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Guidelines for Counseling Persons Infected with Human T-Lymphotropic Virus Type I (HTLV-I) and Type II (HTLV-II)
- Centers For Disease Control and Prevention and the U.S.P.H.S. Working Group.
- Investigators in the Centers for Disease Control and Prevention and the U.S.P.H.S. Working Group comprise Rima F. Khabbaz, MD; Keiji Fukuda, MD; Jonathan E. Kaplan, MD; Cielso Bianco, MD; William Blattner, MD; Michael Busch, MD, PhD; Roger Dodd, MD; Jay Epstein, MD; Ronald Gilcher, MD; Craig Jackson, PhD; Louis Katz, MD; Steven Kleinman, MD; Edward L. Murphy, MD, MPH; George Nemo, PhD; Bernard J. Poiesz, MD; Maria Rios; Elaine Sloand, MD; Marian Sullivan, MS, MPH; Alan E. Williams, PhD. Requests for Reprints: Rima F. Khabbaz, MD, 6-275 MS G03, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333.
Abstract
The human T-lymphotropic viruses type I (HTLV-I) and type II (HTLV-II) are closely related but distinct retroviruses that can infect humans. They differ from the human immunodeficiency viruses that cause the acquired immunodeficiency syndrome. Screening of the U.S. blood supply for HTLV-I/II, which began in 1988, identifies HTLV-I- and HTLV-II-infected persons who need to be counseled regarding their infections. This paper summarizes current information about the HTLV viruses and presents guidelines developed by the Centers for Disease Control and a United States Public Health Service working group for counseling persons infected with HTLV-I and HTLV-II.
Human T-lymphotropic viruses types I (HTLV-I) and II (HTLV-II) were the first human retroviruses discovered [1, 2]. Both belong to the oncovirus subfamily of retroviruses and can immortalize human lymphocytes in vitro. They are only distantly related to the human immunodeficiency viruses (HIV-1 and HIV-2), which belong to the lentivirus subfamily of retroviruses and cause the acquired immunodeficiency syndrome (AIDS). Infections with HTLV-I and HTLV-II are most easily detected serologically. The presence of antibodies to HTLV-I or HTLV-II indicates that a person is infected with the virus.
In November 1988, the Food and Drug Administration issued recommendations to blood establishments to screen the U.S. blood supply for HTLV-I [3]. Since then, all whole blood and blood component donations in the United States have been screened for antibody to HTLV-I. The screening tests that were licensed, as well as the investigational supplementary tests used to confirm seroreactivity (Western immunoblot and radioimmunoprecipitation assay), do not reliably differentiate between antibodies to HTLV-I and to the closely related HTLV-II. In addition, the licensed screening tests, which use HTLV-I antigens, vary in their sensitivity to detect antibodies to HTLV-II [4, 5].
Approximately 2000 HTLV-I/II-infected volunteer blood donors were identified in the first year of screening in the United States; testing, after amplification by the polymerase chain reaction, indicated that approximately one half are infected with HTLV-I and one half with HTLV-II [6]. These donors are counseled and permanently deferred from donating blood. Because the polymerase chain reaction test is not routinely available, many donors and other individuals who tested positive by serologic assays have been told that they are infected with HTLV-I/II. The uncertainty regarding the identity of the infecting virus and the different epidemiologic and clinical correlates of HTLV-I and HTLV-II infections have made counseling of HTLV-I/II-infected persons complicated and sometimes confusing.
Until recently, the only reliable way to differentiate HTLV-I from HTLV-II infection was by polymerase chain reaction [7]. Within the past 2 years, investigational peptide- and recombinant protein-based serologic assays that can more easily differentiate between antibodies to HTLV-I and HTLV-II have been developed [8, 9]. Preliminary data suggest that these investigational tests are potentially useful for typing serum samples [8, 9].
The guidelines for counseling HTLV-I-, HTLV-II-, and HTLV-I/II-infected persons included in this paper are intended for use by health care workers and public health officials in the United States. They may not be applicable in developing countries where the need for breast-feeding may outweigh concerns about transmission of these viruses.
Human T-Lymphotropic Virus Type I
Prevalence
Human T-lymphotropic virus type I infection is endemic in southwestern Japan [10], the Caribbean basin [11], Melanesia [12], and in parts of Africa [13-15]. In some areas where HTLV-I infection is endemic, prevalence rates as high as 15% have been reported in the general population. Seroprevalence increases with age; in older age groups, rates are usually higher in women than in men.
In the United States, HTLV-I/II seroprevalence rates among volunteer blood donors average 0.016% [6]. Approximately one half of HTLV-I/II-seropositive blood donors nationwide are infected with HTLV-I. Donors infected with HTLV-I most often report a history of birth in HTLV-I endemic countries or sexual contact with persons from the Caribbean or Japan. Smaller percentages report a history of either injecting drug use or blood transfusion. Clusters of HTLV-I infections have also been reported in blacks from the southeastern United States [16] and in immigrants from HTLV-I-endemic areas living in Brooklyn, New York [17].
Transmission
Transmission of HTLV-I occurs from mother to child [18], by sexual contact [19], by blood transfusion [20], and by the sharing of contaminated needles. Mother-to-child transmission occurs primarily through breast-feeding [21]; in HTLV-I-endemic areas, approximately 25% of breast-fed infants born to HTLV-I-seropositive mothers acquire the infection. Recent studies suggest that transmission of HTLV-I by breast feeding may be associated with the presence of maternal antibodies to the HTLV-I transactivating protein, tax [22], or with elevated maternal titers of total antibodies to HTLV-I [23]. However, the clinical usefulness of these markers has not been established. Intrauterine or perinatal transmission of HTLV-I occurs but appears to be less frequent than transmission by breast-feeding; approximately 5% of children born to infected mothers but not breast-fed acquire infection [24].
Sexual transmission of HTLV-I appears to be more efficient from males to females than from females to males. In one study of married couples in Japan, the efficiency of sexual transmission from males to females was estimated to be 60.8% during a 10-year period compared with less than 1% transmission from females to males [25]. In another study, the presence of antibody to tax in the male partner was associated with sexual transmission to the female partner [26]. In a study in Jamaica, genital ulcer disease in the male was identified as a risk for female-to-male sexual transmission [27]. In the United States, approximately 25% to 30% of sex partners of HTLV-I/II-seropositive blood donors are also seropositive [28, 29].
Transmission of HTLV-I by blood transfusion occurs with transfusion of cellular blood products (whole blood, red blood cells, and platelets) but not with the plasma fraction or plasma derivatives from HTLV-I-infected blood. Seroconversion rates of 44% to 63% have been reported in recipients of HTLV-I-infected cellular components in HTLV-I endemic areas [20, 30]. Lower rates (approximately 20%) have been reported in recipients of contaminated cellular components in the United States [31]. The probability of transmission by whole blood or packed red blood cells appears to diminish with greater duration of product storage; this finding has been ascribed to depletion of infected cells, presumably T lymphocytes [30, 32]. Sharing of blood-contaminated needles is the probable mode of transmission among injecting drug users.
Human T-lymphotropic virus type I is not transmitted by casual contact. Health care workers caring for HTLV-I-infected persons need only be concerned about percutaneous exposure to HTLV-I-contaminated blood. A health care worker in Japan who accidentally inoculated himself with blood from a patient with adult T-cell leukemia/lymphoma is reported to have seroconverted [33]. However, no seroconversions occurred among 31 other laboratory and health care workers exposed to HTLV-I through puncture wounds [34]. Universal precautions, recommended for contact with all patients, are adequate to guard against HTLV-I transmission to health care workers [35].
Diseases
Two diseases have been definitively associated with HTLV-I: adult T-cell leukemia/lymphoma (ATL) and a chronic degenerative neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
Adult T-cell leukemia/lymphoma is a malignant condition of HTLV-I-infected CD4-positive T lymphocytes. The HTLV-I provirus is monoclonally integrated in the abnormal cell population. A spectrum of clinical and pathologic features has been described, including acute, chronic, lymphomatous, and smoldering forms [36, 37]. The acute form of ATL is characterized by infiltration of lymph nodes, viscera, and skin with malignant cells, resulting in a constellation of clinical features (Table 1). Circulating abnormal lymphocytes, called flower cells, are generally seen. Hypercalcemia, abnormal liver function values, and lytic bone lesions are common. Median survival is 11 months from diagnosis. Conventional chemotherapy is not curative and relapses often occur quickly, although prolonged survival has been reported. Adult T-cell leukemia/lymphoma has been estimated to occur in 2% to 4% of individuals infected with HTLV-I in regions where HTLV-I is endemic and where early childhood infection is common [38, 39]. It occurs most frequently among persons aged 40 to 60 years, suggesting that a latent period as long as a few decades is required for the disease to develop. One case of ATL in an immunocompromised patient has been reported in which infection appears to have been transfusion acquired [40].
Human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis is characterized by progressive and permanent lower-extremity weakness, spasticity, hyperreflexia, sensory disturbances, and urinary incontinence (Table 2). In patients with HAM/TSP, unlike in those with multiple sclerosis, the signs and symptoms do not wax and wane, cranial nerves are not involved, and cognitive function is not affected. Antibodies to HTLV-I are characteristically found in the cerebrospinal fluid [41]. Treatment with corticosteroids has been reported to be useful in some cases [42]. Danazol, a synthetic androgen, reportedly improves symptoms, including bladder dysfunction [43, 44]. Fewer than 1% of HTLV-I-infected persons develop HAM/TSP [45]; it is believed to be immunologically mediated, and it affects women more frequently than men. The latency period for HAM/TSP is shorter than that for ATL; cases of HAM/TSP have been associated with blood transfusion, with a median interval of 3.3 years between transfusion, and development of HAM/TSP [46].
Recently, infective dermatitis, a chronic eczema associated with Staphylococcus aureus and β-hemolytic streptococcus, has been reported in Jamaican children infected with HTLV-I [47]. The full spectrum of HTLV-I-associated diseases may still include other disorders. Cases of polymyositis [48], chronic arthropathy [49], panbronchiolitis [50], and uveitis [51] have been reported in HTLV-I-infected patients.
Human T-Lymphotropic Virus Type II
Prevalence
Until recently, partly due to the lack of serologic tests to differentiate HTLV-II from HTLV-I, no information was available regarding the seroepidemiology or modes of transmission of HTLV-II. Infection with HTLV-II is prevalent among injecting drug users in the United States and Europe [52, 53]; more than 80% of HTLV-I/II seropositivity in drug users in the United States is due to HTLV-II infection [54]. Human T-lymphotropic virus type II also appears to be endemic in American Indian populations, including the Guaymi Indians in Panama [55] and North American Indians in Florida [56] and New Mexico [57]. Approximately one half of U.S. volunteer blood donors seropositive for HTLV-I/II are infected with HTLV-II. Blood donors infected with HTLV-II most often report either a history of drug injection or a history of sexual contact with an injecting drug user [6, 58]. A smaller percentage report a history of blood transfusion.
Transmission
Human T-lymphotropic virus type II is presumed to be transmitted in a similar manner to HTLV-I, but much less is known regarding specific modes and efficiency of transmission of HTLV-II. One study of 20 non-breast-fed children born to HTLV-II-infected women in New York City failed to show evidence of transmission to the newborns [59]. The HTLV-II provirus has been detected in breast milk from HTLV-II-infected mothers [60], but no data are available regarding transmission to breast-fed infants.
Human T-lymphotropic virus type II can be transmitted sexually [61]; the most commonly reported risk factor among HTLV-II-infected female U.S. blood donors is sexual contact with an injecting drug user [6, 58].
The virus can be transmitted by transfusion of cellular blood products (whole blood, red blood cells, and platelets) [31, 32]. The probability of transmission from red blood cells appears to diminish with longer product storage [31].
The high prevalence of HTLV-II among injecting drug users is probably due to the sharing of blood-contaminated needles or other injection paraphernalia [62].
Diseases
Human T-lymphotropic virus type II infection has not been clearly associated with any diseases. The virus was first isolated from two patients with hairy cell leukemia [2, 63], but no evidence of HTLV-II infection was found in 21 additional patients with hairy cell leukemia who were examined [64]. One study failed to show increased rates of any lymphoproliferative illnesses in New Mexico, where HTLV-II is present in American Indians [65]. Rare cases of HAM/TSP-like neurologic illnesses [66] and of mycosis fungoides [67] and large granular lymphocyte leukemia [68] have been reported in HTLV-II-infected persons. Cases of erythrodermatitis and bacterial skin infections have been reported in HIV-1- and HTLV-II-coinfected individuals [69].
Serologic Tests
Serum specimens are screened for antibody to HTLV-I using licensed enzyme immunoassays prepared from HTLV-I whole-virus lysate antigens. These assays vary in their sensitivity to detect antibodies to HTLV-II [4, 5]. Initially reactive specimens are 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 tests are considered nonreactive [3].
Additional tests, such as the Western immunoblot and the radioimmunoprecipitation assay, are needed to correctly interpret repeatably reactive specimens. Such supplementary tests must be inherently capable of identifying antibodies to the core (gag) and the envelope (env) proteins of HTLV-I/II. Indirect fluorescent antibody testing for HTLV-I/II has been used in some laboratories, but it does not distinguish antibodies to specific HTLV gene products. None of the supplementary tests have been licensed by the Food and Drug Administration, but they are available in research institutions, blood banks, some public health laboratories and industry, and as in-house tests in some diagnostic laboratories.
The following criteria for HTLV-I/II seropositivity were adopted by a U.S. Public Health Service (USPHS) working group in 1988 [3]: A specimen that is repeatedly reactive by enzyme immunoassay must demonstrate immunoreactivity to both the gag gene product p24 and to an env gene product (gp46 or gp61/68 or both) to be considered seropositive for HTLV-I/II. Reactive serum specimens not satisfying these criteria but showing immunoreactivity to at least one suspected HTLV gene product are designated “indeterminate.” Both Western immunoblot and radioimmunoprecipitation may be required to determine whether a specimen is positive or indeterminate. Serum specimens with no immunoreactivity to any HTLV gene product in additional, more specific tests are considered false positive. Several studies using provirus amplification have supported the accuracy of these diagnostic criteria; persons whose specimens satisfy the criteria for positivity are always infected with HTLV-I or HTLV-II [7, 70]. In contrast, persons whose specimens are “indeterminate” are rarely infected with either virus; in those who are found to be infected, repeated serologic testing frequently demonstrates seropositivity [70, 71]. In rare instances, persons with reactivity to p19 and to an env gene product (gp46 or gp61/68 or both) but without reactivity to p24 have been found to be infected with HTLV-I/II [72].
A significant advance in HTLV serologic testing has been the development of a recombinant env protein, p21e. Reactivity to p21e (in either enzyme immunoassay or “spiked” Western immunoblot) has been found to be highly sensitive for HTLV-I/II infection, being observed in 100% of infected persons [73]. The specificity of the p21e reactivity, however, has been questioned [74, 75]. For purposes of notification and counseling, it is prudent to confirm the positivity of samples showing p21e serologically by tests that detect env reactivity, such as radioimmunoprecipitation or recombinant protein-based assays [76], or by the polymerase chain reaction, until further information is available concerning this test.
The supplementary serologic tests discussed thus far are incapable of differentiating antibodies to HTLV-I and HTLV-II. The relative intensity of the reactivity to the gag proteins p19 and p24 on the “spiked” Western immunoblot has been used to differentiate HTLV-I from HTLV-II [77], but such differentiation may be unreliable [78]. Recently, several synthetic peptides and recombinant proteins have been developed for this purpose [8, 9, 79]. As with the previously discussed supplementary tests, all of these tests are available for research only. Preliminary data indicate that such assays can be highly specific in differentiating antibodies to HTLV-I and HTLV-II [8, 9, 79]. Not all HTLV-I/II-positive serum specimens, however, can be typed as HTLV-I or HTLV-II using these tests. In these cases, more sophisticated methods, such as provirus amplification or virus isolation, may be needed to differentiate HTLV-I from HTLV-II infection.
Notification and Deferral of Blood Donors
In the United States, blood donors whose serum specimens are repeatably reactive by the HTLV-I enzyme immunoassay and confirmed as seropositive for HTLV-I/II by the additional specific tests discussed above are notified and permanently deferred from donating blood. This deferral policy includes donors confirmed positive with antibodies to HTLV-I, HTLV-II, or HTLV-I/II (differentiation between the infections is not attempted or is unsuccessful). Blood donors with serum specimens repeatably reactive on screening but not confirmed as seropositive for HTLV-I/II (includes HTLV false-positive and indeterminate specimens) should also be notified and deferred if the same result is obtained on two separate donations. In some blood centers, such donors are deferred after the first such donation. Individuals who are repeatably reactive on screening but not confirmed as seropositive for HTLV-I/II should not be told that they are infected with HTLV-I or HTLV-II. The above policies for donor deferral are based on Food and Drug Administration recommendations. In addition, the Food and Drug Administration recommendations regarding the use of blood components should be followed.
Guidelines for Counseling
In consideration of the information presented above, the following guidelines for counseling HTLV-seropositive individuals are recommended. In instances in which viral typing is possible, counseling should be virus specific. As noted above, HTLV-I and HTLV-II are two different retroviruses with different epidemiology and different disease associations. The specific recommendations for persons infected with HTLV-I or HTLV-II should therefore take these differences into account.
Human T-Lymphotropic Virus Type I
Persons found to be seropositive for HTLV-I/II according to the USPHS criteria and positive for HTLV-I by additional testing should be informed that they are infected with HTLV-I. They should be told that HTLV-I is not the AIDS virus, that it does not cause AIDS, and that AIDS is caused by a different virus called HIV. They should be told that HTLV-I is a lifelong infection. They should be given information regarding modes and efficiency of transmission, disease associations, and the probability of developing disease.
In particular, persons infected with HTLV-I should be advised to:
1. Share the information with their physician
2. Not donate blood, semen, body organs, or other tissues
3. Not share needles or syringes with anyone
4. Not breast-feed infants
5. Consider the use of latex condoms to prevent sexual transmission
If the HTLV-I-positive individual is in a mutually monogamous sexual relationship, testing of the sex partner should be recommended to help formulate specific counseling advice. If the sex partner is also positive, no further recommendations are indicated. If the sex partner is negative, the couple should be advised that the use of latex condoms can help prevent transmission of HTLV-I to the negative partner, male or female. Male-infected, female-noninfected couples desiring pregnancy should be made aware of a finite risk for sexual transmission of HTLV-I during attempts at pregnancy, and of a small risk for vertical transmission from mother to infant unrelated to breast-feeding. Such couples might be advised to use latex condoms at all times except the fertile period while attempting pregnancy. The use of latex condoms is strongly recommended for HTLV-I-positive individuals with multiple sex partners or otherwise engaging in nonmutually monogamous sexual relationships. These individuals should be reminded of the risk for acquiring other sexually transmitted infections, including HIV.
Human T-Lymphotropic Virus Type II
Persons found to be seropositive for HTLV-I/II according to the USPHS criteria and positive for HTLV-II by additional testing should be informed that they are infected with HTLV-II. They should be told that HTLV-II is not the AIDS virus, that it does not cause AIDS, and that AIDS is caused by a different virus called HIV. They should be told that HTLV-II is a lifelong infection. They should be given information regarding possible modes of transmission and the lack of firm disease associations.
In particular, they should be advised to:
1. Share the information with their physician
2. Not donate blood, semen, body organs, or other tissues
3. Not share drug needles or syringes with anyone
4. Not breast-feed infants
Although the risks of transmission of HTLV-II by breast-feeding and of disease from HTLV-II are presently unknown, the theoretical risk for transmission and disease, as for HTLV-I, makes it prudent to recommend against breast-feeding by HTLV-II-infected mothers when and where safe nutritional alternatives exist.
5. Consider the use of barrier precautions to prevent sexual transmission
HTLV-II can be sexually transmitted, but the risks for disease are unknown. If the HTLV-II-positive individual is in a mutually monogamous sexual relationship, testing of the sex partner should be recommended to help formulate specific counseling advice. If the sex partner is also positive, no further recommendations are indicated. If the sex partner is negative, the couple should be advised that the use of latex condoms can help prevent transmission of HTLV-II to the negative partner, male or female. The use of latex condoms is strongly recommended for HTLV-II-positive individuals with multiple sex partners or otherwise engaging in nonmutually monogamous sexual relationships. These individuals should be reminded of the risk for acquiring other sexually transmitted infections, including HIV.
Human T-Lymphotropic Virus Type I/II
Persons found to be seropositive for HTLV-I/II according to the USPHS criteria but without differentiation of their infection should be informed that they are positive for HTLV-I/II and that they are likely to be infected with either HTLV-I or HTLV-II. Because of the differences in the epidemiologic and clinical correlates of HTLV-I and HTLV-II, an effort to type the infection should be made. If unsuccessful, these HTLV-I/II seropositive persons should be given information regarding possible modes and efficiency of transmission of HTLV-I and HTLV-II, disease associations of HTLV-I, and the probability of developing disease. Specific counseling advice should be the same as for HTLV-I-infected persons (see HTLV-I section).
Human T-Lymphotropic Virus Indeterminate
Blood donors with serum specimens that are HTLV indeterminate on two occasions at least 3 months apart should be advised that their specimens were reactive in a screening test for HTLV-I but that the results could not be confirmed by a second, more specific test. They should be reassured that “indeterminate” test results are only rarely caused by HTLV-I or HTLV-II infection. Persons testing “indeterminate” for HTLV-I/II on one occasion should be offered retesting to make sure they have not been recently infected with HTLV-I or HTLV-II and are in the process of seroconverting. If they have the same test result, they should be reassured that they are unlikely to be infected with HTLV-I or HTLV-II.
False-Positive Tests
Blood donors with serum specimens that are repeatably reactive by HTLV-I enzyme immunoassay but negative by Western immunoblot on two occasions should be advised that their HTLV-I screening test is falsely positive, and that it could not be confirmed by a second, more specific test. They should be reassured that they are not infected with HTLV-I or HTLV-II.
Medical Follow-up
A periodic medical evaluation of HTLV-I- or HTLV-I/II-infected persons by a physician knowledgeable about these viruses is recommended. This evaluation might include a physical examination, including a neurologic examination, and a complete blood count with peripheral smear examination. Medical evaluation of HTLV-II-infected persons should be considered optional.
- Copyright ©2004 by the American College of Physicians
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