Current Trends
Licensure of Screening Tests for Antibody
to Human T-Lymphotropic Virus Type I
Screening tests for antibody to human T-lymphotropic virus type I
(HTLV-I), the first-recognized human retrovirus, have been licensed
by
the Food and Drug Administration (FDA). These tests have been
recommended by the FDA for screening of blood and cellular
components
donated for transfusion. They have also been approved as diagnostic
tests, which may be useful in evaluating patients with clinical
diagnoses of adult T-cell leukemia/lymphoma (ATL) and tropical
spastic
paraparesis (TSP)/HTLV-I-associated myelopathy (HAM), both of which
have been associated with HTLV-I infection. Because licensure will
probably result in widespread use of these tests, the information
presented below is provided for physicians and public health
officials
who may need to interpret HTLV-I test results and to counsel
persons
whose serum specimens are reactive in these tests. Users of the new
HTLV-I screening tests are cautioned that additional, more specific
tests are necessary to confirm that serum specimens that are
repeatably
reactive in these screening tests are truly positive for HTLV-I
antibody. Users should also be aware that neither the screening
tests
nor more specific tests can distinguish between antibody to HTLV-I
and
antibody to the closely related human retrovirus, human
T-lymphotropic
virus type II (HTLV-II).
HTLV-I does not cause AIDS, and the finding of HTLV-I antibody in
human
blood does not imply infection with human immunodeficiency virus
(HIV)
or a risk of developing acquired immunodeficiency syndrome (AIDS).
BACKGROUND: HTLV-I
HTLV-I was isolated in 1978 and first reported in 1980 (1).
Although a
member of the family of retroviruses, HTLV-I is not closely related
to
HIV, the virus that causes AIDS. HTLV-I does not cause depletion of
T-helper lymphocytes, and it is not generally associated with
immunosuppression.
HTLV-I differs from HIV in its morphologic and genetic structure
and in
that HTLV-I antigens should not cross-react with the antigens of
HIV.
The HTLV-I genome contains four major genes: gag, which encodes
core
proteins of 15,000 (p15), 19,000 (p19), and 24,000 (p24) daltons;
pol,
which encodes a polymerase (reverse transcriptase) protein of
96,000
daltons; env, which encodes envelope glycoproteins of 21,000 (gp21)
and
46,000 (gp46) daltons; and tax, which encodes a transactivator
protein
of 40,000 daltons (p40x). Seroprevalence
HTLV-I infection is endemic primarily in southwestern Japan, the
Caribbean, and some areas of Africa (2). Seroprevalence in
well-characterized areas appears to increase with patient age, with
rates in females markedly higher than those in males beginning in
the
20-30-year age range. Seroprevalence rates as high as 15% in the
general population and 30% in older age groups have been reported
in
some areas of Japan (3). In the Caribbean islands, rates may be as
high
as 5% in the general population and 15% in older age groups (4).
In the United States, HTLV-I infection has been identified mainly
in
intravenous- drug users (IVDUs), with seroprevalence rates ranging
from
7% to 49% (5,6). Elevated rates have also been reported in female
prostitutes (in whom IV-drug use is a major risk factor) (7) and in
recipients of multiple blood transfusions (8). Seropositivity is
rare
among homosexual men and among patients in sexually transmitted
disease
clinics (9,10), and it appears to be nonexistent in hemophilic men
without other risk factors (11). Systematic determination of HTLV-I
seroprevalence in the general population of the United States has
not
been undertaken. However, in a study of 39,898 random blood donors
in
eight U.S. cities, 10 (0.025%) were seropositive for HTLV-I (12).
Transmission
Transmission of HTLV-I infection by blood transfusion is well
documented in Japan, with a seroconversion rate of 63% in
recipients of
the cellular components of contaminated units (whole blood, red
blood
cells, and platelets) (13). Transmission by the plasma fraction of
contaminated units has not resulted in infection; this finding has
been
attributed to the fact that HTLV-I is highly cell-associated.
Transmission among IVDUs is presumed to occur by sharing of needles
and
syringes contaminated with infectious blood.
Transmission from mother to child occurs through breastfeeding;
breastfed infants of seropositive mothers have an approximately 25%
probability of becoming infected (14). However, infection has also
occurred in infants who are not breastfed, suggesting that
intrauterine
and/or perinatal transmission may occur.
Sexual transmission of HTLV-I appears to be relatively inefficient
(15). Transmission from male to female, however, appears to be more
efficient than from female to male (16). Disease Associations
HTLV-I has been etiologically associated with adult T-cell
leukemia/lymphoma (ATL), a malignancy of mature T-lymphocytes
characterized by skin lesions, visceral involvement, circulating
abnormal lymphocytes, hypercalcemia, and lytic bone lesions (17).
ATL
has been recognized in Japan, the Caribbean, and Africa. No
systematic
attempt has been made to record cases of ATL in the United States,
but
74 cases were reported to the National Institutes of Health between
1980 and 1987 (18). Approximately half of these cases occurred in
persons of Japanese or Caribbean ancestry; most of the remainder
were
in blacks from the southeastern United States. ATL tends to occur
equally in men and women, with peak occurrence in persons 40-60
years
of age.
It is thought that a person must be infected with HTLV-I for years
to
decades before ATL develops. The lifetime risk of ATL among
HTLV-I-infected persons has been estimated to be approximately 2%
in
two studies in Japan (19,20). In Jamaica, the lifetime risk of ATL
among persons infected before the age of 20 years was estimated to
be
4% (21).
Because of the long latent period of ATL, the risk of this disease
among persons infected by blood transfusion (many of whom are
elderly
and may not survive their underlying disease) is not thought to be
substantial. In fact, no cases of ATL associated with blood
transfusion
have been reported.
HTLV-I has also been associated with a degenerative neurologic
disease
known as tropical spastic paraparesis (TSP) in the Caribbean and as
HTLV-I-associated myelopathy (HAM) in Japan (22,23). TSP/HAM is
characterized by progressive difficulty in walking, lower extremity
weakness, sensory disturbances, and urinary incontinence. Although
most
cases have been reported from countries in which HTLV-I is endemic,
a
few cases have occurred in the United States (24). TSP/HAM occurs
in
persons of all age groups, with peak occurence in ages 40-49 years.
Rates are higher in females than in males. The lifetime risk of
TSP/HAM
among persons infected with HTLV-I is unknown but appears to be
very
low. The latent period for this disease appears to be less than for
ATL, and the disease probably can be caused by blood transfusion.
Of
420 Japanese patients with HAM from whom information was available,
109
(26%) gave a history of blood transfusion; the mean interval
between
transfusion and onset of neurologic symptoms was estimated to be 4
years (M. Osame, unpublished data).
HTLV-I does not cause AIDS, and the finding of HTLV-I antibody in
human
blood does not imply infection with HIV or a risk of developing
AIDS.
BACKGROUND: HTLV-II
HTLV-II is closely related to HTLV-I. The genome of HTLV-II encodes
viral proteins that are similar to those of HTLV-I, and there is
extensive serologic cross-reactivity among proteins from HTLV-I and
HTLV-II.
No specific information is available regarding the seroepidemiology
or
the modes of transmission of HTLV-II. There is some evidence that
some
of the HTLV-I seropositivity in the United States, especially in
IVDUs,
may be caused by HTLV-II (5).
Two cases of disease have been associated with HTLV-II infection.
HTLV-II was first isolated from a patient with a rare T-lymphocytic
hairy cell leukemia (25). In the second case, HTLV-II was isolated
from
a patient who had the more common B-lymphocytic form of hairy cell
leukemia and who also suffered from a T-suppressor
lymphoproliferative
disease (26). No serologic evidence of HTLV-II infection has been
found
in 21 additional cases of hairy cell leukemia (27). Thus, the
disease
associations of HTLV-II are unclear, and nothing is known regarding
lifetime risk of disease among infected persons.
SEROLOGIC TESTS FOR HTLV-I
Interpretation
The screening tests that have been licensed by the FDA are enzyme
immunoassays (EIAs) to detect HTLV-I antibody in human serum or
plasma.
Specimens with absorbance values greater than or equal to the
cutoff
value determined by the manufacturer are defined as initially
reactive.
Initially reactive specimens must be retested in duplicate to
minimize
the chance that reactivity is due to technical error. Specimens
that
are reactive in either of the duplicate tests are considered
repeatably
reactive. Specimens that do not react in either of the duplicate
repeat
tests are considered nonreactive. Additional, more specific
serologic
tests are necessary to confirm that serum specimens repeatably
reactive
in the screening tests are positive for HTLV-I antibody. Users of
the
screening tests must have available to them additional, more
specific
tests to properly interpret repeatably reactive screening tests.
Such
tests are available in research institutions, industry, and some
diagnostic laboratories. No such tests have been licensed by the
FDA.
Tests used to confirm HTLV-I seropositivity must be inherently
capable
of identifying antibody to the core (gag) and envelope (env)
proteins
of HTLV-I. (The immunoreactivities of the polymerase (pol) and
transactivator (tax) proteins of HTLV-I have not been well-defined
in
current test systems.) Specific tests include Western immunoblot
(WIB)
and radioimmunoprecipitation assay (RIPA). Indirect fluorescent
antibody (IFA) testing for HTLV-I has been used in some
laboratories,
but IFA does not detect antibody to specific HTLV-I gene products.
WIB appears to be the most sensitive of the more specific tests for
antibody to gag protein products p19, p24, and (gag-derived) p28,
whereas RIPA appears to be most sensitive for antibody to the env
glycoproteins gp46 and (env precursor) gp61/68. Based on experience
with these tests in several laboratories, the following
confirmatory
criteria for HTLV-I seropositivity have been adopted by the Public
Health Service Working Group: a specimen must demonstrate
immunoreactivity to the gag gene product p24 and to an env gene
product
(gp46 and/or gp61/68) to be considered "positive." Serum specimens
not
satisfying these criteria but having immunoreactivities to at least
one
suspected HTLV-I gene product (such as p19 only, p19 and p28, or
p19
and env) are designated "indeterminate." Serum specimens with no
immuno- reactivity to any HTLV-I gene products in additional, more
specific tests are designated "negative." Both WIB and RIPA may be
required to determine whether a serum specimen is positive,
indeterminate, or negative.
Although additional, more specific tests have been somewhat
standardized, the quantities and the molecular weights of HTLV-I
proteins produced by various cell lines vary considerably. Hence,
the
cell of origin for HTLV-I antigens used in either WIB or RIPA, as
well
as the method of antigen preparation, may markedly influence test
sensitivity and interpretation of immunoreactivity against
individual
HTLV-I proteins. Laboratories performing these tests, however,
should
be able to detect antibody to the gag and env gene products of
HTLV-I
in WIB and/or RIPA. Sensitivity, Specificity, and Predictive Value
Using the WIB and RIPA available in research laboratories and the
confirmatory criteria described above to define the presence of
HTLV-I
antibody, the sensitivities of the three EIAs that have been
licensed
by the FDA have been estimated from the performance of the tests on
a
reference panel of 137 antibody-positive serum specimens. All three
EIAs were repeatably reactive for 137 of 137 panel serum specimens,
yielding an estimated sensitivity of 97.3%-100% by the binomial
distribution at 95% confidence. Specificity* of the EIAs was
estimated
for each test from screening of at least 5000 normal U.S. blood
donors
in nonendemic areas. Estimated specificities ranged from 99.3% to
99.9%
by the binomial distribution at 95% confidence. However, a
specificity
greater than 99% but less than 100% may still yield a low positive
predictive value when the screening test is used in a
low-prevalence
population. For example, in the study of U.S. blood donors cited
above,
68 donors were repeat reactors in the screening test, but only 10
(15%)
were determined to be HTLV- I-seropositive in more specific
testing.
This relatively low positive predictive value emphasizes the need
for
additional, more specific testing of specimens repeatably reactive
in
the EIA.
Neither the EIAs nor the additional, more specific tests can
distinguish between antibodies to HTLV-I and HTLV-II. More
sophisticated techniques, such as virus isolation and gene
amplification (polymerase chain reaction (PCR)) are required to
differentiate HTLV-I from HTLV-II infection. USE OF HTLV-I
SCREENING
TESTS IN BLOOD BANKS
The FDA recommends that whole blood and cellular components donated
for
transfusion be screened for HTLV-I antibody using a licensed EIA
screening test. The FDA further recommends that units that are
repeatably reactive by EIA be quarantined, then destroyed, unless
otherwise stipulated by the FDA. Source plasma (obtained from
plasma
donors) intended for use in further manufacturing need not be
screened
for HTLV-I antibody.
DONOR DEFERRAL AND NOTIFICATION
FDA recommends permanent deferral of donors whose sera are
repeatably
reactive in EIA and confirmed as positive for HTLV-I antibody by
additional, more specific testing. Such donors should be notified
and
counseled accordingly.
Donors whose serum specimens are repeatably reactive in the EIA but
not
confirmed as positive for HTLV-I antibody need not be notified on
the
first occasion. Although the donated units must be destroyed, the
donors remain eligible for future donation. If, however, the donors
test repeatably reactive in the EIA on a subsequent donation, they
should be deferred indefinitely as donors and notified and
counseled
accordingly.
GUIDELINES FOR COUNSELING
Counseling should be considered a routine adjunct depending on the
results of HTLV-I testing. Given some of the uncertainties related
to
testing, e.g., the inability to distinguish between antibodies to
HTLV-I and HTLV-II, and the low probability that disease will occur
in
seropositive persons, every effort should be made to minimize the
anxiety provoked by a repeatably reactive screening test,
particularly
one that is not confirmed as HTLV-I-seropositive by additional
testing.
Persons confirmed as seropositive for HTLV-I should be notified
that
they have antibody to HTLV-I and are likely infected with HTLV-I or
HTLV-II. They should be given information concerning disease
associations and possible modes of transmission. In addition, they
should be advised that they have been permanently deferred as blood
donors and should neither give blood for transfusion nor share
needles
that have been used for percutaneous injection or infusions with
other
persons. Breastfeeding of infants should be discouraged. The
paucity of
data concerning sexual transmission of HTLV-I/HTLV-II does not
permit a
firm recommendation concerning sex practices; specific
recommendations,
such as the use of condoms to reduce the potential risk of sexual
transmission, should be developed in consultation with a
health-care
professional.
Persons whose serum specimens are repeatably reactive on more than
one
occasion in the EIA but not confirmed as positive for HTLV-I
antibody
in more specific testing should be informed that they have
inconclusive
test results that do not necessarily imply infection with HTLV-I or
HTLV-II. Nevertheless, they should be notified that they have been
deferred indefinitely as donors and should not donate blood for
transfusion. Periodic follow-up of such donors with EIA, more
specific
serologic tests, and possibly sophisticated techniques such as
virus
isolation and/or PCR may provide more reliable information
regarding
the presence of viral infection. Reported by: Public Health
Service
Working Group.**
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*Specificity was calculated as follows: (total donations screened
minus
total number repeatably reactive in EIA) divided by (total
donations
screened minus number confirmed as positive by additional testing).
**D Anderson, MD, J Epstein, MD, L Pierik, J Solomon, PhD, Food and
Drug Administration. W Blattner, MD, C Saxinger, PhD, National
Cancer
Institute; H Alter, MD, H Klein, MD, Clinical Center; P McCurdy,
MD, G
Nemo, MD, National Heart, Lung, and Blood Institute, National
Institutes of Health. J Kaplan, MD, J Allen, MD, R Khabbaz, MD, M
Lairmore, PhD, CDC.
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