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This phase 2b, open-label, randomized controlled trial evaluates the efficacy and safety of dolutegravir (DTG) alone versus dolutegravir combined with tenofovir disoproxil fumarate (TDF) in individuals with HTLV-1 infection and associated clinical manifestations. The primary objective is to compare changes in HTLV-1 proviral load at 24 and 48 weeks. Secondary outcomes include clinical, functional, immunological, and quality-of-life measures.
Human T-lymphotropic virus type 1 (HTLV-1) infection is a neglected condition associated with severe neurological and hematological diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Currently, no effective antiviral therapy exists.
Preclinical and clinical data suggest that integrase inhibitors such as dolutegravir may reduce HTLV-1 proviral load. Additionally, combination therapy with tenofovir may enhance antiviral activity. This study builds on prior pilot data demonstrating partial virological response to DTG.
Participants will be randomized (1:1) to receive DTG alone or DTG plus TDF for 48 weeks. Outcomes will include virological, immunological, clinical, and patient-reported measures. The study aims to provide evidence for therapeutic strategies targeting HTLV-1.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dolutegravir | Active Comparator | Dolutegravir 50 mg p.o. daily |
|
| Combination therapy | Experimental | Daily Dolutegravir 50 mg Daily Tenofovir 300 mg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Combination of Dolutegravir + Tenofovir DF for treatment of HTLV-1 infection | Combination Product | In a previous study Dolutegravir was able to reduce HTLV-1 proviral load, but a few patients did not respond to therapy. We intend to use a combination of Dolutegravir + TDF to improve the response rate. There is no previous evidence on the use of such combination for treating HTLV-1 infection. |
| Measure | Description | Time Frame |
|---|---|---|
| HTLV-1 Proviral Load | Measurement of HTLV-1 Proviral Load by RT-PCR. Results will be expressed as copies/ml of whole blood | From baseline to the end of treatment at 48 weeks |
| Changes in Pain intensity (DN4 doleur scale) | Change in intensity of pain measured by DN4 doleur scale (0 to 10, with values >4 indicating neuropathic pain) | Baeline, 24 and 48 weeks |
| Changes in Spasticity | Changes in limbs spasticity, as measured by Ashworth scale. The Ashworth Scale uses a simple ordinal scale ranging from 0 to 4, where the highest values mean increased spasticity | BL, 24 and 48 weeks |
| Changes in muscle strenght | Evaluation of muscle strenght by Kendall Muscle Grading system (Kendal scale), which ranges from 0 to 10, with highest values indicating better muscle strenght | BL, 24 and 48 weeks |
| Changes in motor score scales | Evaluation of changes in motor performance using the lower extremity motor score (LEMS) is a subscale of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) that assesses lower extremity muscle strength.The score range is 0-5 for each of 5 key muscles (hip flexors, knee extensors, ankle dorsi-flexors, long toe extensors and ankle plantar flexors) of each leg, with a maximum score of 50 (the lower values indicates worse motor function) | BL, 24, 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Nocturia frequency | Nocturia frequency across the study | Baseline, 24 and 48 weeks |
| Cytokines levels | Measurement of levels of (Tumon Necrosis Factor-Alpha) TNF-alpha, IL-6, IL-2, IL-4, IL-10, Interferon γ-induced Protein (IP-10), Gamma-Interferon (Gamma-IFN), in picogram/cubic milimiter. Values may varies from undetectable levels to any detectable concentration, expressed in pg/mm3. |
| Measure | Description | Time Frame |
|---|---|---|
| Quantification of HTLV-1 | To evaluate active replication of HTLV-1, we will measure the number of copies of Long Terminal Repeat (LTR) circles to detect HTLV-1 unintegrated proviral genome and HTLV-1 plasma RNA levels. Presence of any number of copies of LTR indicates ongoing active viral replication | BL, at 24 and 48 weeks |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Carlos Brites, MD, PhD | Contact | +5571992329552 | crbrites@gmail.com | |
| Estela Luz | Contact | +5571999867515 | eluz5@yahoo.com.br |
| Name | Affiliation | Role |
|---|---|---|
| Carlos Brites, MD, PhD | Hospital Universitário Professor Edgard Santos, Federal University of Bahia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Universitário Professor Edgard Santos | Recruiting | Salvador | Estado de Bahia | 40110-060 | Brazil |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32369988 | Background | Marino-Merlo F, Balestrieri E, Matteucci C, Mastino A, Grelli S, Macchi B. Antiretroviral Therapy in HTLV-1 Infection: An Updated Overview. Pathogens. 2020 May 1;9(5):342. doi: 10.3390/pathogens9050342. | |
| 39338913 | Background | Fernandez T, Marconi C, Montano-Castellon I, Deminco F, Brites C. A Systematical Review on ART Use in HTLV Infection: Clinical, Virological, and Immunological Outcomes. Pathogens. 2024 Aug 27;13(9):721. doi: 10.3390/pathogens13090721. |
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Anonimized clinical data can be shared with other researchers upon reasonable request
IPD will be available from January 2029 to June 2029
Researchers with an approved protocol will be abel to access the databank upon reasonable request to the study PI
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Health professionals who will evaluate patient´s neuro-functional performance will be blinded on treatment arm
|
| Dolutegravir (DTG) | Drug | Active comparator will be DTG, 50 mg/day |
|
| BL, 24 and 48 weeks |
| RAND 36-Item Health Survey | The RAND Corporation Health-Related Quality of Life (RAND-36) domains are scored on a 0 to 100 range, so that a high score defines a more favorable health-related quality of life (HRQoL). The scale measure several domains of HRQoL. | Baseline and at 48 weeks |
| Frequency of Adverse events and Serious adverse events |
frequency of incident AE associated with the treatment drugs |
| baseline to 48 weeks |
| Measurement of Levels of sCD14 and sCD163 | Levels of soluble cluster of diferentiation 14 (sCD14) and 163 (sCD14), expressed in ng/mL, will be measured to evaluate levels of monocytes´ activation across the trial. Higher levels indicate increased monocytes´ activation. | BL, 24 and 48 weeks |
| 41413309 | Background | Fernandez T, Arriaga MB, Mayoral R, Netto EM, Brites C. Dolutegravir use is related to lower HTLV-1 proviral load in people co-infected by HIV-1. Commun Med (Lond). 2025 Dec 18;6(1):54. doi: 10.1038/s43856-025-01312-9. |
| 41834485 | Background | Brites C, Montano-Castellon I, Arriaga MB, Marconi C, Mayoral R, Luz E, Figueredo CA, Fiuza BSD, Netto EM. Dolutegravir Reduces Human T-Cell Lymphotropic Virus Type 1 Proviral Load and Improves Neurological Outcomes in a Phase 2 Controlled Trial. Clin Infect Dis. 2026 May 20;82(5):e910-e920. doi: 10.1093/cid/ciag163. |
| ID | Term |
|---|---|
| D015490 | HTLV-I Infections |
| D015493 | Paraparesis, Tropical Spastic |
| D015459 | Leukemia-Lymphoma, Adult T-Cell |
| D009443 | Neuritis |
| ID | Term |
|---|---|
| D006800 | Deltaretrovirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D007239 | Infections |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D009187 | Myelitis |
| D002494 | Central Nervous System Infections |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D013118 | Spinal Cord Diseases |
| D000090862 | Neuroinflammatory Diseases |
| D015458 | Leukemia, T-Cell |
| D007945 | Leukemia, Lymphoid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
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| ID | Term |
|---|---|
| D000068698 | Tenofovir |
| C562325 | dolutegravir |
| ID | Term |
|---|---|
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D000225 | Adenine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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