Public Health Service
Inter-Agency Guidelines for
Screening Donors of Blood, Plasma,
Organs, Tissues, and Semen for Evidence
The Public Health Service staff members listed below
served as authors of Public Health Service
Inter-Agency Guidelines for Screening Donors of
Blood, Plasma, Organs, Tissues and Semen for
Evidence of Hepatitis B and Hepatitis C.
CENTERS FOR DISEASE CONTROL
Coordinator
Miriam J. Alter, Ph.D.
Bruce L. Evatt, M.D.
Harold S. Margolis, M.D.
FOOD AND DRUG ADMINISTRATION
Robin Biswas, M.D.
Jay S. Epstein, M.D.
Stephen M. Feinstone, M.D.
John S. Finlayson, Ph.D.
Donald Tankersley, M.S.
NATIONAL INSTITUTES OF HEALTH
Harvey J. Alter, M.D.
Jay H. Hoofnagle, M.D.
The Hepatitis Branch, Centers for Disease Control, maintains an
automated
telephone system that provides information on the different types
of viral
hepatitis. Messages have been designed for both health-care
professionals
and the lay public. The number is 404-332-4555.
These guidelines address the use of tests for the hepatitis B
and C
viruses to screen donations of blood and plasma collected for
transfusion
or further manufacture into injectable products, as well as to
screen
donors of organs, tissues, and semen. These guidelines are intended
to
serve as a resource to individuals and organizations involved in
testing,
counselling, and evaluating donors tested for these viruses, and
are based
on currently available knowledge.
INTRODUCTION
Several infectious agents transmit through infected blood and
blood
products. To decrease the potential for disease transmission,
donors are
screened for risk factors by medical history and for evidence of
infection
by specific testing. The Food and Drug Administration (FDA)
currently
requires that all donations of whole blood and transfusable
components as
well as plasma for fractionation into injectable derivatives be
subjected
to a serologic test for syphilis, hepatitis B surface antigen
(HBsAg), and
antibody to the human immunodeficiency virus (anti-HIV). The FDA
also
currently recommends testing donations of whole blood and
components for
transfusion for antibody to human T lymphotropic virus type I
(anti-HTLV-I)
and antibody to hepatitis C virus (anti-HCV), and is considering
recommending testing for antibody to hepatitis B core antigen
(anti-HBc).
Blood banks in the United States voluntarily began testing
donations for
anti-HBc and alanine aminotransferase (ALT) in 1986 and 1987 and
for
anti-HCV in 1990.
HEPATITIS B
Background
Post-Transfusion Hepatitis B
The discovery in 1965 of Australia antigen, now referred to as
HBsAg,
and its subsequent association with hepatitis B virus (HBV) led to
the
development of sensitive, specific markers of HBV infection (1-4).
During
acute and chronic HBV infection, HBsAg is produced in excess
amounts,
circulating in blood as both 22-nm spherical and tubular particles.
HBsAg
can be identified in serum 30-60 days after exposure to HBV and
persists
for variable periods depending on the resolution of the infection.
Antibody
to HBsAg (anti-HBs) develops after a resolved infection and is
responsible
for long-term immunity (5). Anti-HBc develops in both resolved
acute
infections and chronic HBV infections and persists indefinitely
(6).
Immunoglobulin M (IgM) anti-HBc appears early in infection and
persists for
greater than or equal to 6 months (7). It is a reliable marker of
acute HBV
infection.
Transmission of HBV by transfusion of blood or blood products
is rare
because of routine screening of blood donors for HBsAg and because
of
current donor selection and deferral procedures. Screening blood
donors for
HBsAg began in 1969 and became mandatory in 1972. Retrospective
testing of
blood donors using first generation tests such as immunodiffusion
to detect
HBsAg, found that 52%-69% of recipients of HBsAg-positive blood
developed
hepatitis B (8,9). In addition, recipients of blood from paid
donors were
at higher risk of developing post-transfusion hepatitis than were
recipients of blood from non-paid donors (10,11). A combination of
more
sensitive third-generation tests (reversed passive hemagglutination
and
radioimmunoassay (RIA)) for HBsAg screening and exclusive use of
non-paid
donors reduced the rate of post-transfusion hepatitis B to
0.3%-0.9%/transfusion recipient by the mid-1970s (12,13).
A small number of HBV carriers appears to circulate HBsAg at
undetectable levels, and anti-HBc may be the only serologic marker
detectable in blood from these individuals. Thus, even with the
greater
than 99% sensitivity of the current tests for HBsAg, including both
RIA and
enzyme immunoassay (EIA), not all HBV carriers are detected by
screening
for HBsAg, and a small number of transfusion recipients still
develop
hepatitis B (14-16). Anti-HBc screening of blood donors was
instituted in
1986 and 1987 as a surrogate marker for non-A, non-B hepatitis
(17,18) and
may have contributed to the prevention of hepatitis B. However,
surveillance data from reported cases of acute hepatitis suggest
that the
incidence of post-transfusion hepatitis B declined before anti-HBc
testing
began (19,20). In the period 1982-1985, an average of 3% of acute
cases of
hepatitis B had a history of blood transfusion in the 6 months
preceding
onset of illness. In the period 1986-1988, the percentage of cases
reporting a history of blood transfusion declined to an average of
1%. Most
of this decline occurred before anti-HBc testing was initiated and
was
temporally associated with changes in the donor population related
to the
prevention of human immunodeficiency virus (HIV) infection. The
current
incidence of post-transfusion hepatitis B is estimated to be around
0.002%/transfusion recipient (21 and CDC, unpublished data).
Modes of Transmission
Transmission of HBV occurs via percutaneous or permucosal
routes, and
infective blood or body fluids can be introduced at birth, through
sexual
contact or by contaminated needles. Infection can also occur in
settings of
continuous close personal contact (such as in households or among
persons
in institutions for the developmentally disabled), presumably via
inapparent or unnoticed contact of infective secretions with skin
lesions
or mucosal surfaces. Persons at increased risk of acquiring HBV
infection
include members of the following groups: a) parenteral drug users,
b)
heterosexual men and women and homosexual men with multiple
partners, c)
household contacts and sexual partners of HBV carriers, d) infants
born to
HBV-infected mothers, e) patients and staff in custodial
institutions for
the developmentally disabled, f) recipients of certain
plasma-derived
products (including patients with congenital coagulation defects),
g)
hemodialysis patients, h) health and public-safety workers who have
contact
with blood, and i) persons born in areas of high HBV endemicity and
their
children.
Persons at risk of exposure to HBV, including those mentioned
above,
who are shown or judged likely to be susceptible should receive
hepatitis B
vaccine (22). Ideally, hepatitis B vaccine should be provided to
such
persons before they engage in behaviors, occupations, or treatments
that
place them at risk of infection. Prophylactic treatment (hepatitis
B immune
globulin and hepatitis B vaccine) to prevent HBV infection after
exposure
to HBV should be provided for infants born to HBsAg-positive
mothers,
persons with accidental percutaneous or permucosal exposure to
HBsAg-positive blood, sexual partners of an HBsAg-positive person,
and
infants less than 12 months of age whose primary care giver has
acute
hepatitis B (22). Hepatitis B vaccine should also be given to all
susceptible household contacts of HBV carriers.
Natural History of Infection
HBV is a major cause of acute and chronic hepatitis, cirrhosis,
and
primary hepatocellular carcinoma worldwide (23). The most serious
consequences of HBV infection are primarily the result of chronic
HBV
infection, which occurs in 6%-10% of infected adults, approximately
25% of
infected children aged 1 to 5 years, and 70%-90% of infected
infants
(23-25). Each year in the United States, an estimated 300,000
persons,
primarily young adults, are infected with HBV. Approximately half
become
ill with jaundice or other symptoms of hepatitis, more than 10,000
patients
require hospitalization, and an average of 350 die of fulminant
disease.
The United States currently contains an estimated pool of
750,000-1,000,000
infectious HBV carriers. Approximately 25% of carriers develop
chronic
active hepatitis, which often progresses to cirrhosis. HBV carriers
also
have a risk of developing primary liver cancer that is 12-300 times
higher
than that of other persons. An estimated 4,000 persons die each
year from
hepatitis B-related cirrhosis, and more than 800 die from hepatitis
B-related liver cancer.
A recent study reported that among patients with compensated
chronic
liver disease due to hepatitis B, alpha interferon was effective in
inducing a sustained loss of HBV replication and achieving
remission,
assessed biochemically and histologically, among over a third of
patients
(26). In about 10% of patients treated with interferon, HBsAg
disappeared
from serum.
Sensitivity of the Available Tests
Sensitive tests are available commercially for the detection of
HBsAg
by either RIA or EIA. Information from the package inserts of these
tests
indicates that the sensitivity of both the RIA and EIA for the
detection of
HBsAg is less than 0.5 ng/ml. As noted previously, despite these
sensitivities, a small number of HBV carriers may have undetectable
levels
of HBsAg and test as a false negative. Most of these low level
HBsAg
carriers, however, will most likely be detected by the anti-HBc
test
currently performed on units of blood or blood components for
transfusion.
Guidelines for Screening
Testing
All donations of whole blood, plasma, and other components
are
required to be tested for HBsAg by a sensitive and specific
FDA
licensed test, such as RIA or EIA (27).
If the initial test result is non-reactive, the unit is
considered
to be non-reactive for HBsAg. The unit may be transfused or
used
for further manufacture into transfusable components,
provided all
other requirements are met.
If the initial test result is reactive, the unit is
considered to
be initially reactive.
The sample should be retested in duplicate in a single
test
run, using a test kit of the same type and from the
same
manufacturer as used for the initial test.
If the repeat test results are both non-reactive, the
unit is
considered to be non-reactive and may be used as
mentioned
earlier. The donor may return for subsequent donations.
If either one or both repeat tests are reactive, the
result is
designated repeatedly reactive and the unit should not
be
transfused or manufactured into other products that do
not
require HBsAg reactive source material. The donor with
repeatedly reactive test results is deferred, but prior
to
notification it is recommended that the results be
confirmed by
neutralization according to the manufacturer's
instructions.
If the neutralization test is positive, the donor is
permanently deferred from future donations.
The donor of a repeatedly reactive unit that is not
confirmed by
neutralization may later, at the discretion of the blood
center, be
considered for reentry as a donor if the procedures are
followed in
accordance with the recommendations of the FDA (28).
It is recommended that a serum sample from donors of
organs,
tissues, or semen intended for human use be tested for
HBsAg using
the same procedures as outlined earlier. Every effort
should be
made to use material only from donors testing negative for
HBsAg.
It is recognized that emergency situations involving
life-supporting organs may arise that do not permit the use
of an
HBsAg test before implantation or that involve the use of
material
from an HBsAg-positive donor. In such situations, the
recipients
should be informed by their medical-care providers that
they will
or have received untested tissue or tissue from an
HBsAg-positive
donor, and prophylaxis with hepatitis B immune globulin and
hepatitis B vaccine (using the dosage recommended for
immunocompromised patients) (22) should be considered.
Notification of Donors
If the repeatedly reactive HBsAg test is confirmed as
positive by
neutralization or if neutralization tests are not
performed, it is
recommended that collection facilities ensure that donors
are
notified of their test results and their permanent deferral
from
donation. It is recommended that notification include
written
information, presented to the donor by sealed letter or at
a
face-to-face interview. Organ or tissue procurement
organizations
should report this information to the donor's physician
when the
donor is deceased.
It is recommended that the information contained in such
notification inform donors that: a) a positive test result
could
indicate that they recently developed hepatitis B or that
they may
have chronic hepatitis; b) they are likely to be infectious
to
others; and c) there is a safe and effective vaccine that
can
prevent the spread of HBV to their household contacts and
sexual
partners. Donors should be referred to their medical-care
provider
to determine the significance of a positive test and the
need for
screening and vaccination of contacts. These
recommendations are
similar to those for HBsAg-positive persons identified in
other
settings (22).
Collecting facilities also should be prepared to provide
the
results of all tests performed related to hepatitis
screening
(e.g., anti-HBc, ALT, and anti-HCV) to donors with a
repeatedly
reactive or confirmed positive HBsAg test result or to
their
physicians. The facility should transmit this information
to the
donors or inform donors that this information can be
forwarded to
their physicians by the facility.
Collecting facilities also should comply with state and
local
requirements for the reporting of HBsAg-positive results
(29). If a
transfusion recipient or a recipient of transplanted tissue
develops hepatitis B, it is recommended that the diagnosing
physician report the case to both the local health
department and
the collection facility.
Recommendations for Medical Evaluation and Counselling
The following information may be of assistance to the
medical-care
provider in evaluating and counselling an HBsAg-positive
individual:
The medical evaluation should first verify that HBsAg is
present
and whether its presence indicates acute or chronic HBV
infection.
A follow-up serum specimen should be tested for HBsAg.
If negative, the donor most likely had a transient
acute
infection.
If HBsAg is still present, testing for IgM anti-HBc
would be
helpful in distinguishing between acute and chronic
hepatitis
B, as this antibody is usually detected only in acute
hepatitis
B. If IgM anti-HBc is not present and/or HBsAg persists
for 6
months, chronic HBV infection is present.
If HBsAg is detected in follow-up specimens, the medical
evaluation
should also include an assessment of the extent of liver
disease.
This evaluation should include a history, physical
examination, and
laboratory studies such as ALT, aspartate aminotransferase
(AST),
bilirubin, albumin, and prothrombin time. If chronic HBV
infection
is present, serial determinations of aminotransferases
would be
appropriate. Patients should also be tested for hepatitis B
e
antigen (HBeAg), a serologic marker of high levels of virus
(30).
Healthy or inactive HBV carriers will have HBsAg but not
HBeAg, and
will have normal aminotransferase levels. The persistence
of HBsAg
with elevated aminotransferase values most likely indicates
chronic
hepatitis B. Most such patients will have HBeAg in serum.
These
patients should be evaluated for the potential need and
benefit of
therapy.
It is important that medical providers counsel chronic HBV
carriers
that they can transmit HBV to others or that they refer
carriers to
their local health department for counselling. Such
counselling
should also include screening sexual partners and household
contacts of HBV carriers for susceptibility to HBV
infection and,
if susceptible, vaccinating them with hepatitis B vaccine.
The best
single test for screening in this setting is total (not
IgM)
anti-HBc. Vaccination of susceptible individuals should be
carried
out using age-appropriate doses and schedules as
recommended for
the available hepatitis B vaccines (22).
The individual should not donate blood, plasma, body
organs, other
tissue, or semen.
Household articles such as toothbrushes and razors that
could
become contaminated with blood should not be shared, and
cuts or
skin lesions should be covered to prevent the spread of
infectious
secretions or blood.
When seeking medical or dental care, HBsAg-positive persons
should
be advised to inform those responsible for their care of
their
HBsAg status so that they can be appropriately evaluated.
If the sexual partner of the HBV carrier is not immune to
hepatitis
B, the partner should be advised to take precautions. The
most
effective precaution is vaccination with hepatitis B
vaccine. The
efficacy of latex condoms in preventing infection with HBV
is
unknown, but their proper use may reduce the risk of
transmission.
For the prevention of many sexually transmitted diseases,
including
hepatitis and HIV infection, the number of sexual partners
should
be reduced, infected persons should inform prospective
sexual
partners so that they can take appropriate precautions, and
infected persons should protect a partner during sexual
activity by
taking appropriate precautions to prevent that individual
from
coming into contact with the infected person's blood,
semen, urine,
feces, saliva, cervical secretions, vaginal secretions, or
mucous
membranes (31).
The high risk of perinatal transmission of HBV is well
documented.
Infants born to HBsAg-positive women should be given
hepatitis B
immune globulin and the hepatitis B vaccine series (22).
HEPATITIS C
Background
Transfusion-Associated Non-A, Non-B Hepatitis
In May 1990, serologic tests that detect anti-HCV by EIA were
licensed
and became commercially available in the United States. Studies
have shown
that HCV is the etiologic agent of the majority of parenterally
transmitted
or bloodborne non-A, non-B hepatitis worldwide (32-34). This type
of non-A,
non-B hepatitis was first identified and characterized in studies
of
post-transfusion hepatitis conducted in the early 1970s. Using
sensitive
tests for hepatitis virus infection, investigators showed that 90%
of the
post-transfusion hepatitis in the United States was not due to
either
hepatitis A or B. This form of hepatitis became known as non-A,
non-B
(35,36). In these early studies, the incidence rates of non-A,
non-B
hepatitis were as high as 21% after blood transfusion (9,12). The
shift
from a paid to a non-paid blood donor base substantially reduced
the
incidence of post-transfusion non-A, non-B hepatitis (12,37), and
by the
late 1970s, prospective studies of transfusion recipients showed an
average
incidence of 10% (38,39). Retrospective studies of donors
implicated in the
transmission of non-A, non-B hepatitis found that such donors were
more
likely to have anti-HBc and/or elevated ALT levels than were donors
whose
blood did not transmit non-A, non-B hepatitis (17,18,40,41). These
studies
suggested that screening donors for both of these surrogate markers
would
reduce the incidence of post-transfusion non-A, non-B hepatitis by
as much
as 50%. As noted, blood banks voluntarily began such testing in the
United
States during 1986 and 1987.
Surveillance data from reported cases of acute non-A, non-B
hepatitis
suggest that the incidence of post-transfusion non-A, non-B
hepatitis
declined in the 1980s even before surrogate testing of blood donors
began
(34). In the period 1982-1985, an average of 17% of acute cases of
non-A,
non-B hepatitis had a history of blood transfusion in the six
months
preceding onset of illness. In the period 1986-1988 the percentage
of cases
reporting a history of blood transfusion declined to an average of
6%,
although the overall incidence of the disease remained stable. Most
of this
decline was temporally associated with changes in the donor
population
related to the prevention of HIV infection. Currently, the
incidence of
post-transfusion non-A, non-B hepatitis is estimated to be
1%-4%/transfusion recipient (42,43).
Hepatitis C Virus and Antibody Detection Studies
Recently, a portion of the genome of a virus believed to be the
major
etiologic agent of non-A, non-B hepatitis was cloned from the
plasma of a
chimpanzee with chronic non-A, non-B hepatitis (44). This original
clone
(clone 5-1-1) was shown to be derived from a single-stranded RNA
molecule
present only in parenterally transmitted non-A, non-B hepatitis
infections
and not related to any other hepatitis viruses. The expression
product of
clone 5-1-1 was used to develop a prototype RIA to detect
circulating
antibodies in parenterally transmitted non-A, non-B
hepatitis-infected
chimpanzees and humans. A more refined serologic assay (EIA) for
these
circulating antibodies was developed by expressing a variant of
this clone
(designated C100-3) in yeast to produce large quantities of
recombinant
viral antigen (32). The antibodies detected by use of this viral
antigen
appear to be directed against non-structural proteins of hepatitis
C virus
(HCV). Using both the prototype RIA (developed for research) and
the EIA
(developed for commercial use), several research groups have shown
that HCV
is responsible for most cases of both post-transfusion and
community-acquired non-A, non-B hepatitis (33,34). More recent
studies have
demonstrated that other recombinant antigens, some representing
structural
components of HCV, can be used to detect additional circulating
antibodies.
These additional antigens may provide the basis for future test
kits with
enhanced sensitivity and specificity.
In one recent study, 80% of patients with post-transfusion
non-A, non-B
hepatitis were found to develop anti-HCV detectable by EIA (42).
The mean
interval between date of transfusion and anti-HCV seroconversion
was 18
weeks; 61% of patients seroconverted within 15 weeks of
transfusion, about
90% by 26 weeks, but one patient did not seroconvert until 12
months. In a
study of community-acquired non-A, non-B hepatitis, approximately
70% of
patients developed anti-HCV (34); of these, 45% were
anti-HCV-positive
within 6 weeks after onset of illness, 99% by 6 months, but 1
patient did
not seroconvert until 9 months.
Patients with non-A, non-B hepatitis who remain negative for
anti-HCV
even after prolonged follow-up may be infected with another non-A,
non-B
agent (45), may have another viral or nonviral etiology for their
liver
injury, or may have hepatitis C but lack (or have resolved) an
antibody
response that can be detected by the current assay (46).
Modes of Transmission
Epidemiologic and experimental studies indicate that HCV is
transmitted
by the parenteral route. Persons at increased risk of acquiring
hepatitis C
include parenteral drug users; health-care workers with
occupational
exposure to blood; hemodialysis patients; and recipients of whole
blood,
blood cellular components, or plasma. Although in the past all
recipients
of coagulation factor concentrates were at increased risk of HCV
infection,
current manufacturing procedures for factor VIII (Antihemophilic
Factor)
include virus inactivation procedures effective against HIV and HBV
that
appear also to have reduced the risk of HCV transmission from these
concentrates (47,48). Although viral inactivation procedures
effective
against HIV and HBV have also reduced the infectivity of factor IX
concentrates, these preparations are still considered to carry a
substantial risk of HCV transmission (47,48). To date, there has
been no
evidence of transmission of HCV from health-care workers to
patients
through medical care procedures (injections, surgery, and dental
work) or
transmission from other percutaneous exposures (acupuncture,
tattooing)
(49,50). However, 40% of patients with acute hepatitis C have no
identifiable risk factor for infection.
Sexual activity and other types of person-to-person contact
have not
been generally recognized as important mechanisms of transmission
for
hepatitis C. However, two case-control studies found that non-A,
non-B
hepatitis patients with no history of parenteral exposures were
more likely
to have histories of exposures to sexual partners or household
contacts who
had had hepatitis in the past (49,50), and one of these studies
also found
an association between acquiring disease and a history of exposure
to
multiple heterosexual partners (50). Neither of these studies found
an
association between acquiring acute non-A, non-B hepatitis and
homosexual
activity. Because sexual transmission of blood-borne viruses
generally is
recognized to be more efficient between homosexual men compared
with
heterosexual men and women, it is unclear why heterosexual activity
has
been found to be associated with acquiring non-A, non-B hepatitis
when
homosexual activity has not. Some serologic surveys of heterosexual
men and
women and homosexual men who attended clinics for sexually
transmitted
diseases or who had a history of multiple partners have found the
prevalence of anti-HCV to be 5- to 15-fold higher (5%-15%) than
that of
controls or blood donors (none-1%) (51-54). These increased rates,
however,
were substantially lower than the rates of serologic markers for
HBV
(30%-60%) or HIV (35%-96%) in the same sexually active populations.
Several
other studies have examined the prevalence of anti-HCV among the
household
and sexual contacts of patients with chronic hepatitis C. Among two
of
these studies, 6% of 34 family members (55) and 8% of 88 family
members
(56), respectively, were found to be anti-HCV positive.
Anti-HCV-positive
contacts included parents, spouses, children, and siblings. In the
United
States, one study found no anti-HCV-positive contacts among 34
sexual and
17 household contacts of 40 patients with chronic hepatitis C (57).
The risk of perinatal transmission of HCV is also unclear.
Studies of
infants born to women with non-A, non-B hepatitis before testing
for
anti-HCV became available documented both transient and persistent
ALT
elevations in some infants (58,59). In two recent studies of
infants born
to anti-HCV-positive women, none of 17 and 1 of 11 (9%),
respectively,
seroconverted to anti-HCV (54,60). The one infant who seroconverted
also
had persistently elevated ALT levels. In a third study of 25
infants born
to anti-HIV- and anti-HCV-positive women, 11 (44%) seroconverted to
anti-HCV between 6 and 12 months of age (61). Four of these 11
infants had
transient ALT elevations and two had persistent ALT elevations; all
11 were
infected with HIV. Thus, in the absence of coexistent HIV
infection,
perinatal transmission of HCV rarely appears to occur.
Further definition of the role of sexual, perinatal, and other
possible
routes of transmission for hepatitis C are needed. There is no
evidence
that HCV is transmitted through such common exposures as sharing
meals or
eating utensils, sneezing or coughing, or other casual contact.
Natural History of Infection
Adjusting both for disease underreporting (62) and for the
proportion
of HCV infections that are asymptomatic (12), an estimated 150,000
to
170,000 new HCV infections occur annually in the United States.
Approximately 25% become ill with jaundice or other symptoms of
hepatitis,
greater than 4,000 patients require hospitalization, and about 600
die of
fulminant disease. An average of 50% of patients with either
post-transfusion or community-acquired hepatitis C followed for at
least 12
months develop biochemical evidence of chronic liver disease
(49,63,64). Of
patients with transfusion-associated chronic non-A, non-B hepatitis
who
undergo biopsy within 5 years after onset, greater than or equal to
40%
have histologic evidence of chronic active hepatitis and 10%-20%
have
evidence of cirrhosis (63); many of these patients have no clinical
manifestations of their disease. In contrast, of biopsied patients
with
community-acquired chronic non-A, non-B hepatitis, less than 20%
have
evidence of chronic active hepatitis and 3% have evidence of
cirrhosis
within 4 years after onset of disease (64). Because serial biopsies
have
demonstrated progression from chronic active hepatitis to
cirrhosis,
studies that include prolonged follow-up of patients with chronic
hepatitis
C, regardless of the source for infection, ultimately might show a
higher
proportion of patients with cirrhosis.
Individual case studies have reported the development of
hepatocellular
carcinoma (HCC) after transfusion-associated non-A, non-B hepatitis
(65-67). Several recent studies have reported high rates of
anti-HCV among
patients with HCC (68-70). The establishment of a direct link
between HCV
and HCC, however, must await the results of well-controlled
studies.
Although it is apparent that chronic liver disease is a
frequent
outcome of hepatitis C, such disease may take years to develop, and
the
majority of infected individuals, even those with documented
cirrhosis, may
be asymptomatic. Some individuals, however, do suffer from severe
disease.
Recent studies have reported that alpha interferon therapy may have
a
beneficial effect among some patients (71,72). In these studies,
such
therapy resulted in marked improvement of serum aminotransferase
activity
among approximately half of the patients treated, with most of
these
patients also having improvement in liver histology. However,
improvement
of aminotransferase activity was sustained among only 10%-51%
(71,72) of
the patients, and the duration of the histologic response and the
impact on
the long-term course of the disease were not defined.
Sensitivity and Specificity of Current Tests
The sensitivity and specificity of the currently available
tests for
anti-HCV are not well defined. Not all donors implicated in the
transmission of hepatitis C are anti-HCV positive. In one study,
approximately 25% of patients with post-transfusion hepatitis C
received
units from donors who tested negative for anti-HCV by EIA (42).
Limited data concerning the specificity of the licensed EIAs
are
available from studies using supplemental assays. Two supplemental
tests
for specificity have been used on an investigational basis: an
immunoblot
(IB) type assay and a neutralization or blocking (NT) type assay.
In one
study, of 28 EIA-reactive donors implicated in the transmission of
hepatitis C, 89% were found to be anti-HCV positive by supplemental
testing
(IB); of 21 non-implicated donors reactive by EIA, only 33% were
positive
by supplemental testing (42). Most samples that were judged false
positives
had initial EIA absorbance readings of less than 1.0.
In two studies of randomly selected blood donors reactive for
anti-HCV
by EIA, only 19%-26% were anti-HCV positive on supplemental testing
(IB)
and 20%-24% were judged indeterminant (73,74). In both of these
studies,
EIA reactive donors who were positive by the supplemental test were
more
likely to have an elevated ALT level (or anti-HBc positivity) than
were EIA
reactive donors who were negative by the supplemental test.
As with any screening test, the proportion of repeatedly
reactive EIA
results that are falsely positive may vary depending on the
prevalence of
the infection in the population screened. Serologic surveys of
groups other
than blood donors have found that supplemental tests were positive
among
84% (by IB) of EIA-reactive samples from previous transfusion
recipients
(74), among 80% (by NT) of EIA-reactive samples from parenteral
drug users
(CDC, unpublished data), and among 20% (by NT) of EIA-reactive
samples from
healthy adults randomly selected from the general population (CDC,
unpublished data).
Thus, persons most likely to be infected with HCV, such as
donors
implicated in the transmission of HCV, donors with elevated ALT
levels, and
persons with identifiable risk factors for hepatitis C, are those
in whom
repeatedly reactive EIA results are most likely to be judged
positive by
supplemental tests. In contrast, persons less likely to be infected
with
HCV, such as donors not implicated in the transmission of HCV,
donors with
normal ALT values, and persons with no known risk factors for
hepatitis C,
are those in whom repeatedly reactive EIA results are most likely
to be
judged false positive by the supplemental tests.
Guidelines for Screening
Testing
It is recommended that all donations of whole blood and
components for
transfusion be tested for anti-HCV by EIA.
If the initial test result is non-reactive, the unit should be
considered non-reactive for anti-HCV. The unit may be
transfused or
used for further manufacture into injectable components,
provided all
other requirements are met.
If the initial test result is reactive, the unit is considered
to be
initially reactive.
The sample should be retested in duplicate in a single test
run,
using a test kit of the same type from the same
manufacturer used
for the initial test.
If the repeat tests are both non-reactive, the unit is
considered
to be non-reactive and may be used as mentioned earlier.
The donor
may return for subsequent donations.
If either one or both of the duplicate tests are reactive,
the
result is designated repeatedly reactive, and the unit must
not be
used for transfusion. The donor should be indefinitely
deferred
from donation of whole blood and components for
transfusion.
The FDA does not currently recommend testing of plasma
collected for
fractionation for anti-HCV and currently permits the plasma
from
repeatedly reactive units to be used for further manufacture
into
injectable products. This position has been taken because it is
unclear
whether anti-HCV screening may adversely affect the safety of
plasma
derived products, particularly immune globulins. This
provisional
position of the FDA will be reevaluated in the light of
additional
information that may emerge, including the results of
experimental
studies that have been initiated.
Donors indefinitely deferred from donation of blood or
components for
transfusion because of repeatedly reactive anti-HCV test
results should
not be reentered into the donor pool at this time. When further
information about HCV serology becomes available, and if highly
sensitive confirmatory tests are developed and licensed, a
procedure
for reentering donors repeatedly reactive for anti-HCV in an
isolated
instance may be developed. Collecting facilities should be
aware that
such a procedure may require the retesting of a stored sample
from the
original repeatedly reactive donation.
Until the risk of sexual transmission of HCV is better defined,
there
is no recommendation to exclude sexual partners of anti-HCV
repeatedly
reactive donors from donating whole blood and components for
transfusion provided all other requirements are met.
It is recommended that serum from donors of organs, tissues, or
semen
intended for human use be tested for anti-HCV by EIA using the
same
procedures as outlined earlier. This testing policy should
apply both
to newly acquired tissue and to material in inventory, whether
such
inventory is stored at the collection facility or at points of
use.
Every effort should be made to use material only from donors
testing
negative for anti-HCV. It is recognized that emergency
situations
involving life-supporting organs may arise that do not permit
the use
of an anti-HCV test before implantation or that involve the use
of
material from an anti-HCV repeatedly reactive donor. In such
situations, the recipients should be informed by their
medical-care
provider that they will or have received untested tissue or
tissue from
an anti-HCV repeatedly reactive donor.
Notification of Donors
It is recommended that collection facilities ensure that donors
with
repeatedly reactive test results are notified of these results
and of
their indefinite deferral from donation. Blood donors are
indefinitely
deferred from donation for transfusion products but currently
remain
eligible to give plasma for fractionation. It is recommended
that
notification include written information presented to the donor
either
by sealed letter or at a face-to-face interview. Organ or
tissue
procurement organizations should report this information to the
donor's
physician when the donor is deceased.
When the EIA is used to screen populations low in the
prevalence of HCV
infection, the proportion of positive results that are falsely
positive
will be high. The rate of anti-HCV repeat reactivity among U.S.
blood
donors has been reported at 0.5%-1.4% (73-75). Licensed
confirmatory
tests are currently not available. Supplemental tests for
specificity,
as discussed previously, are available as a testing service for
research purposes performed by the manufacturers of licensed
screening
tests, or for distribution on an investigational basis. When
such tests
are utilized, research studies indicate that their results may
be of
value in the interpretation of a repeatedly reactive screening
test.
It is recommended that donors testing repeatedly reactive for
anti-HCV
by EIA without supplemental testing be informed that this
screening
test result has not been confirmed and that the anti-HCV
repeatedly
reactive result may be a false positive. Donors should also be
told
that a repeatedly reactive test result could indicate infection
with
HCV. To determine the significance of a repeatedly reactive
test,
particularly if the donor also has an elevated ALT level, it is
recommended that the donor be referred to a physician for
further
evaluation.
When a supplemental test * is available and the result is
positive,
donors may be informed that the test indicates the presence of
hepatitis C infection and should be referred to a physician for
further
evaluation.
When a supplemental test* is available and the result is
negative and
the ALT level is within normal limits, the donor may be
informed that
the initial test is likely to be a false positive, although
this is
impossible to prove at present in the absence of a confirmatory
test of
proven sensitivity and specificity.
If the donor's ALT level is elevated, the donor should be
referred to a
physician for further evaluation, regardless of the results of
supplemental anti-HCV testing.
Collecting facilities should be prepared to provide all the
results of
tests performed related to hepatitis screening (e.g., HBsAg,
ALT, and
anti-HBc) to donors with a repeatedly reactive anti-HCV test
result or
to their physicians. The facility should transmit this
information to
the donors or inform donors that this information can be
forwarded to
their physicians by the facility.
If a transfusion recipient or a recipient of transplanted
tissue
develops non-A, non-B hepatitis or hepatitis C, it is
recommended that
the diagnosing physician report the case to both the local
health
department and the collection facility.
It is recommended that professional societies make a concerted
effort
to educate physicians and other health-care providers about a)
the
known and potential risks for HCV infection, including blood
transfusion; b) the need to ascertain complete risk behavior
histories
from their patients; c) the appropriate evaluation of high-risk
patients for evidence of infection; and d) the current status
of
investigations on the use of alpha interferon to treat chronic
non-A,
non-B hepatitis.
Targeted "lookback" (tracing prior recipients of blood products
from
donors who now test positive for anti-HCV) or general screening
programs for populations at increased risk of HCV infection are
not
recommended because: a) currently available screening tests
cannot
distinguish between ongoing infection and recovery, and thus,
the
meaning of a reactive test result in any one individual is not
clear;
b) available knowledge about routes of transmission for HCV
other than
parenteral is limited; and c) only selected persons are
eligible for
therapy for their chronic liver disease, and the potential
long-term
benefits of such therapy are unknown.
Screening programs aimed at prior transfusion recipients also
are not
recommended because they are likely to be ineffective for
several
reasons: a) most HCV- infected former donors self-deferred or
were
excluded as a consequence of earlier screening policies; b) few
hospitals have transfusion records prior to the early 1980s,
thus most
recipients at risk will not be traceable; and c) based on the
results
of "lookback" programs for HIV, response by prior recipients to
notification is poor (76).
---------------
No supplemental test for anti-HCV has yet been licensed by the
FDA. When
licensure occurs, specific guidance for notification can be
obtained from
the package insert or directions that accompany the product, and
will be
provided by the FDA otherwise as appropriate.
Recommendations for Medical Evaluation and Counselling
The following information may be of assistance to medical-care
providers in evaluating and counselling an anti-HCV-positive
individual:
The medical evaluation should first verify that anti-HCV is
present; then, attempt to assess whether the repeatedly
reactive
test result is a true positive; and finally, determine
whether the
patient has acute or chronic HCV infection.
A follow-up serum specimen should be tested for
anti-HCV.
If the specimen is positive, supplemental testing
should be
performed when available.
The patient should be asked about risk factors for
hepatitis C
as a part of a medical history and examined for
evidence of
liver disease. Laboratory tests might include ALT, AST,
bilirubin, albumin, and prothrombin time.
The history of a risk factor, clinical evidence of liver
disease,
and abnormal aminotransferase levels all support the
specificity of
an anti-HCV positive result.
Currently available tests do not distinguish between acute
or
chronic HCV infection or between ongoing infection and
recovery.
Sequential tests for ALT levels may be helpful in
distinguishing
acute and chronic hepatitis.
If ALT levels remain elevated for greater than or equal
to 6
months, chronic hepatitis C is likely.
If initially elevated ALT levels fall to within the
normal
range and remain there greater than or equal to 6
months, acute
hepatitis C was likely.
If ALT levels are initially and repeatedly normal: a)
the
anti-HCV result may have been a false positive; b) the
patient
may have resolved acute hepatitis C; or c) the patient
may have
chronic HCV infection with no or minimal associated
liver
disease.
All individuals found to be anti-HCV positive need to be
considered
potentially infectious and should be counselled concerning
infectivity.
Individuals should not donate blood, body organs, other
tissue, or
semen.
Household articles such as toothbrushes and razors that
could
become contaminated with blood should not be shared, and
cuts or
skin lesions should be covered to prevent the spread of
infectious
secretions or blood.
When seeking medical or dental care, anti-HCV-positive
individuals
should be advised to inform those responsible for their
care of
their anti-HCV status so that they can be appropriately
evaluated.
The magnitude of the risk of infecting others by sexual
intercourse
is unknown, but appears to be much less than that for other
bloodborne sexually transmitted diseases (e.g., HBV, HIV).
Transmission of HCV has rarely been documented from
persons
with chronic disease to their steady sexual partners
despite
long-term, ongoing sexual activity. Although
anti-HCV-positive
individuals should be informed of the potential for sexual
transmission, at this time there is insufficient data to
recommend
changes in current sexual practices for persons with a
steady
sexual partner.
Having multiple sexual partners has been associated
with an
increased risk of acquiring hepatitis C. For the prevention
of many
sexually transmitted diseases, including hepatitis and HIV
infection, the number of sexual partners should be reduced,
infected persons should inform prospective sexual partners
so that
they can take appropriate precautions, and infected persons
should
protect a partner during sexual activity by taking
appropriate
precautions to prevent that individual from coming into
contact
with the infected person's blood, semen, urine, feces,
saliva,
cervical secretions, vaginal secretions, or mucous
membranes (25).
The efficacy of latex condoms in preventing infection with
HCV is
unknown, but their proper use may reduce transmission.
Consideration may be given to testing exposed sexual
partners for
anti-HCV and, if positive, evaluating them for the presence
or
development of chronic liver disease.
The risk of perinatal transmission appears to be very low.
At the
present time, there is no evidence to support advising
against
pregnancy based on anti-HCV status alone, or to advise any
special
treatments or precautions for pregnant women or their
offspring.
The prognosis for an asymptomatic anti-HCV-positive
individual over
the long term is not known. Many may not suffer any
consequences.
Some may develop permanent scarring of the liver and
develop severe
consequences such as chronic active hepatitis and
cirrhosis. It is
hoped that in the future more information will become
available on
the natural history of this infection and the benefits of
potential
therapies.
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