Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP

Yoshimi Enose-Akahata, Bridgette Jeanne Billioux, Shila Azodi, Jennifer Dwyer, Ashley Vellucci, Nyater Ngouth, Satoshi Nozuma, Raya Massoud, Irene Cortese, Joan Ohayon, Steven Jacobson, Yoshimi Enose-Akahata, Bridgette Jeanne Billioux, Shila Azodi, Jennifer Dwyer, Ashley Vellucci, Nyater Ngouth, Satoshi Nozuma, Raya Massoud, Irene Cortese, Joan Ohayon, Steven Jacobson

Abstract

Objective: Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro. Given the substantial clinical experience in human immunodeficiency virus infection and its excellent safety profile, this agent may be an attractive therapeutic option for HAM/TSP patients.

Methods: Sixteen subjects with HAM/TSP received raltegravir 400 mg orally twice daily in an initial 6-month treatment phase, followed by a 9-month post-treatment phase. HTLV-1 PVLs were assessed using droplet digital PCR from the PBMCs every 3 months, and from the CSF at baseline, month 6, and month 15. We also evaluated the ability of raltegravir to regulate abnormal immune responses in HAM/TSP patients.

Results: While a downward trend was observed in PBMC and/or CSF PVLs of some patients, raltegravir overall did not have any impact on the PVL in this HAM/TSP patient cohort. Clinically, all patients' neurological scores and objective measurements remained relatively stable, with some expected variability. Immunologic studies showed alterations in the immune profiles of a subset of patients including decreased CD4+ CD25+ T cells and spontaneous lymphoproliferation.

Interpretation: Raltegravir was generally well tolerated in this HAM/TSP patient cohort. A subset of patients exhibited a mild decrease in PVL as well as variations in their immune profiles after taking raltegravir. These findings suggest that raltegravir may be a therapeutic option in select HAM/TSP patients.

Clinical trial registration number: NCT01867320.

Conflict of interest statement

The authors have declared that no conflict of interest exists.

© 2021 Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Schema of clinical trial of raltegravir for HAM/TSP patients.
Figure 2
Figure 2
HTLV‐1 PVL in HAM/TSP patients with raltegravir. (A) Group analysis of HTLV‐1 PVL in PBMCs of 16 HAM/TSP patients. Closed circles represent median of HTLV‐1 PVL and error bars represent range. (B) Group analysis of HTLV‐1 PVL in CSF cells of 16 HAM/TSP patients. Closed circles represent median of HTLV‐1 PVL and error bars represent range. (C) Classification of HAM/TSP patients into three groups based on change of HTLV‐1 PVL in PBMCs during the treatment. Group 1: Decreased HTLV‐1 PVL; Group 2: Stable (no significant change); Group 3: increased HTLV‐1 PVL. (D) Classification of HAM/TSP patients into three groups based on change of HTLV‐1 PVL in CSF cells during the treatment. Group 1: Decreased HTLV‐1 PVL; Group 2: No significant change; Group 3: increased HTLV‐1 PVL. Cut off value (12.19%) was determined based on coefficient of variation of PBMC HTLV‐1 PVL of 13 HAM/TSP patients with chronic infection in natural history of 1–9 years.
Figure 3
Figure 3
HTLV‐1 mRNA expression in PBMC of HAM/TSP patients with raltegravir. (A) Group analysis of tax mRNA expression in PBMCs of HAM/TSP patients after ex vivo culture for 20 h. Error bars represent standard deviation. (B) Group analysis of HBZ mRNA expression in PBMCs of HAM/TSP patients at pre‐culture. Error bars represent standard deviation. (C) Correlation of HTLV‐1 PVL in PBMC and HTLV‐1 tax mRNA expression in PBMC of HAM/TSP patients at baseline and at month 6 of raltegravir treatment. Closed circles and opened circles represent the data at baseline (R = 0.6168, P = 0.0109) and at month 6 of raltegravir treatment (R = 0.6206, P = 0.0103), respectively. (D) Percentage change in tax mRNA expression among the three HAM/TSP groups based on the percentage changes of HTLV‐1 PVL in the 6‐month treatment phase compared to the baseline. Error bars represent standard deviation. (E) Percentage change in HBZ mRNA expression among the three HAM/TSP groups based on the percentage changes of HTLV‐1 PVL in the 6‐month treatment phase compared to the baseline. Error bars represent standard deviation. (F) Group analysis of HTLV‐1 Tax protein expression in CD4+CD25+ T cells of HAM/TSP patients after ex vivo PBMC culture for 20 h. Error bars represent standard deviation. (G) Group analysis of HTLV‐1 Tax and IFN‐γ expressions in CD4+CD25+ T cells of HAM/TSP patients after ex vivo PBMC culture for 20 h. Error bars represent standard deviation.
Figure 4
Figure 4
Immunological changes in peripheral blood and CSF of HAM/TSP patients with raltegravir. (A) Group analysis of frequencies of CD25+ cells in blood and CSF CD4+ T cells of HAM/TSP patients. (B) Group analysis of frequencies of antibody secreting B cells in CSF B cells of HAM/TSP patients. (C) Group analysis of frequencies of CD25+ cells in blood and CSF CD8+ T cells of HAM/TSP patients. (D) Group analysis of frequencies of CD122+ cells in blood and CSF CD8+ T cells of HAM/TSP patients. Error bars represent standard deviation. In (A), (C), (D), the control ranges of blood and CSF of 27 healthy volunteers (25%–75% percentile) are highlighted in gray.
Figure 5
Figure 5
Spontaneous lymphoproliferation in HAM/TSP patients with raltegravir. (A) Group analysis of spontaneous lymphoproliferation in PBMCs of HAM/TSP patients at ex vivo culture of Day 4. Error bars represent standard deviation. (B) Representative dot plot of CFSE staining in CD4+ and CD8+ T cells of a HAM/TSP patient (HAM #14) after ex vivo culture of Day 4. (C) Group analysis of spontaneous CD4+, CD4+CD25+, and CD8+ T cell proliferation in PBMCs of HAM/TSP patients at ex vivo culture of Day 4. Error bars represent standard deviation.

References

    1. Gessain A, Vernant JC, Maurs L, et al. Antibodies to human T‐lymphotropic virus type‐I in patients with tropical spastic paraparesis. Lancet. 1985;2(8452):407‐470.
    1. Osame M, Usuku K, Izumo S, et al. HTLV‐I associated myelopathy, a new clinical entity. Lancet. 1986;1(8488):1031‐1032.
    1. Umehara F, Izumo S, Nakagawa M, et al. Immunocytochemical analysis of the cellular infiltrate in the spinal cord lesions in HTLV‐I‐associated myelopathy. J Neuropathol Exp Neurol. 1993;52(4):424‐430.
    1. Nagai M, Yamano Y, Brennan MB, Mora CA, Jacobson S. Increased HTLV‐I proviral load and preferential expansion of HTLV‐I Tax‐specific CD8+ T cells in cerebrospinal fluid from patients with HAM/TSP. Ann Neurol. 2001;50(6):807‐812.
    1. Nagai M, Usuku K, Matsumoto W, et al. Analysis of HTLV‐I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV‐I carriers: high proviral load strongly predisposes to HAM/TSP. J Neurovirol. 1998;4(6):586‐593.
    1. Yamano Y, Nagai M, Brennan M, et al. Correlation of human T‐cell lymphotropic virus type 1 (HTLV‐1) mRNA with proviral DNA load, virus‐specific CD8(+) T cells, and disease severity in HTLV‐1‐associated myelopathy (HAM/TSP). Blood. 2002;99(1):88‐94.
    1. Yamano Y, Araya N, Sato T, et al. Abnormally high levels of virus‐infected IFN‐gamma+ CCR4+ CD4+ CD25+ T cells in a retrovirus‐associated neuroinflammatory disorder. PLoS One. 2009;4(8):e6517.
    1. Yamano Y, Takenouchi N, Li H‐C, et al. Virus‐induced dysfunction of CD4+CD25+ T cells in patients with HTLV‐I‐associated neuroimmunological disease. J Clin Invest. 2005;115(5):1361‐1368.
    1. Enose‐Akahata Y, Azodi S, Smith BR, et al. Immunophenotypic characterization of CSF B cells in virus‐associated neuroinflammatory diseases. PLoS Pathog. 2018;14(4):e1007042.
    1. Brooks KM, Sherman EM, Egelund EF, et al. Integrase inhibitors: after 10 years of experience, is the best yet to come? Pharmacotherapy. 2019;39(5):576‐598.
    1. Seegulam ME, Ratner L. Integrase inhibitors effective against human T‐cell leukemia virus type 1. Antimicrob Agents Chemother. 2011;55:2011‐2017.
    1. Barski MS, Minnell JJ, Maertens GN. Inhibition of HTLV‐1 infection by HIV‐1 first‐ and second‐generation integrase strand transfer inhibitors. Front Microbiol. 2019;10:1877.
    1. Trevino A, Parra P, Bar‐Magen T, Garrido C, de Mendoza C, Soriano V. Antiviral effect of raltegravir on HTLV‐1 carriers. J Antimicrob Chemother. 2012;67(1):218‐221.
    1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444‐1452.
    1. Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology. 1984;34(10):1368‐1372.
    1. Kaufman M, Moyer D, Norton J. The significant change for the Timed 25‐foot Walk in the multiple sclerosis functional composite. Mult Scler. 2000;6(4):286‐290.
    1. Schmidt F, Oliveira AL, Araujo A. Development and validation of a neurological disability scale for patients with HTLV‐1 associated myelopathy/tropical spastic paraparesis (HAM/TSP): the IPEC‐1 scale. Neurology. 2012;78(supplement 1):P03258.
    1. Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three‐arm study of high‐dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med. 1983;308(4):173‐180.
    1. Goodkin DE, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: improving assessment sensitivity with box‐and‐block and nine‐hole peg tests. Arch Phys Med Rehabil. 1988;69(10):850‐854.
    1. Brunetto GS, Massoud R, Leibovitch EC, et al. Digital droplet PCR (ddPCR) for the precise quantification of human T‐lymphotropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of HAM/TSP patients and identification of viral mutations. J Neurovirol. 2014;20(4):341‐351.
    1. Enose‐Akahata Y, Ngouth N, Ohayon J, et al. Effect of teriflunomide on cells from patients with human T‐cell lymphotropic virus type 1‐associated neurologic disease. Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e986.
    1. Oh U, Yamano Y, Mora CA, et al. Interferon‐beta1a therapy in human T‐lymphotropic virus type I‐associated neurologic disease. Ann Neurol. 2005;57(4):526‐534.
    1. Enose‐Akahata Y, Abrams A, Massoud R, et al. Humoral immune response to HTLV‐1 basic leucine zipper factor (HBZ) in HTLV‐1‐infected individuals. Retrovirology. 2013;10:19.
    1. Enose‐Akahata Y, Vellucci A, Jacobson S. Role of HTLV‐1 Tax and HBZ in the pathogenesis of HAM/TSP. Front Microbiol. 2017;8:2563.
    1. Matsuoka M, Jeang KT. Human T‐cell leukaemia virus type 1 (HTLV‐1) infectivity and cellular transformation. Nat Rev Cancer. 2007;7(4):270‐280.
    1. Saito M, Matsuzaki T, Satou Y, et al. In vivo expression of the HBZ gene of HTLV‐1 correlates with proviral load, inflammatory markers and disease severity in HTLV‐1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Retrovirology. 2009;6:19.
    1. Enose‐Akahata Y, Jacobson S. Immunovirological markers in HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Retrovirology. 2019;16(1):35.
    1. Azimi N, Jacobson S, Leist T, Waldmann TA. Involvement of IL‐15 in the pathogenesis of human T lymphotropic virus type I‐associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL‐2/15R beta receptor. J Immunol. 1999;163(7):4064‐4072.
    1. Itoyama Y, Minato S, Kira J, et al. Spontaneous proliferation of peripheral blood lymphocytes increased in patients with HTLV‐I‐associated myelopathy. Neurology. 1988;38(8):1302‐1307.
    1. Bangham CR, Araujo A, Yamano Y, Taylor GP. HTLV‐1‐associated myelopathy/tropical spastic paraparesis. Nat Rev Dis Primers. 2015;1:15012.
    1. Matsuzaki T, Nakagawa M, Nagai M, et al. HTLV‐I proviral load correlates with progression of motor disability in HAM/TSP: analysis of 239 HAM/TSP patients including 64 patients followed up for 10 years. J Neurovirol. 2001;7(3):228‐234.
    1. Demontis MA, Hilburn S, Taylor GP. Human T cell lymphotropic virus type 1 viral load variability and long‐term trends in asymptomatic carriers and in patients with human T cell lymphotropic virus type 1‐related diseases. AIDS Res Hum Retroviruses. 2013;29(2):359‐364.
    1. Hanon E, Hall S, Taylor GP, et al. Abundant tax protein expression in CD4+ T cells infected with human T‐cell lymphotropic virus type I (HTLV‐I) is prevented by cytotoxic T lymphocytes. Blood. 2000;95(4):1386‐1392.
    1. Gillet NA, Malani N, Melamed A, et al. The host genomic environment of the provirus determines the abundance of HTLV‐1‐infected T‐cell clones. Blood. 2011;117(11):3113‐3122.
    1. Melamed A, Laydon DJ, Gillet NA, Tanaka Y, Taylor GP, Bangham CR. Genome‐wide determinants of proviral targeting, clonal abundance and expression in natural HTLV‐1 infection. PLoS Pathog. 2013;9(3):e1003271.
    1. Gross C, Thoma‐Kress AK. Molecular mechanisms of HTLV‐1 cell‐to‐cell transmission. Viruses. 2016;8(3):74.
    1. Fox J, Hilburn S, Demontis M‐A, et al. Long terminal repeat circular DNA as markers of active viral replication of human T lymphotropic virus‐1 in vivo. Viruses. 2016;8(3):80.
    1. Yamano Y, Cohen CJ, Takenouchi N, et al. Increased expression of human T lymphocyte virus type I (HTLV‐I) Tax11‐19 peptide‐human histocompatibility leukocyte antigen A*201 complexes on CD4+ CD25+ T Cells detected by peptide‐specific, major histocompatibility complex‐restricted antibodies in patients with HTLV‐I‐associated neurologic disease. J Exp Med. 2004;199(10):1367‐1377.
    1. Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015;3(3):219‐227.
    1. Yamano Y, Sato T. Clinical pathophysiology of human T‐lymphotropic virus‐type 1‐associated myelopathy/tropical spastic paraparesis. Front Microbiol. 2012;3:389.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi