
ingestion of
contaminated food or water
· Hepatitis A is the most common type of hepatitis reported in
the United
States
· Each year, hepatitis A infects at least 1.4 million people
worldwide, and
cases are underreported. In the United States, there are an estimated
134,000
cases annually · Appetite loss· Jaundice· Dark
urine
· In the
United States, those at increased risk include:
· travelers to
areas of high incidence for hepatitis A
· people living in, or relocating to, areas of high incidence
· certain ethnic and geographic populations that experience
cyclic hepatitis A
epidemics, such as native peoples of Alaska and the Americas
· persons engaging in high risk sexual activity (such as men
having sex with
men)
· residents of a community experiencing an outbreak of hepatitis
A
· users of illicit injectable drugs
· persons who have clotting-factor disorders (hemophiliacs and
other recipients
of therapeutic blood products)
· certain institutional workers (e.g., caretakers for the
developmentally
challenged)
· employees of child day-care centers
· laboratory workers who handle live hepatitis A virus
· handlers of primate animals that may be harboring hepatitis A
virus
· Hepatitis A vaccination is also indicated for people with
chronic liver
disease (including alcoholic cirrhosis, chronic hepatitis B, chronic
hepatitis
C, autoimmune hepatitis and primary biliary cirrhosis)
· Outbreaks have also been attributed to food handlers who can
contract
hepatitis A and transmit the hepatitis A virus to others. The Advisory
Committee on Immunization Practices (ACIP) of the Centers for Disease
Control
and Prevention (CDC) states that to decrease the costs associated with
outbreaks, vaccination of food handlers may be considered where it is
deemed
cost-effective
Symptoms
· Fever
· Nausea
· Vomiting
· Diarrhea
· Fatigue
· Abdominal pain
· Appetite loss
· Jaundice
· Dark urine
· Infection
has been shown to be spread:
· by ingestion of contaminated drinking water or ice, uncooked
fruits or
vegetables grown with or washed in contaminated water, or raw or
uncooked
shellfish (oysters, clams or mussels)
· in day-care centers where children have not been
toilet-trained
· by infected food handlers
· after breakdowns in usual sanitary conditions, such as after
floods and other
natural disasters
· through blood transfusions or by sharing contaminated needles
and syringes
Travelers at Risk
· The U.S. Centers
for Disease Control and Prevention (CDC)
recommends hepatitis A vaccination for travelers going to hepatitis A
endemic
areas
Endemic Regions
Consequences of Infection
Original Paper
The
Hepatitis Knowledge Newsletter is edited by F.H. Anderson, MD.,
FRCP(C),
Natalie Rock, BSN, RN, Susan Campbell, RN. Room B-206, Dept. of
Medicine, Van.
Gen. Hosp. 855 W 12th. Vancouver V5Z 1M9. Phone: (604)209-9976 Fax:
(604)875-4429.
The
Newsletter is supported by an
educational grant from Schering Canada Inc. and GlaxoWellcome Canada.
Hepatitis B: A Brief
History:
In 1965, Dr. Blumberg who
was studying haemophilia, found an
antibody
in two patients which
reacted against an antigen from an
Australian Aborigine.
Later the antigen was
found in patients with serum type
hepatitis and was initially
designated "Australian
Antigen". Subsequent study
has shown the Australia
Antigen to be the
hepatitis B surface antigen. Dr. Blumberg
was subsequently
awarded the Nobel Prize
for his discovery. Initially there
appeared to be three
particles associated with
hepatitis B infection: a large
"complete" particle called the
"Dane particle", a small
circular 20nm particle
and an oblong 40nm particle.
Further research
identified the Dane particle as the
hepatitis B viron and the other
two particles as excess
surface protein. This former
terminology is no longer used
and the virus is referred
to according to its structure.
Hepatitis B Virus: A
Complex Structure
The hepatitis B viron
consists of a surface and a core. The
core contains a DNA
polymerase and the e
antigen. The DNA structure is double
stranded and circular.
There are four major
polypeptide reading frames (genes): the
S (surface),
the C (core), the P
(polymerase) and the X (transcriptional
transactivating).
The S gene consists of
three regions, the pre-S1, pre-S2 and
encodes the surface
proteins
(HBsAg).
Very rarely a mutation may occur in the S gene and may abort
the HBsAg with the result
that a person may be HBsAg
negative but still have virus
present as determined by
HBV DNA. The C gene is divided into
two regions,
the
pre-core and the
core, and codes for two different proteins, the Core antigen
(HBcAg) and the e antigen
(HBeAg). A not uncommon mutant is
the pre-core mutant,
which may stop production
of HBeAg, and these persons will
be HBsAg positive,
HBV DNA positive, but
HBeAg negative. A third mutant which
appears to have a
mutant in the core has
been described and is referred to as
HBV2. These patients
are HBsAg positive, but
lack HBeAg and HBV DNA, thus also
anti-HBc.
Another mutant, the YMDD
mutant, will be described at a
later date.
To make it even more
complex, the HBsAg particles are
antigenically complex and
these
antigenic
determinants have been identified. There is a single common
determinant designated a,
and four major subdeterminants
designated d,y,w and r.
Thus, the four major
determinants are: adw, adr, ayw and
ayr.
Multiple Tests are
Available
Because of the complexity
and the antigenic differences of
the virus, there are
a number of tests
available for hepatitis B:
Antigens
HBsAg = presence of the virus
HBcAg = not detected in blood
HBeAg = correlates with the viral replication and infectivity
Antibodies
anti-HBs = antibodies to the surface
anti-HBc = antibodies to the core can be either IgM (acute) or IgG
(chronic)
anti-HBe = antibodies to e and indicates low infectivity and probable
recovery
Other Markers
HBV DNA = indicates virus presence and activity
DNA polymerase = determines the presence of HBV DNA
HBsAg in liver cells (Orcein stain = Shakata cells) = HBsAg inside
hepatocytes
Hep B:The Complexities
Carrier Rates Vary
Greatly
Country and Carrier rate%:
Scandinavia 0.1
USA/Canada 0.1
Spain 2.0
Southern Italy 3.0
Greece 5.0
Hong Kong 15.0
Taiwan 15.0
Alaskan Eskimos 45.0
High Infectivity
Hepatitis B DNA is found
in many body fluids including
saliva, urine, semen and
menstrual blood. It has
also been shown that the virus can
be transmitted by
ingesting contaminated
blood. Hence, hepatitis B may be
transmitted by:
» mother to infant
at the time of birth
» sexually
» horizontally through shared utensils such as razors,
toothbrushes, etc.
» through unsterile instruments such as tattoo needles, dental
equipment, etc.
» parenteral drug use through shared needles, syringes, etc.
» hospital staff through needle prick
» blood sucking arthropods (usually in the tropics)
Extra-Hepatic Associations
Although uncommon, a
number of conditions associated with
hepatitis B
antigen/antibody
complexes have been recognized. These
include:
Key Concepts:
- Chronic liver disease,
including cirrhosis, represents the
10th most common cause of death in the U.S. Viral hepatitis is the
commonest
cause of chronic liver disease with an estimated 1.25 million, 2.7
million and
70,000 individuals with chronic hepatitis B virus (HBV), hepatitis C
virus
(HCV) and hepatitis D virus (HDV) infection, respectively.
- In the U.S., the prevalence of markers of past or chronic HBV
infection is
low until age 12, increasing thereafter, and is similar among males and
females. The factors associated with chronic HBV infection are
ethnicity
(highest in non-Hispanic blacks), number of sexual partners, marital
status,
foreign birth, level of education, and illicit drug use.
- In the U.S., chronic HCV infection is more common in males than
females and
the peak prevalence is in those aged 30-39 years. HCV alone or in
combination
with alcohol accounts for about (60% of newly diagnosed cases of
chronic liver
disease.
- The prevalence of HDV in the U.S. is low. The groups with the highest
prevalence of infection are injection drug users and
multiply-transfused
individuals (e.g. hemophiliacs).
- The risk factors for acquisition of HBV, HCV and HDV are
well-established.
Understanding the modes of transmission is critical in designing
prevention
strategies to reduce the burden of chronic liver disease.
- The geographical distribution of viral genotypes of HBV, HCV and HDV
are
known. Correlations between specific viral genotypes and clinical
outcomes,
such as disease severity and response to anti-viral treatments, are
under
study.
The burden of chronic liver disease in the U.S. is unknown, although
estimates
of prevalence and incidence indicate the chronic viral hepatitis is the
commonest cause of chronic liver disease. The asymptomatic nature of
chronic
liver disease means that many persons affected with disease are
unrecognized.
Three different sources of information are available to estimate the
relative
contribution of HCV, HBV, and HDV to the total burden of chronic liver
disease
in the U.S. These include: (i) death registries; ii) population-based
prevalence and incidence studies; and (iii) convenience samples or
referred
patients. Population-based studies provide the most accurate estimates
of
disease prevalence and incidence, whereas death registries and
convenience
samples generally provide information on the symptomatic subset of
persons with
chronic liver disease.
Table 1. Trends in chronic liver disease and cirrhosis mortality, United States, 1980-1997
1980 1997
Number of deaths 30,583 8 25,175 10
Rank (total)
Age-adjusted death rate/
100,000 Male, age-adjusted
death rate/100,000 Female,
age-adjusted death rate/100,000 12.2 -- -- 7.4 12.4 5.4
CDC: National Vital Statistics Reports
(http://www.cdc.gov/nchs/about/major/dvs/mortdata.htm)
Death Registry Statistics
- Mortality Estimates for Chronic
Liver Disease
The Centers for Disease Control and Prevention (CDC) National Center
for Health
Statistics captures trends in death rates in the United States
(http://ww.cdc.gov/nchs/about/major/dvs/mortdata). In 1997, chronic
liver
disease including cirrhosis ranked as the 10th most frequent cause of
death
(Table 1). Mortality varied by age with a rate of 16.7 per 100,000
among those
45-54 years, 24.1 per 100,000 among those 55-64 years, and 31.4 per
100,000
among those 65-74 years. Death rates among men were twice as high as
women and
rates among blacks and Hispanics were higher than whites. For example,
the
death rate per 100,000 among persons aged 45-64 years was 19.0 for
whites, 27.5
for blacks, and 32.6 for Hispanics. Mortality from cirrhosis and
chronic liver
disease over the past four decades has changed. Death rates increased
steadily
in the 1950s and 1960s, peaked in the mid-1970s, and declined
thereafter. In
1997, the age-adjusted death rate from chronic liver disease and
cirrhosis was
7.4 per 100,000 population, a decline of 38.3% since 1979.
The underlying etiology
of liver disease among those dying
of liver disease also has changed over time. Among the listed causes of
death
due to chronic liver disease in 1989, alcohol was the most common,
present in
46.1%. However, nearly half of the liver-related deaths were of
unspecified
cause and HCV-associated liver disease was underrepresented because
testing for
HCV was not available at the time. A revised estimate of the causes of
death
due to chronic liver disease in the United States between 1970-1988,
based upon
prevalence data from other sources, showed that alcohol alone accounted
for
only 24% of deaths and viral hepatitis accounted for 54% (Figure1).
While useful in
documenting changes in mortality due to
chronic liver disease over time, death registries capture only the most
severe
end of the disease spectrum and interpretation of changes in death rate
can be
difficult in the absence of additional information. For example, a
decline in
death rate may be the result of a change in the rate of detection, a
true
reduction in incidence, or improved survival among prevalent cases.
Table 2. Estimates of chronic disease burden for
viral hepatitis in the United States, 2000
Disease
Burden
HBV
HCV
HDV
Chronic
infections
1.25 million
2.7 million
70,000
Chronic
liver disease
Sources:
NHANES III and CDC, unpublished data
Prevalence of Viral
Hepatitis in the
U.S.
Population-based studies provide the best estimates of the burden of
chronic
HBV disease in the U.S. The population-based NHANES surveys have
provided
useful estimates of the total number of persons infected with chronic
viral
hepatitis in the U.S. (Table 2). NHANES II was conducted between 1976
and 1980
and NHANES III was conducted between 1988 and 1994.
In the NHANES III survey, serum samples from participants were tested
for
anti-HBc first, and if positive, HBsAg and anti-HBs were obtained.
Chronic HBV
infection was defined by the presence of HBsAg and anti-HBc. The
age-adjusted
seroprevalence of HBV infection was 4.9% (95% CI: 4.3%, 5.6%), with
0.5% of
patients having anti-HBc as their only marker of past HBV infection
(1). The
prevalence was similar in males (5.7%, 95% CI: 4.9%, 6.6%) and females
(4.1%,
95% CI: 3.4%, 5.0%). The prevalence of past and chronic HBV infection
was low
until the age of 12 years (Figure 2), thereafter increasing in all
racial
groups. The highest prevalence was in non-Hispanic blacks (Figure 2).
Independent predictors of chronic HBV infection after adjustment for
age were
non-Hispanic black ethnicity, high number of sexual partners, cocaine
use,
divorced or separated marital status, foreign birth, and having less
than a
high school education. However, there were interactions between race,
sociodemographic variables and behavioral risk factors. The increased
prevalence of HBV infection after age 12 (puberty) and the association
of HBV
infection with number of sexual partners and early age of first
intercourse,
are consistent with sexual contact being the primary mode of HBV
transmission.
The relative contribution of injection drug use to the burden of HBV
disease
cannot be discerned from the NHANES data since information on this risk
behavior was not collected. Additionally, NHANES sampled only civilian,
noninstitutionalized persons living in households, which may
underestimate the
seroprevalence of HBV by omitting persons (homeless and incarcerated)
who would
be predicted to be at higher risk of infection.
The seroprevalence of HBV
in the U.S. is low compared to
other areas of the world. However, surveys among specific ethnic
subgroups
within the U.S. highlight focal areas of high prevalence. The
prevalence of
HBsAg-positivity among Alaskan natives was 6.4%, on average, with
prevalence
rates varying from 0-20% in different villages (2). In first-generation
Asian-Americans from Taiwan, mainland China, the Philippines, Vietnam,
Korea
and Japan, HBsAg positivity ranged from 5% to 15%; other serological
markers of
HBV infection ranged from 43% to 65% (3). These high prevalence groups
are
often the target of specific intervention programs (2).
The age-adjusted
seroprevalence of HBV infection was 5.5% in
the NHANES II survey and 4.9% in the NHANES III survey, a difference
that was
not statistically different 1. These data suggest the
prevalence of
HBV did not change significantly between the years 1976 and 1994. Since
routine
immunization of infants only began in 1992 and adolescents in 1995, the
study
time period may be too short to detect the benefits of HBV vaccination
on
disease prevalence (4). Other studies in populations with higher
endemic rates
of HBV infection have demonstrated the positive impact of a
comprehensive
program of infant and childhood vaccination (5, 6). In Taiwan, the
prevalence
of HBV infection (HBsAg-positivity) in children less than 9 years of
age
declined from 10% in 1984, prior to the vaccination program, to <1%
in 1994,
10 years after the implementation of the program. More importantly, the
annual
incidence of hepatocellular carcinoma in children decreased from 0.52
per
100,000 in 1974-1984 to 0.13 per 100,000 in 1984-1986 (5). Thus,
vaccination
programs are changing the seroprevalence of HBV in the world. Prior to
1980,
most countries in Southeast Asia were areas of high HBV endemicity with
seroprevalence rates as high as 15-20%. Now, China is the only country
in Asia
considered to be hyperendemic for HBV infection. Korea, the
Philippines, Taiwan
and Thailand have intermediate endemicity (prevalence rates 2-7%), and
Japan,
Singapore, Sri Lanka and Malaysia have low endemicity (prevalence rates
<2%)
(7).
Table 3. Prevalence of HCV infection in the U.S. and other countries*
Prevalence
Author, Year N Population Anti-HCV HCV RNA Comments
Alter, 2000 21,241 Noninstitutionalized civilians 1.8% 1.3% Excluded incarcerated and
from 89 randomly selected homeless individuals.
locations in U.S. (NHANES III) Oversampled from ages(5
and (60, blacks and
Mexican Americans.
Bellentani, 6,917 Residents of 2 Northern Italian 2.6% 2.3% 69% of eligible residents
1999 towns (Dionysos Study) participated. "Well-to-do"
population - in top 10 per
capita income cities in Italy.
Excluded ages (12 and (65
yrs.
Dubois, 1997 6,283 Volunteers from 4 regions in 1.15% 0.93% Individuals had to be
France who were undergoing registered with the maj
Routine medical check-ups social security system (85%
of residents). Excludes ages
less than 20 and more than
59 yrs.
* Includes only population-based studies
In the NHANES III survey, the prevalence of anti-HCV was 1.8% (95% CI:
1.5%,
2.3%) corresponding to an estimated 3.9 million persons who have been
infected
with HCV8. Again, since this study excluded incarcerated and
homeless individuals, the true seroprevalence may be slightly higher.
The
prevalence of HCV RNA detection among anti-HCV positive persons was
73.9% (95%
CI: 65.8%, 83.0%), which corresponds to an estimated 2.7 million
individuals
with chronic HCV infection. HCV was more prevalent among males (2.5%)
than
females (1.2%) and more prevalent among non-Hispanic blacks (3.2%) than
non-Hispanic whites (1.5%). Those aged 30-39 years had the highest
prevalence
and accounted for 65% of all persons with detectable anti-HCV. The
lowest rates
of anti-HCV detection were among persons aged = 19 or ( 70 years.
Using NHANES III
seroprevalence data and age-specific
incidence rates from the CDC sentinel surveillance study, the annual
incidence
of acute HCV infection in the U.S. over the past 30-40 years has been
estimated
by modeling (9). This model predicts a low incidence period prior to
1965 (0-45
new infections per 100,000 persons), a transition period in the 1970s,
and a
high incidence period in the late 1980s with 100-200 new HCV infections
per
100,000 persons per year. The model predicts that persons born between
1940-1965 would be at greatest lifetime risk of acquiring HCV
infection. The
model also was used to predict changes in prevalence over time. The
number of persons
with infection of ( 20 years' duration, who will be potentially at risk
for
cirrhosis and other complications, was estimated to increase
substantially
before peaking in 2015 (assuming no change in the incidence of HCV
infection
and ignoring the potential benefits of anti-viral therapy).
The prevalence of HCV in
the U.S. varies with the population
studied. For example, in blood donors, the seroprevalence of anti-HCV
is only
0.3%, a lower prevalence than in the general population because blood
donors are
a highly select group of individuals that have been screened for risk
factors
and serologic markers of other infectious agents (10-11). Among
referred or
hospitalized patients with chronic liver disease, HCV infection is
common and
likely represents the "tip of iceberg" in terms of the total
population of HCV-infected individuals. A referred or hospitalized
population
represents the subgroup of HCV-infected persons with more serious
complications
of disease and the demographics of hospitalized patients differs from
that of
HCV-infected persons in the general population.
For example, in the
Central Harlem study, the chronic liver
disease cases were 65% male and 75% African-American and the
case-fatality rate
was 14% (14). The presumed etiology of chronic liver disease was HCV in
12%,
alcohol 29%, and HCV plus alcohol in 46%; the remainder were of other
etiologies (14).
A brief comparison of the
results of NHANES with
population-based surveys from other countries services to highlight
geographical similarities and differences in HCV prevalence (Table 3).
In a
study of 6283 volunteers from 4 of 22 geographical regions in France,
aged 20
to 59 years, the age- and gender-adjusted anti-HCV positive rate was
1.15% (95%
CI: 0.8%, 1.3%) and prevalence was inversely related to
socioprofessional
status (12). In the Dionysos study in Northern Italy, the prevalence of
anti-HCV was 2.6%; prevalence increased with age and, in contrast to
the U.S.,
was more common in women than men (ratio of men to women = 0.7) (13).
Since Hepatitis D is not a reportable disease and not included in the
International Classification of Diseases, population-based data on the
seroprevalence of chronic HDV are not available. An estimated 70,000
persons
have chronic HDV infection in the U.S. (CDC, unpublished data) (Table
2).
Seroprevalence rates in the U.S. vary dramatically depending upon the
subgroup
evaluated but the pattern, in general, is typical of an area of low
endemicity
(15). Seroprevalence is low in blood donors (1.4% to 8%), intermediate
in
residents of mental institutions and other settings of less intense
percutaneous or mucosal exposure, and highest in those with repeated
percutaneous exposures such as injection drug users (20-53%) and
hemophiliacs
(48-80%) (16-19). Among patients with chronic HBV infection referred to
gastroenterologists, the HDV seroprevalence rates vary from 13% to 41%,
average
27% (20, 20A, 21).
Highly endemic areas are
surprisingly disparate
geographically and include the Amazon basin, parts of northern South
America,
parts of Africa, and Romania. In these areas, the HDV seroprevalence is
20% in
HBsAg-positive persons and up to 90% in persons with HBV-associated
chronic
liver disease (15, 21a). Intermediate areas of HDV seroprevalence
include
southern Italy, parts of Eastern Europe, the Middle East, Africa and
some
Pacific Island groups. These areas have prevalence rates up to 15%
among
HBsAg-positive individuals and 30-50% in persons with HBV-associated
liver disease.
As the seroprevalence of HBV infection declines in response to
vaccination
programs, the prevalence of HDV infection can be expected to fall as
well (5,
6). A study from Italy found the prevalence of HDV infection decreased
from
23.4% in 1987 to 14.4% in 1992 among the HBV patients referred to liver
clinics
(22). While ascertainment bias or changes in referral practices may
explain the
change in anti-HDV prevalence between 1987-1992, a lower prevalence of
HDV
infection in the 0-29 years age group but not in the older subjects
suggested
there was a true decline in prevalence (22). In addition to a decreased
pool of
chronic HBsAg carriers, reductions in family size, improved
socioeconomic
conditions, and changes in intravenous drug use behaviors may be
additional
factors that contributed to the decline in prevalence (22).
Incidence of Chronic
Viral Hepatitis
Sentinel surveillance for chronic liver disease is a relatively new
undertaking
of the CDC and provides an additional measure of the disease burden
associated
with chronic viral hepatitis. Beginning in 1998, the CDC began
surveillance for
newly diagnosed cases of chronic liver disease among adults in three
geographically district areas of the U.S. (Connecticut, California and
Oregon).
The goals of surveillance were to provide annual estimates of the
number of
patients with newly diagnosed chronic liver disease within the general
population, determine the proportion of chronic liver disease cases due
to
viral hepatitis, and to examine risk factors and comorbid conditions
that
influenced disease expression.
Data from the first 21
months of surveillance in New Haven
County, Connecticut showed an "incidence" of chronic liver disease of
31/100,000 persons (22a). Hepatitis C virus infection alone or in
combination
with alcohol was the commonest cause of chronic liver disease,
accounting for
58% of cases (22a). Chronic HBV infection alone or in combination with
HCV
accounted for only 4% of cases. In 14% of cases insufficient
information was
available to make a diagnosis. A comparison of this incidence rate to
that of
Jefferson County, Alabama in 1989 (CDC, unpublished data) shows a
substantial
increase in the incidence of chronic liver disease in the past decade
and a
greater proportion of chronic liver disease attributable to HCV
infection
(Figure 3).
Risk Factors for Hepatitis B Virus
Hepatitis B virus is a parenterally transmitted virus which is acquired
from
exposure to infected blood or body secretions. Adolescents and adults
account
for the majority of reported cases of hepatitis B in the U.S. and
sexual
contact is the most common route of transmission. Perinatal and early
childhood
infections are much less frequent.
Perinatal Infection
The CDC estimates that at least 20,000 infants are at risk annually for
HBV
infection through perinatal sources (23). Rates of HBsAg-positivity in
mothers
vary among ethnic groups with higher rates among Asians (foreign-born),
Hispanics and Blacks. The risk of transmission is higher in
HBeAg-positive
mothers. Rates of HBeAg-positivity average 30% among women of Asian
descent and
20% among all other racial groups (24). Identification of
HBsAg-positive
mothers is critical for the prevention of HBV transmission from mother
to infant.
Currently, the CDC estimates that at least 90% of women are being
screened for
HBsAg prior to or at the time or delivery (4). However, the women who
are not
being screened are at greater risk of being HBsAg-positive (25).
Early Childhood Infection
Specific ethnic groups residing in the U.S., including Alaskan Eskimos,
Pacific
Islanders, and infants of first-generation immigrant mothers from
countries of
moderate to high HBV endemicity, are at risk of early childhood
infection. The
estimated risk of HBV acquisition within the first 5 years of life
ranges from
5% to 40% for these children, with the highest risk for infants of
HBsAg-positive mothers who are not infected at birth. Immunization of
infants
as part of the childhood immunization schedule and catch-up vaccination
of
susceptible children is the primary method of preventing infection.
Focused
vaccination programs, which started in the late 1980s, have
successfully
reduced the prevalence of HBV infection in children (6).
Infection Among Adults
Sexual activity is the most common mode of HBV transmission in North
America
and other countries where the prevalence of HBV infection is low. There
was an
initial decline in the incidence of HBV infection among men having sex
with men
in the 1980s, followed a subsequent decline among heterosexual men and
women,
and injection drug users in the 1990s. That being said, injection drug
use and
sexual activities remain the most frequently identified risk factors
among
adults with HBV infection (24). As with perinatal transmission, sexual
transmission is facilitated by active viral replication in the infected
individual (26). Factors positively correlated with HBV infection in
adults are
number of sexual partners, number of years of sexual activity, and a
history of
sexually transmitted diseases (STDs). In general, vaccination coverage
of
adults in high-risk groups, such as men who have sex with men and
patients with
STDs, has been low (27).
In the U.S. and Western
Europe, injection drug use remains
an important mode of HBV transmission. Risk of infection increases with
duration of drug use, so that serological markers of ongoing or prior
HBV
infection are almost universal after five years of use (28).
Other recognized modes of
HBV transmission include working
in a health-care setting (( 3% of cases in the U.S,); and transfusions,
dialysis and other overt blood contacts (1% total). Nosocomial spread
of HBV
infection in hospitals, particularly in dialysis units, has been well
described
(29). HBV infection has been linked to multiple-use heparin vials and
exposure
to contaminated dental instruments and finger-stick devices (24, 29a).
Transmission from health care worker to patient, while rare, has been
reported
(30). Acupuncture has been associated with outbreaks of HBV infection
(31).
In about one-third of
persons with HBV infection, no risk
factor can be identified (32). These persons tend to be of lower
socioeconomic
level and belong to minority populations. Undisclosed sexual risks or
illicit
drug use may account for a proportion of these unknown cases.
Risk Factors for
Hepatitis C Virus Transfusion of infected
blood or
blood products, use of contaminated dialysis equipment, transplantation
of
infected organs, and sharing of contaminated needles among injection
drug users
are well-recognized modes of HCV transmission. Sexual contact and
perinatal
exposure are associated with HCV infection but HCV transmission by
these routes
is relatively inefficient.
The prevalence of
specific risk factors in persons with HCV
infection has changed over the past 10 years. Although transfusion of
HCV-infected blood or blood products was a common mode of HCV
transmission in
the past, this currently represents a rare mode of transmission.
Following the
introduction of blood donor screening and surrogate hepatitis tests,
the
proportion of patients with acute community-acquired hepatitis who
reported a
history of blood transfusion declined from an average of 17% in 1982 -
85, to
6% in 1986-88, to 4% in 1990-93 (33, 34). As transfusion-related cases
of HCV
declined, the proportion attributed to non-transfusion-related causes
increased
(34). Therefore, in cross-sectional studies of risk factors among
persons with
HCV infection, blood transfusion and injection drug use account for an
approximately
equal proportion of cases (about 30% each) in those whose exposure
occurred
more than 10 years ago (33). In persons whose exposure occurred within
the last
10 years, injection drug use is the most common mode of acquisition,
accounting
for 60% of cases (33). The prevalence of other risk factors (e.g.
occupational)
have remained relatively constant over time (33).
In addition to the
changing prevalence of risk factors over
time, the proportion of persons without identifiable risk factors, so
called
"sporadic" HCV infection, has decreased. Among acutely infected
persons identified by the CDC Sentinel Surveillance study between
1989-1994,
33% had no identifiable risk factor. More recently, that proportion has
dropped
to 10% (35). Individuals with "sporadic" infection are characterized
by lower socioeconomic status (in one third), reports of high-risk
behavior
such as imprisonment, a history of one or more STDs, and use of
non-injection
illicit drugs suggesting that some of the "Sporadic" cases may be
secondary
to occult percutaneous exposures (36). Underreporting of past high risk
behaviors such as injection drug use, overlooked transfusions received
in
infancy, and unrecognized percutaneous exposure within the community
may
explain a proportion of the sporadic cases of HCV infection. The
prevalence of
HCV infection is different "risk" groups is summarized in Table 4.
Table 4. Estimated prevalence of hepatitis C in different "at risk" groups
Risk
Factor
Prevalence of HCV
treated
before 1987
Injection
drug users
72 - 89%
Chronic
hemodialysis
0 - 64% (average 10%)
Persons
reporting history of STD
1 - 10% (average 6%)
Persons
receiving blood transfusion
5 - 9%
prior
to 1990
Infants
born to HCV RNA
5% (average)
positive
mothers
Men
who have sex with men
4% (average)
Long-term
sexual partners of
0.5 - 3%
HCV-infected
persons in
monogamous
relationship
Volunteer
blood donors
0.16%
Adapted
from MMWR: Recommendations for prevention and
control of hepatitis C
virus
(HCV) infection and HCV-related chronic
disease. Centers for Disease
Control
and Prevention, 1998;47-5.
Blood Transfusion
Prior to 1985, the incidence of transfusion-associated hepatitis (TAH)
was 8-10
per 100 persons transfused (37). Transfusion practices changed in the
mid-1980's in response to concerns regarding HIV, with a subsequent
fall in the
rate of TAH by about 50% (37). With the introduction of first
generation anti-HCV
tests in the early 1990's, the rate of HCV acquisition via blood
products
declined by a further 80%and current estimates of the incidence of TAH
are
<1% (37). Donation of blood by seronegative donors during the
infectious
window period prior to seroconversion, accounts for the vast majority
of the
current residual risk of TAH (-80%). Nucleic acid testing for HCV RNA
can
reduce the infectious window from 70 days (average) to 10-29 days (38).
Thus,
the use of nucleic acid testing to screen blood products is expected to
reduce
the risk of HCV from 1:100,000 (current risk per unit transfused) to
1:500,000
- 1:1,000,000 (38).
Patients requiring blood
products (clotting factors, immune
globulin) from pooled donors have a high rate of HCV-positivity. The
prevalence
of anti-HCV in patients with hematological disorders who were
transfused with
clotting factors prior to the institution of viral inactivation and
removal
measures, is nearly 100%. Changes in product manufacturing as well as
the use
of screening assays have significantly reduced the incidence of HCV
transmission in this population.
Injection Drug Use
The prevalence of HCV infection among drug users in the U.S. varies
from 72% to
89% (48). The factor most consistently associated with anti-HCV
positivity is
duration of drug use. In the largest study of injection drug users, HIV
coinfection, Black race, drug use within the preceding 6-month period,
and use
of injection cocaine were also found to be independently associated
with HCV
infection (39). Acquisition of HCV infection is rapid among drug users
with
anti-HCV seroprevalence rates of 54%, 78%, 83%, and 94%, among users of
less
than a year, 1 year, 5 years, and more than 10 years, respectively
(39). Among
newly diagnosed cases of chronic liver disease secondary to HCV in
1998, -60%
report an antecedent history of intravenous drug use (CDC, Chronic
Liver
Disease Surveillance, unpublished data).
Dialysis and Other
Nosocomial Sources
Dialysis units are the commonest setting for nosocomial transmission of
HCV. A
1995 national surveillance study of 2647 dialysis centers found an
anti-HCV
prevalence of 10.4% in patients and 2.0% in staff (40). However only
39% and
16% of dialysis units performed routine testing of patients and staff,
respectively. Additionally, serological assays may underestimate the
prevalence
of HCV infection in dialysis patients, since they are relatively
immunocompromised.
Virological assays
identify a greater proportion of infected
individuals (41). The annual incidence of HCV infection in one study
was 3% and
none of the patients who seroconverted had received a transfusion or
used
injection drugs (41a). Dialysis-specific risk factors associated with
anti-HCV
positivity include a history of prior blood transfusion volume of blood
transfused,
and duration of hemodialysis. Failure to ascertain community exposures
to HCV,
such as injection drug use, may lead to an overestimation of the
contribution
of dialysis to risk of HCV acquisition. The mechanism of HCV
transmission in
dialysis units is believed to be breaches in routine dialysis unit
procedures
and precautions (42). Person-to-person transmission of HCV among
patients not
sharing dialysis equipment but treated in the same room has been
documented
(43). Although hemodialysis patients constitute a risk group for HCV
acquisition, they account for only 1% of persons with chronic
infection. Other
than dialysis, nosocomial transmission of HCV is rare in the U.S.
The seroprevalence of
anti-HCV among healthcoare workers in
the U.S. ranges from 0.7 to 2.0% (48). The variability in
seroprevalence
reflects the different exposures associated with specific healthcare
jobs, the
prevalence of HCV in the patient population served by the healthcare
worker,
and the frequency of other risk factors for HCV in the healthcare
worker. The
incidence of HCV seroconversion following needlestick injury or
accidental cuts
with sharp instruments is 1.8% on average (varies from 0% to 7%) (48).
The
presence of viremia in the source is associated with a higher rate of
seroconversion
than if the source is anti-HCV positive alone. Other factors which may
influence the risk of HCV seroconversion include whether the needle was
hollow-bore, the size of the inoculums, and host susceptibility.
Transmission
from physician to patient has been documented with in the context of an
invasive surgical procedure (44) but such reports are extremely rare.
Perinatal Exposure
While passively acquired anti-HCV is frequent in newborns of
HCV-infected
mothers, transmission of infection only occurs in 5% (average) (45,
46).
Factors that have been associated with the risk of transmission are
presence of
HCV viremia, maternal HIV status, and viral titer at the time of
delivery.
Breastfeeding does not appear to increase the risk of HCV transmission
(45).
Table 5. HBV genotypes and serotypes: Geographical distribution
Genomic Areas of High
Group Serotype Prevalence
A adw2 ayw 1 Northwestern Europe,
U.S. Central Africa
B adw2 ayw1 Indonesia, China Vietnam
C adw2 adrq+ East Asia Korea, China, Japan
adrq- ayr Polynesia Vietnam
D ayw2 ayw3 Mediterranean area India
E ayw4 West Africa
F adw4q- Central and South America,
adw2 ayw4 Polynesia
G adw2 France, U.S.
References:Magnius Lo and Norder H, Intervirology 38:24-34, 1995.
Blitz L. Pujol F, Swenson P, et al. J Clin Microbiol 36:648-51,1998.
Stuyver L, De Gendt S, Van Geyt C, et al. J Gen Virol 81:67-74,2000
Risk Factors for
Hepatitis D
Infection
Injection drug use is the commonest mode of HDV transmission in the
U.S. (15).
Sexual transmission of HDV is less efficient than transmission of HBV,
but is a
well-recognized risk factor. In men having sex with men who deny a
history of
injection drug use, the risk of HDV infection increases with the number
of
sexual partners and frequency of rectal intercourse (49). Among
prostitutes,
prevalence rates of HDV range from 6% to 21% with the highest rates
among
prostitutes who also use injection drugs (50).
Chronic Hepatitis B Virus
Four subtypes of HBsAg named adw, ayw, adr and ayr were identified in
the
1970's. An additional nine different subtypes were later identified,
designated
ayw 1-4, adw 1-4, and adrq +/ adrq-. Sequencing of viral genomes and
comparison
of complete genomes in the 1980's led to a reclassification of HBV
heterogeneity into genotypes (Table 5). At the level of the S-gene, a
difference of ( 4% nucleotides defines different HBV genotypes (51).
Table 6. Distribution of HCV genotypes in the U.S.
Author, Year N Population Genotypes (%) 1a 1b 2a
Alter, 2000 250 Randomly selected civilians 57 17 3.5 11 7.4 0.9 3.2
from 89 locations (NHANES III)
Zein, 1996 179 Consecutive patients from 4 58 21 2.0 13 5 1 --tertiary referral centers
Mahaney, 1994 98 Referred for treatment trials 36 38 6.1 9.2 6.1 1.0 --
Reddy, 1996 414 Participants in treatment trial 32 26 5 10 13 -- 9
McHutchison,1998 456 Participants in treatment trial 72 18 9 -- --
Davis, 1998 354 Participants in treatment trial 56 17 25 -- --
While associations
between HBV genotypes and specific
clinical outcomes require further study, an interesting relationship
between
HBV genotype and the G-to-A mutation at nucleotide 1896 in the precore
region
has been elucidated. The precore mutation has been found to be most
frequently
associated with genotype D and rarely associated with genotype A.
Mutations in
the core region in genotype D HBV are predicted to increase the
stability of
the stem-loop structure, which is critical for the viral pregenomic
encapsidation signal, whereas these same mutations in HBV genotype A
have a
destabilizing effect on the stem region (52). Additional studies have
suggested
HBV genotypes may be important determinants of disease severity.
Preliminary
data have linked HBV genotype with responsiveness to interferon among
HBeAg-negative patients (52a) and risk of HCC (53). Genotype D and
total number
of accumulated mutations throughout the HBV precore/core gene have been
associated with more severe recurrent disease following liver
transplantation
(54).
Chronic Hepatitis C Virus
At least six different genotypes and more than 90 subtypes of HCV have
been
identified (55). HCV genotype 1 predominates in the U.S., accounting
for
approximately 65-75% of infections (Table 6). The genotype distribution
among
HCV RNA positive persons in NHANES III was 56.7% type 1a, 17.0% type
1b, 3.5%
type 2a, 11.4% type 2b, 7.4% type 3a, 0.9% type 4 and 3.2% type 6.
There was a
lower prevalence of type 1b and higher prevalence of type 1a in the
NHANES III
study (population-based) compared to referred or treated patient
populations
(Table 6). In other parts of the world, genotypes 1b (Europe, East
Asia), 2a
(Southeast Asia), 3a (India), 4 (Egypt and the Middle East), and 5A
(South
Africa) predominate (Figure 4). The time of divergence of the HCV
genotypes
isolated from different geographical regions has been estimated to be
more than
500-2000 years for viral types and more than 300 years for viral
subtypes (56).
Whether specific HCV
genotypes are associated with more
severe histological disease or greater risk of cirrhosis or
hepatocellular
carcinoma is controversial. For example, several studies, predominantly
from
Europe and Southeast Asia, have found HCV type 1b to be more prevalent
in
patients with cirrhosis and hepatocellular carcinoma than in patients
with
chronic hepatitis or asymptomatic blood donors. This finding is
compatible with
HCV type 1b being more pathogenic, but additional studies have shown
that the
association is likely due to a cohort effect, i.e. there is an
overrepresentation of HCV type 1b among older patients who had a longer
duration of disease (57).
Chronic Hepatitis D Virus
Genetic analyses of HDV isolates from different geographical areas
indicate
there are at least three genotypes (60). Genotype 1 is the most common
and
geographically diverse with distribution in Western Europe, North
Africa, the
Middle East, Turkey, Japan, Taiwan, and the U.S. Genotypes II and III
have a
much more restricted distribution. Type II has been isolated from
patients in
Japan and Taiwan, where it coexists with genotype I. Genotype III has
been
found in patients from Peru and Columbia. These different distribution
patterns
likely reflect interactions between the HDV genotypes and dominant HBV
genotypes in specific geographical areas, such as has been described
for HDV
genotype III and HBV genotype F in northern South America (61). The
genotype
distribution also reflects the migration of populations over time, and
geographical clustering of cases indicate that HDV was introduced
relatively
recently into the U.S. compared to Southern Europe and Northern Africa
(62).
Studies on the relationship between HDV genotype and severity of
disease are
limited. Preliminary studies have linked genotype II with milder
disease and
genotype III with severe disease (63, 20a). Disease severity in
patients with
genotype I appears to vary from mild to severe.
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Chronic Viral Hepatitis in the United
States
Norah Terrault, MD, MPH
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