Version May 2024
INTRODUCTION — The human T-lymphotropic virus type I (HTLV-I) is a retrovirus that infects 10 to 20 million people worldwide, as estimated by seroprevalence studies. However, HTLV-I is associated with disease in only approximately 5 percent of infected individuals [1,2].
The diagnosis and treatment of HTLV-I infection and what is known about the disease associations will be reviewed here. The virology, pathogenesis, and epidemiology of HTLV-I are discussed separately. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology".)
DISEASE ASSOCIATIONS — The majority of HTLV-I-infected individuals will remain asymptomatic, but there are two well-recognized disease associations caused by the virus:
●Adult T cell leukemia-lymphoma (ATL)
●HTLV-I-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP).
In addition, several other clinical entities have been described in infected patients (table 1).
Adult T cell leukemia-lymphoma — HTLV-I was first isolated from a patient with a cutaneous T cell lymphoma in 1980 [3]. Since then it has become clear that the cumulative lifetime risk of ATL in a patient with HTLV-I infection is between 2 and 5 percent. The risk is slightly higher in males; the onset of ATL is typically delayed for 20 to 30 years after the viral infection [4]. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)
ATL is characterized by clonal proliferation of CD4+ T cells containing randomly integrated HTLV-I provirus, often associated with T cell receptor gene rearrangements. These cells have a distinct morphology with indented nuclei containing condensed chromatin and basophilic cytoplasm (picture 1). Four distinct clinical forms of ATL are recognized [5].
Acute — Acute ATL accounts for 47 to 57 percent of cases and follows an aggressive course with a median survival of six months. Clinical features include: skin lesions (nodules, ulcers, generalized papular rash), lytic bone lesions, hypercalcemia, and pulmonary infiltrates. The latter may be due either to direct leukemic infiltration or to opportunistic infections such as Pneumocystis jirovecii (formerly carinii) pneumonia (PCP) resulting from acquired immunodeficiency syndrome (AIDS)-like immunodeficiency. Central nervous system (CNS) involvement occurs in up to 10 percent of cases. Laboratory findings include raised levels of lactate dehydrogenase and alkaline phosphatase as well as hypercalcemia.
Lymphomatous — The lymphomatous form of ATL occurs in approximately 20 to 25 percent of cases. The clinical features include lymphadenopathy, hepatosplenomegaly, and skin lesions. Hypercalcemia is also common, but circulating tumor cells are unusual.
Chronic — The chronic form, which accounts for 20 percent of cases, has a better prognosis with a median survival of approximately two years. Hypercalcemia does not occur, and there is no CNS or gastrointestinal involvement.
Smoldering — Smoldering ATL is the least common type (approximately 5 percent of cases); median survival is more than five years. Skin and pulmonary lesions do occur, but other clinical features such as lymphadenopathy, hepatosplenomegaly, and hypercalcemia are absent. Less than 5 percent of peripheral CD4+ cells are involved, with proviral deoxyribonucleic acid (DNA) integrated in a monoclonal fashion.
Markers of disease progression — Several serum markers have been found to be elevated, especially in the acute form of ATL. These include serum CD25 (interleukin-2 receptor), serum thymidine kinase activity, and serum neuron-specific enolase [6-8]. Investigators have proposed that CD25 and enolase, the levels of which are highly correlated, may serve as markers of disease progression and might be monitored during treatment. However, these tests are not currently used in clinical practice.
Treatment — Use of standard regimens for advanced, aggressive non-Hodgkin lymphoma (NHL) is moderately effective, with most patients achieving initial partial or complete remission. However, early relapse is usual and median survival is only eight months.
A phase III trial comparing biweekly CHOP with a more aggressive chemotherapeutic regimen of VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone) plus AMP (doxorubicin, ranimustine, and prednisone) plus VECP (vindesine, etoposide, carboplatin, and prednisone) in 118 Japanese patients demonstrated significantly higher complete response rates with the more aggressive regimen (40 percent versus 25 percent, respectively) [9]. However, overall survival at three years was similar and toxicity-related morbidity and death was greater in the aggressive chemotherapy arm. Thus, the use of intensive combination chemotherapy remains investigational.
Allogeneic stem cell transplantation has been reported to benefit some patients already in remission [10].
Chemotherapy for ATL is discussed in detail separately. (See "Treatment and prognosis of adult T cell leukemia-lymphoma".)
HTLV-I-associated myelopathy/tropical spastic paraparesis — Although the first clinical description of TSP was published from the Caribbean in 1956 [11], it was not until 1985 that investigators reported the association of this condition with antibodies to HTLV-I in serum and cerebrospinal fluid (CSF) [12,13]. A group in Japan called the condition HAM in 1986 [14], but it was soon realized that TSP and HAM were the same entities.
Clinical features — HAM/TSP is more common in females than males, in keeping with the higher prevalence of HTLV-I infection in females [15-17]. It affects less than 2 percent of HTLV-I carriers, with onset ranging from four months to 30 years (median 3.3 years) after infection [15]. In another prospective cohort analysis, HTLV-1-associated myelopathy was found in 3.7 percent (95% CI 1.4-8.0) and HTLV-II myelopathy in 1.0 percent (95% CI 0.3-2.5) [16].
The risk factors for developing HAM/TSP are not well understood. One important risk factor appears to be a high provirus load [18]. In addition, certain polymorphisms in the interleukin (IL)-10 promoter and in the IL28B gene, which is involved in interferon lambda expression, may be associated with both provirus load and the risk of HAM/TSP [19,20].
The illness is characterized by an insidious onset of slowly progressive weakness and spasticity of one or both legs, together with hyperreflexia, ankle clonus, extensor plantar responses, and lumbar pain [21,22]. Other features include back pain, detrusor instability leading to nocturia, urinary frequency, incontinence, and minor sensory changes, especially paresthesias and loss of vibration sense [23]. Cognitive function is unaffected and there is no upper limb involvement.
Individuals with HTLV-1 infection also appear to have an excess of neurological manifestations, even if they do not meet criteria for HAM/TSP. (See 'Other neurological abnormalities' below.)
Diagnosis — Diagnostic criteria were agreed upon by a World Health Organization (WHO) panel in 1989 (table 2) [24]. In addition to the laboratory diagnostic tests listed in table 2, the use of HTLV-1 proviral load in the central nervous system (CNS) has been proposed as a new parameter for diagnosis of HAM/TSP [25].
Magnetic resonance imaging of the brain and spinal cord may be normal or may show atrophy of the cervical or thoracic cord and/or white matter lesions in the subcortical and periventricular regions [26,27]. Cerebrospinal fluid (CSF) examination reveals a low level lymphocytosis in approximately one-third of cases as well as a mildly elevated protein concentration [28]. Anti-HTLV-I antibodies are detectable in the CSF with a high CSF/serum ratio. Virus can be cultured from CSF lymphocytes and proviral DNA detected by PCR [29]. Neurophysiologic studies may reveal evidence of posterior column dysfunction as well as a peripheral neuropathy.
Treatment — Management of HAM/TSP is primarily symptomatic, as disease-modifying treatment options are limited. A multidisciplinary International Retrovirology Association expert panel supports the use of systemic corticosteroids in patients with progressive disease (high-dose pulsed methyl prednisolone for induction; low-dose (5 mg) oral prednisolone for maintenance therapy) [30]. Systemic corticosteroids have been reported in some case series to slow progression [31], reduce neurologic disability [32], and improve pain [33], presumably through their anti-inflammatory effect [34]. However, other studies have reported no such benefit [27,35], and there have been no randomized clinical trials.
An anti-CCR4 monoclonal antibody, mogamulizumab, which has some efficacy in adult T cell leukemia and is available in Japan for that indication, may also have benefit in HAM/TSP. In a preliminary trial of 21 patients with HAM/TSP, varying doses of mogamulizumab were associated with improvements in spasticity and reductions in motor disability, as well as reductions in HTLV-I proviral load and markers of CNS inflammation [36]. Further study is warranted to define clinical efficacy, long-term safety, and optimal dosing of mogamulizumab for HAM/TSP.
Other agents with suggested benefit in small trials or observational studies include the anabolic steroid danazol [37] and interferon-beta1a [38,39].
Antiviral therapy has not been shown to be effective in the treatment of HAM/TSP [30].
Prognosis — In a study of 123 patients with a 14-year follow-up, HAM/TSP was demonstrated to progress from disease onset to using a wheelchair over a median of 21 years [40].
A prospective cohort study [16], which included 160 patients with HTLV-I, revealed six cases of HAM/TSP diagnosed over a 12-year period (as well as a further four cases in 405 subjects with HTLV-II infection). Clinical progression was highly variable in this small cohort. The most severely affected subjects were using a wheelchair, while patients with mild cases only experienced difficulty rising from a chair.
Other disease manifestations
Other neurological abnormalities — In addition to myelopathy, HTLV-1 infection is also associated with other neurological abnormalities, including isolated mild cognitive deficits, peripheral neuropathy, neurogenic bladder dysfunction, and amyotrophic lateral sclerosis [41]. In one study of 606 HTLV-1 infected individuals in Brazil, HTLV-1 proviral loads in patients with these neurologic manifestations were significantly higher than in asymptomatic carriers [42]. Another study found that HTLV-1 and HTLV-II infected patients were more likely than seronegative controls to have symptoms of leg weakness, impaired tandem gait, and urinary incontinence as well as physical examination findings of Babinski sign and impaired vibration sense [43].
The frequency of neurologic signs and symptoms without definite HAM/TSP in HTLV-1-infected patients is uncertain. A study that included 251 HTLV-1-infected individuals in Brazil reported that over a maximum of eight years of follow-up, approximately 30 percent developed neurological manifestations without fulfilling the case definition for HAM/TSP [44]. However, these findings need to be interpreted with caution. No control group was used and self-reported symptoms to a team of neurologists, urologists, rheumatologists, psychologists, and dentists were used in determining the frequency of the neurological findings.
Infective dermatitis — Infective dermatitis was first described in Jamaica in 1966 [45]. Subsequently, its association with HTLV-I infection was recognized in several endemic areas, including Japan and the Caribbean [46,47]. The onset is usually in early childhood, and the condition tends to improve with age. In a series of 42 cases from Brazil, the mean age of onset was 2.6 years (range 2 months to 11 years), with skin lesions appearing during the first year of life in about one-third of patients [48]. Remission occurred in 36 percent of cases, at a mean age of 15 years.
It is characterized by an eczematous, exudative rash affecting the scalp, postauricular region, face, axillae and groins. This may be associated with nasal involvement, including watery discharge and crusting of the anterior nares, and dermatopathic lymphadenopathy. Although the condition is caused primarily by HTLV-1 infection, secondary infection with Staphylococcus aureus or beta-hemolytic streptococci is common. Consequently, it usually responds well to antibiotics but tends to relapse upon stopping therapy.
In the Brazilian case series, almost one-half of the patients who had long-term follow-up were also ultimately diagnosed with HTLV-associated myelopathy/tropical spastic paraparesis [48]. (See 'HTLV-I-associated myelopathy/tropical spastic paraparesis' above.)
Uveitis — The association of HTLV-I infection with uveitis was first reported in Japan in 1989 [49]. It is more common in younger patients with HTLV-I (under the age of 50) and slightly more frequent in females, but its exact incidence among HTLV-I carriers remains uncertain. The condition presents with visual disturbance, including floaters and blurred or "foggy" vision, and is bilateral in nearly half of those affected [50]. Ocular signs include: iritis, vitreous opacities, retinal vasculitis and retinal hemorrhages and exudates. There is a good response to topical or systemic corticosteroids but relapse is common upon discontinuation of therapy.
Rheumatologic and pulmonary disorders — A variety of rheumatologic conditions have been described in association with HTLV-I infection. A chronic inflammatory arthropathy has been reported in some patients, affecting predominantly the shoulders, wrists, and knees [51]. Synovial biopsy from involved joints reveals synovial cell proliferation together with lymphocytic infiltration [51].
Sjögren's disease has been described in a group of HTLV-I-infected patients with and without HAM/TSP [52]. Clinical features were similar to those seen in HTLV-I-negative Sjögren's disease and included dry eyes and mouth, ocular signs, and histologic evidence of glandular involvement. Some patients also had other autoimmune features such as arthropathy, Raynaud's, and interstitial pneumonitis.
Investigators in Jamaica reported HTLV-I positivity in 11 of 13 patients presenting with polymyositis and concluded that there was likely to be a causative relationship [53].
A lymphocytic alveolitis was first reported in 1987 in five Japanese patients with HAM/TSP [54]. Subsequent studies from Japan have also described radiographic and pathologic findings consistent with a lymphocytic bronchiolitis associated with HTLV-1 infection [55-59]. However, since these features may be found in asymptomatic patients, their clinical significance remains uncertain.
Aboriginal Australians have one of the highest prevalence rates of bronchiectasis in the world. One prospective study among aboriginal Australians found a very high seroprevalence of HTLV type 1 among hospitalized patients with bronchiectasis (nearly 60 percent) compared with historical background HTLV-1 prevalence rates (7 to 14 percent), suggesting that HTLV-1 infection may contribute to the risk of developing this pulmonary disease in this population [60].
A high prevalence of bronchiectasis has also been reported in a UK cohort of HTLV-1 positive patients attending a national referral center [61]. Overall, 3.4 percent had bronchiectasis confirmed by high resolution chest CT, compared with a reported prevalence of 0.1 percent in the general population. The risk of bronchiectasis was higher among those with symptomatic HTLV-1 infection (ie, HAM/TSP, ATL, HTLV-associated inflammatory disease) compared with asymptomatic patients (relative risk 19.2).
Immune thrombocytopenia (ITP) — HTLV-I infection was found in 17 (22.1 percent) of 77 Japanese patients with ITP [62]. Response to steroid treatment was poor and five patients required splenectomy.
Gastric cancer — Some epidemiologic data suggest that the incidence of gastric cancer may be lower in patients with HTLV-1 infection. For example, the incidence of gastric cancer is lower in Kamigoto compared with Nagasaki, Japan; in contrast the rate of HTLV-1 positivity in Kamigoto is high (30 percent among age groups at risk for gastric cancer) compared with other areas in Japan [63]. Some reports have also noted a low prevalence of Helicobacter pylori infection among patients infected with HTLV-1 [64].
A retrospective cohort study was performed in 5686 patients aged >40 years in Kamigoto to assess the relationship between serologic evidence of HTLV-1 infection, H. pylori infection, and the subsequent development of gastric cancer over a decade of follow-up [63]. HTLV-1 infection was associated with a reduced risk of H. pylori infection and a lower risk of gastric cancer (OR, 0.38; 95% CI, 0.21-0.70).
DIAGNOSIS — The diagnosis of HTLV-I infection is generally based upon serologic testing to detect antibodies to the virus. An enzyme-linked immunosorbent assay (ELISA) is the most frequently used screening test, using antigens prepared from whole virus lysate or by recombinant technology [65]. Particle agglutination is an alternative [66]. Western blotting (WB) is normally used for confirmatory testing, which requires detection of antibodies to both gag and env viral gene products. WB also distinguishes between infection with HTLV-I and the less pathogenic HTLV-II [67]. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology".)
Some individuals with a positive screening ELISA test may have an indeterminate Western blot test, with incomplete antibody reactivity to HTLV-I antigens. The clinical significance of this finding is unclear, but may reflect prior exposure, cross-reactivity to other infectious agents, or infection with a novel retrovirus [68].
Polymerase chain reaction (PCR)-based testing to detect proviral DNA in peripheral blood mononuclear cells is an alternative diagnostic test. This test will also differentiate HTLV-I from HTLV-II infection. Advantages of this type of analysis are its ability to provide quantitation of proviral load in the blood [69], and its applicability in detecting proviral DNA in tumor cells or other tissue samples [70].
ANTIVIRAL TREATMENT AND PREVENTION — Treatment is not indicated for asymptomatic individuals, and management of such patients is confined to the early diagnosis of clinical manifestations and to the prevention of transmission to others. The latter includes avoidance of breastfeeding in endemic areas, screening of blood donors, as well as the promotion of safe sex and discouraging needle sharing [71]. (See "Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology".)
There have been only limited studies of specific antiretroviral therapy for HTLV-I infection [72]. As noted above, the combination of the nucleoside analogue reverse transcriptase inhibitor (NRTI) zidovudine (ZDV), with IFN-alfa, has been used with some benefit in patients with ATL [73,74]. However, it is unclear whether the ZDV activity relates to its antiviral effect or to direct cytotoxicity.
The data on lamivudine (3TC), another NRTI, are mixed with some in vitro and in vivo benefits noted, despite an apparent absence of antiviral activity. In one study, 3TC inhibited long-term growth of HTLV-I-infected peripheral blood mononuclear cells despite a lack of antiviral activity at clinically relevant concentrations [75]. Another report demonstrated HTLV-I resistance in its reverse transcriptase to 3TC but not to four other NRTIs (ZDV, didanosine [ddI], stavudine [d4T], and zalcitabine [ddC]) [76]. 3TC has been administered alone and in combination to a few HTLV-I-infected patients with mixed results.
●Two patients with HAM/TSP were treated with 3TC plus ZDV; one patient had a 2-log reduction in proviral load after three months, which was sustained, but she did not experience neurologic improvement [77]. The second patient had a 1-log increase in proviral load.
●A randomized, double-blind, placebo-controlled study of six months combination therapy with 3TC and ZDV in 16 patients with HAM showed no significant differences in clinical parameters or proviral load between treatment and placebo [78].
●A series of five patients with HAM/TSP who received 3TC alone documented an approximate 10-fold decline in HTLV-I DNA initially followed by fluctuations between baseline and the lowest point thereafter [79].
SUMMARY AND RECOMMENDATIONS
●General – The human T-lymphotropic virus (HTLV-I) is a retrovirus, which infects 10 to 20 million people worldwide, but is associated with disease in only approximately 5 percent of individuals. (See 'Introduction' above.)
●Disease associations – Two well-recognized disease associations are caused by the virus: Adult T cell leukemia-lymphoma (ATL) and HTLV-I-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP). (See 'Disease associations' above.)
•Adult T cell leukemia-lymphoma – Four distinct clinical forms of ATL are recognized: acute, lymphomatous, chronic, and smoldering. These various forms of disease have varying presentations and prognosis. The most common clinical presentation is acute ATL, which has the poorest overall survival of approximately six months. Treatment of ATL is discussed elsewhere. (See 'Adult T cell leukemia-lymphoma' above and "Treatment and prognosis of adult T cell leukemia-lymphoma".)
•HTLV-I-associated myelopathy/tropical spastic paralysis – HTLV-I associated myelopathy/tropical spastic paraparesis is characterized by an insidious onset of slowly progressive weakness and spasticity of one or both legs, together with hyperreflexia, ankle clonus, extensor plantar responses, and lumbar pain. No therapy is of proven benefit in HAM/TSP, but corticosteroids may slow progression and reduce both disability and pain. (See 'HTLV-I-associated myelopathy/tropical spastic paraparesis' above.)
•Other disease manifestations – Other disease manifestations include neuropathy, infiltrative skin disorders, uveitis, and rheumatologic and pulmonary disorders. (See 'Other disease manifestations' above.)
●Diagnosis – The diagnosis of HTLV-I infection is generally based upon serologic testing with ELISA followed by a confirmatory Western blot test. (See 'Diagnosis' above.)
●Treatment and prevention – Treatment is not indicated for asymptomatic HTLV-1 infection. (See 'Antiviral treatment and prevention' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David T Scadden, MD, who contributed to an earlier version of this topic review.
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