Introduction: HTLV Infection
This text was written by an infectious disease specialist from the perspective of Infectious Disease Specialty, focusing on aspects where the specialty is most heavily involved in caring for people with HTLV-1 infection. Examples include general clarifications to patients and their families about the infection and assistance to people with HTLV infection, whether asymptomatic or symptomatic. Infectology contributes significantly to issues of clinical and laboratory diagnosis, transmission and prevention methods, and information on microbiological aspects. When antiretroviral medications are recommended, it is advisable for the infectious disease specialist to participate in patient care.
When symptoms are present, i.e., when there is manifest disease, other Medical Specialties are necessary, such as Hematology, Neurology, Urology, Internal Medicine (General Practitioner), or Physiatry, among others. Occasionally, other health areas such as Nursing, Physiotherapy, and Nutrition may also be important in patient care. When the infection is associated with leukemia, the role of the Hematologist is fundamental and often sufficient, without the need for co-management with an infectious disease specialist.
Etiology (the cause, the virus, microbiology): HTLV-I
Human T-cell Lymphotropic Viruses types I and II (HTLV I and II) are type C human retroviruses. They belong to the Orthoretrovirinnae family and the Deltaretrovirus genus. The virus, isolated in 1980 from a patient with cutaneous T-cell lymphoma, was initially associated with adult T-cell leukemia (ATL) in Japan in 1977 and later detected in various parts of the world.
Epidemiology
HTLV-1
HTLV-I is endemic in the Caribbean, southern Japan, parts of Africa, and South America, where prevalence rates are slightly lower. In Salvador, Bahia, one of the rare studies conducted on a primary sample basis, HTLV-1 seroprevalence reached 1.8%, being higher in women (2%) compared to males (1.2%). In Rio de Janeiro, São Paulo, and Minas Gerais, the prevalence is 0.3-0.33%; in Paraná and Rio Grande do Sul, it is 0.08%.
The virus can be transmitted vertically (mother to child), through breastfeeding, blood products, shared devices by intravenous drug users (needles), or sexual contact.
Most HTLV-I infections are asymptomatic in the general population. In HIV-HTLV-1 co-infection, it is unknown if there is a higher likelihood of disease development. When HTLV-I causes disease, it can lead to Adult T-cell Leukemia (ATL) or HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP).
CD4 cells (CD4+ T Lymphocytes) are the main target of HTLV-I infection. HTLV-I-infected CD4 cells are found in the cerebrospinal fluid (CSF) of patients with HAM/TSP. In ATL, there is circulation of monoclonal transformed cells carrying HTLV-I provirus.
HTLV-II
HTLV-II is endemic among Intravenous Drug Users (IDUs), with a seroprevalence of approximately 20%. It has not been definitively demonstrated that HTLV-II causes human disease, but some reports suggest it may cause a syndrome similar to HAM/TSP. The effect of HTLV-I/II on HIV progression is controversial, with different studies reaching opposite conclusions.
Clinical Presentation
Adult T-cell Leukemia/Lymphoma (ATLL)
There is a 5% lifetime risk for HTLV-I infected individuals to develop this condition. The disease presents with B symptoms and lymphadenopathy. B symptoms consist of fever, night sweats, and weight loss. The following symptoms are frequently associated: extreme fatigue, general malaise, generalized pruritus, and anorexia. Cutaneous involvement, in the form of plaques or nodules, is common.
Classification of ATLL Clinical Forms
Predominant findings on physical examination and laboratory tests at disease onset include: lymphadenopathy, hepatomegaly, splenomegaly, and skin lesions. Hypercalcemia is frequently associated with ATLL. Other findings include: abdominal pain, diarrhea, pleural effusion, ascites, cough, expectoration, and abnormal chest X-ray (interstitial patterns denoting infectious conditions). Clinically, ATLL is classified as follows:
Acute form: Most common, characterized by an aggressive leukemic phase. Patients often present with elevated leukocyte count, generalized lymphadenopathy, hypercalcemia with or without osteolytic lesions, and skin rash.
Lymphomatous form: Characterized by lymphadenopathy without peripheral blood involvement. Many patients present with advanced disease, although hypercalcemia is less frequent. Skin lesions are common and include erythematous rashes, papules, and nodules, sometimes with ulceration.
Chronic form: Frequently associated with exfoliative skin rash. Presents with absolute T-lymphocytosis, increased lactate dehydrogenase (LDH), and absence of hypercalcemia.
Indolent form: Normal leukocyte count with 5% or more abnormal T lymphocytes in peripheral blood; skin and pulmonary lesions may be present, but without hypercalcemia. Progression from chronic or indolent form to acute form occurs in 25% of cases.
HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)
There is a 0.5-2.0% lifetime risk for HTLV-I infected individuals to develop this condition. It consists of a progressive disease with lower limb stiffness, weakness, lower back pain, and bladder dysfunction. HIV-HTLV-I coinfected patients have higher CD4 counts than patients with HIV infection without HTLV-I. Opportunistic infections may occur at higher CD4 counts than in HTLV-I-negative patients. Immunosuppression may occur, leading to Strongyloides infestation and decreased reactivity to tuberculin skin test (PPD). It is important to note that the vast majority of infected individuals will not develop disease.
Laboratory Diagnosis
Laboratory diagnosis is made by ELISA for HTLV-I or HTLV-II, which has higher sensitivity than Western blot and PCR.
Important tests for Adult T-cell Leukemia/Lymphoma (ATLL)
- Complete blood count with differential, where leukocyte count ranges from normal to 500,000/mm3. Morphological examination of lymphoid cells is often the first sign for ATLL diagnosis. Cells with hyperlobulated nuclei (flower cells) may be observed in peripheral blood of leukemic cases.
- Bone marrow aspiration with morphological analysis of lymphocytes.
- Peripheral blood immunophenotyping, with a minimum T-cell panel including CD3, CD4, CD7, CD8, and CD25.
- Biopsy with histopathology and immunohistochemistry of the affected site (bone marrow, lymph node, skin, etc.).
- Cerebrospinal fluid examination should be considered in patients with aggressive forms of ATLL to detect leukemic infiltration or opportunistic infections.
- HTLV-1 seropositivity, confirmed by real-time PCR or Western Blot test.
Treatment
Asymptomatic Infection
There is no evidence of benefit from antiviral therapy. Moreover, as the HTLV genome is integrated into the host DNA, its eradication is unlikely.
Adult T-cell Leukemia/Lymphoma (ATLL)
Some antiretrovirals used in HIV treatment have activity against HTLV-1. A global meta-analysis showed that antiretroviral therapy with zidovudine (AZT) combined with interferon-alpha (IFN-alpha) is highly effective in the leukemic form of ATLL, significantly increasing progression-free survival and overall survival compared to chemotherapy alone. This therapy alone in chronic and indolent forms of ATLL significantly reduces the progression rate to aggressive forms and is associated with 100% overall survival at 5 years. The AZT plus IFN-alpha combination has been considered a change in the natural history of the disease. The lymphomatous form of ATLL is the only one that seems to benefit from chemotherapy in combination with IFN-alpha plus AZT.
Medications that can be used
- Zidovudine - The initial dose of zidovudine used in ATL treatment is 900mg/day, orally and divided into three doses. After 1 to 2 months, the AZT dose can be reduced to 600mg/day (divided into two doses). Zidovudine is acquired by the Ministry of Health and distributed to state health departments within the scope of Pharmaceutical Assistance. Dispensing zidovudine for HTLV-1-associated leukemia/lymphoma treatment requires the attending physician to fill out a specific request form at an Antiretroviral Medication Dispensing Unit (UDM), available on the website [http://azt.aids.gov.br](http://azt.aids.gov.br/), in the "Forms" section.
- Interferon-alpha - The dose is 5-6 million IU/m2/day SC, continuous use, with patients generally not tolerating a total daily dose above 9 million IU. The maximum recommended daily dose can be achieved by escalating administration of increasing doses, according to the patient's tolerance level. After 1 to 2 months, the INF-alpha dose can be reduced to 3-5 million IU/day. Note: Treatment with AZT and IFN-alpha should be maintained until grade 3 or 4 toxicity manifests or refractoriness is demonstrated. Ministry of Health Secretariat of Health Surveillance.
- Antineoplastic chemotherapy - For lymphomatous forms, the chemotherapy regimen is the one adopted in the institutional approach. Note: Due to the toxicity caused by zidovudine in this combination, it is suggested that the use of AZT plus INF-alpha be initiated only in the second cycle of chemotherapy.
- Antiparasitics - Albendazole 400mg orally for 3 consecutive days associated with Ivermectin 12mg orally, on the first and eighth days.
- Anti-infectives - Sulfamethoxazole (400mg) + trimethoprim (80mg), orally, continuous, at a dose of 1 tablet every 12 hours, three times a week; fluconazole (100mg/day), orally, continuous, at a dose of 2 tablets every 12 hours; and acyclovir (200mg), orally, continuous, at a dose of 2 tablets every 12 hours.
HTLV-1-Associated Myelopathy (HAM) and Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (HAM/TSP)
Here's the English translation as an editor:
Currently, there is no established effective treatment for HAM/TSP. However, some approaches have been attempted, including antiretroviral therapy (ART), interferon-alpha, antioxidants, and bone marrow transplantation, with limited success. Corticosteroid treatment may be beneficial in cases of acute myelitis, while patients with slow progression are better managed with symptomatic and physical therapy. Generally, corticosteroids, cyclophosphamides, interferon-alpha, immunoglobulins, plasmapheresis, and danazol have been used with inconsistent results.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have been tried based on in vitro activity against HTLV-I. Zidovudine (AZT) 1-2 g/day or lamivudine (3TC) 150 mg twice daily alone or AZT (250 mg twice daily) and 3TC (150 mg twice daily) were used in 3 small studies. Although a decrease in HTLV-I proviral load was observed, symptoms did not improve in most patients. Tenofovir (TDF) has recently shown good in vitro activity against HTLV-I. In a small randomized study of HIV-negative patients, 6 months of Zidovudine (AZT) 300 mg twice daily and lamivudine (3TC) 150 mg twice daily had no effect on HTLV proviral load or clinical symptoms. If Antiretroviral Therapy (ART) is initiated in co-infected patients, include zidovudine (AZT), tenofovir (TDF), and/or lamivudine (3TC) in patients with HAM/TSP or ATL if possible. Reducing proviral load (PVL) has been considered a potential strategy to prevent disease progression. Studies suggest that combining histone deacetylase inhibitors (HDACi) with AZT may decrease PVL in infected non-human primates, although viral load tends to increase again after treatment discontinuation.
Therefore, managing HTLV-1 infections and their associated manifestations requires an individualized approach, considering the disease subtype and treatment response.
Prevention
The Centers for Disease Control and Prevention (CDC) in Atlanta recommends that even people with asymptomatic infection should not breastfeed, donate blood, share needles, and should use latex condoms.
References
Brasil. Ministério da Saúde. PROTOCOLO CLÍNICO E DIRETRIZES TERAPÊUTICAS: LEUCEMIA MIELOIDE CRÔNICA DO ADULTO. 2021. Disponível em UR:// https://www.gov.br/saude/pt-br/assuntos/pcdt/arquivos/2021/leucemia-mieloide-cronica-do-adulto-pcdt.pdf/view . Acessado em 20 de janeiro de 2025.
Brasil. Ministério da Saúde. CONITEC. Protocolo de Uso de Zidovudina para Tratamento do Adulto com Leucemia/Linfoma Associado ao Vírus HTLV-1. 2016. Disponível em URL://http://antigo-conitec.saude.gov.br/images/Protocolos/Relatorio_ProtocoloUso_Zidovudina_2016.pdf . Acessado em 20 de janeiro de 2025.
Magalhães PMR et al. Vírus Linfotrópicos de células T humanas (HTLV-1 e HTLV-2): revisão de literatura. Brazilian Journal of Health Review, Curitiba, v.4, n.5, p. 20900-20923 sep./oct. 2021. DOI:10.34119/bjhrv4n5-193.
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. Ann Intern Med. 1993;118(6):448-54. [PMID:8382459]Comment: A practical set of guidelines from the CDC.
Joel N. Blankson, M.D., Ph.D. HTLV-I/II. Last updated: December 30, 2019. Johns Hopkins HIV Guide.
Mashkani B, Jalili Nik M, Rezaee SA, Boostani R. Expert Review of Neurotherapeutics. 2023 Jul-Dec;23(12):1233-1248. doi:10.1080/14737175.2023.2272639.
How to Control HTLV-1-Associated Diseases: Preventing Cellular Infection Using Antiviral Therapy. Pasquier A, Alais S, Roux L, et al. Frontiers in Microbiology. 2018;9:278. doi:10.3389/fmicb.2018.00278.
Highly Active Antiretroviral Treatment Against STLV-1 Infection Combining Reverse Transcriptase and HDAC Inhibitors. Afonso PV, Mekaouche M, Mortreux F, et al. Blood. 2010;116(19):3802-8. doi:10.1182/blood-2010-02-270751.
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