Long term, high dose interferon-alpha treatment in HTLV-I-associated myelopathy/tropical spastic paraparesis: a combined clinical, virological and immunological study

doi:10.1016/S0022-510X(96)05319-1

Journal of the Neurological Sciences

Volume 147, Issue 2, 15 April 1997, Pages 135-144

https://doi.org/10.1016/S0022-510X(96)05319-1 Get rights and content

Abstract

The efficacy of long-term, high dose interferon-α (IFN-α) therapy was studied in seven patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). IFN-α was administered at a dose of 6 × 10⁶ international units daily for the initial 2 weeks and thereafter 3 times a week for the following 22 weeks. Five patients showed a sustained improvement in motor performance during and up to 6 months after the completion of IFN-α. The other patient who responded to IFN-α initially dropped out at 3 months because of depression, while another patient first deteriorated and thereafter dropped out. In the six responders, the absolute number of peripheral blood lymphocytes (PBL) harboring the HTLV-I genome as evaluated by the quantitative polymerase chain reaction method decreased significantly during the therapy period (28.6 ± 16.6% reduction, P = 0.0083), whereas the one deteriorated patient showed a 2.5-fold increase in HTLV-I-infected cells. The autoproliferation of CD4⁺ T clone cells from a single cell culture was markedly depressed even after the cessation of IFN-α in the responders who completed long-term IFN-α therapy. In addition, the CD8⁺DR⁺ T cells in the peripheral blood and soluble IL-2 receptor levels in the sera increased significantly during the therapy in all patients (P = 0.0431 and P = 0.0041, respectively). Therefore, the results of our study suggested that both the reduction of HTLV-I proviral DNA load and immunomodulation by long-term IFN-α therapy contributed to its sustained clinical benefits.

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INF-α is the only drug that was tested for the treatment of HAM/TSP in a randomized controlled trial, which demonstrated that a 4-week IFN-α therapy improved neurological symptoms (Izumo et al., 1996). However, according to the national registry of patients with HAM/TSP in Japan, INF-α is currently used by only a small proportion of patients, presumably because of the lack of evidence of its long-term benefit and various adverse effects (Arimura et al., 2007; Coler-Reilly et al., 2016; Tsutsumi et al., 2019; Yamasaki et al., 1997). Corticosteroid therapy is currently the most widely accepted treatment for HAM/TSP, although no randomized, controlled trial was performed (Bangham et al., 2015; Coler-Reilly et al., 2016).
Human T-cell leukemia virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare inflammatory disease causing unremitting and progressive neurological disorders, such as spastic paraparesis, neurogenic bladder, and sensory disturbance of the lower extremities. Although there is no cure, immune-modulating agents such as corticosteroids are most widely used to slow disease progression. Biomarkers for the clinical assessment of HAM/TSP should be identified because the prediction of functional prognosis and the assessment of treatment efficacy are challenging due to the slowly progressive nature of the disease. The lack of surrogate biomarkers also hampers clinical trials of new drugs. This review summarizes biomarker candidates for the clinical assessment of patients with HAM/TSP. Most of the reported biomarker candidates are associated with viral components or inflammatory mediators because immune dysregulation provoked by HTLV-1 infection is thought to cause chronic inflammation and damage the spinal cord of patients with HAM/TSP. Although information on the diagnostic accuracy of most of the reported biomarkers is insufficient, several molecules, including inflammatory mediators such as CXCL10 and neopterin in the cerebrospinal fluid, have been suggested as potential biomarkers of functional prognosis and treatment response. Several clinical trials for HAM/TSP are currently underway, and we expect that these studies will provide not only evidence pertaining to treatment, but also novel findings regarding the utility of biomarkers in this disease. The establishment of clinical biomarkers will improve patient care and promote the development of therapies for HAM/TSP.
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Motor disability has been shown to improve, but this is usually not sustained. Other agents, such as interferon-alfa,79 cyclosporine A,80 methotrexate,81 and pentoxifylline,82 have been used with variable success. Prosultiamine83 and pentosan polysulfate sodium84 have shown some promise in small open trials.
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Treatment caused a significant reduction in PBL count and a non-significant trend to reduction in serum immunoglobulin and CSF IgG (Kuroda et al., 1992). In another open trial, 6.0 MU natural human IFN-α was administered to 7 Japanese HAM patients for 22 weeks and resulted in sustained improvement in 5 (70%) (Yamasaki et al., 1997). An uncontrolled follow-up surveillance study found 66.2% of 152 patients were mildly or markedly improved at 4 weeks and 36.7% of 30 patients were improved 5 or more months after therapy was stopped (Arimura et al., 2007).
Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered when it was linked to an unusual T-cell lymphoma in 1980. It was later linked to a number of other diseases, particularly neurologic ones. These include encephalomyelitis, myelopathy, polymyositis, inclusion body myositis, peripheral neuropathy, autonomic neuropathy, amyotrophic lateral sclerosis-like disease, and uveitis. This chapter will provide an overview of the virus discovery, the epidemiology of HTLV-1 infection, basic virology, and basic aspects of the immunologic response to the infection. It will briefly discuss features of adult T-cell leukemia and aspects of its pathogenesis. The primary focus of the chapter is the neurologic diseases associated with HTLV-1. It will discuss clinical features, diagnosis, imaging, laboratory features, electroencephalogram and evoked potential studies, attempted treatment strategies, and prevention measures. In addition many aspects of pathogenesis are discussed.
The impact of interferon-alpha treatment on clinical and immunovirological aspects of HTLV-1-associated myelopathy in northeast of Iran
2012, Journal of Neuroimmunology
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They found that 6 out of their 7 patients responded to this treatment. Moreover, the number of peripheral blood lymphocyte with HTLV-1 genome significantly decreased during the treatment (Yamasaki et al., 1997). Later, in 1999, the safety and efficacy of the long-term administration of subcutaneous recombinant IFN-α was reported in a 37‐year old Brazilian patient with HAM/TSP with a sustained improvement in the motor performance after a 2 year follow up (Gazzola et al., 1999).
Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory myelopathy. The pathophysiology of HAM/TSP is not yet fully understood; therefore, effective therapy remains a challenging issue. This study was designed to evaluate the efficacy of interferon-alpha (IFN-α) in HAM/TSP patients in the Northeast of Iran. Forty-nine patients with a definite diagnosis of HAM/TSP were enrolled in this clinical trial. For six months, the patients received three million international units of subcutaneous IFN-α-2b per each injection. The dose regimen was daily injection for the first month, three times administration per week for the months 2 and 3, twice weekly injection for the months 4 and 5 and weekly injection for the sixth month. The clinical and laboratory responses were evaluated based on neurologic examinations and immunovirological markers. IFN-α had significant but temporary effect on the motor and urinary functions of the patients. Comparing to the baseline values, proviral load was significantly decreased one month after treatment in responders (495.20 ± 306.87 to 262.69 ± 219.24 p = 0.02) and non-responders (624.86 ± 261.90 to 428.28 ± 259.88 p = 0.03). Anti‐HTLV-1 antibody titers were significantly decreased among responders (1152.1 ± 200.5 to 511.6 ± 98.2 p = 0.009) and non-responders (1280.1 ± 368.1 to 537.6 ± 187 p = 0.007). Flow cytometry showed no significant changes in CD4, CD8, CD4CD25 and CD16CD56 counts with IFN-α. The positive impact of IFN-α was observed during the treatment period with significant effects on some clinical aspects of HAM/TSP.
Treatment of HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis: Toward Rational Targeted Therapy
2008, Neurologic Clinics
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The benefit of long-term interferon-α therapy, however, has not been well studied. A small study extending interferon-α treatment to 24 weeks reported sustained clinical response [86]. The main marker of efficacy during interferon-α therapy appears to be a reduction in HTLV-I proviral load [60].
The treatment of HAM/TSP is a challenge. No agent has shown to significantly modify the long-term disability associated with HAM/TSP. Advances in our understanding of the pathogenesis of HAM/TSP have led to the identification of several biomarkers and therapeutic targets. Clinical trials in HAM/TSP continue to be opportunities for further qualification and refinement of biomarkers and therapeutic targets. The validation of HAM/TSP relevant biomarkers and the identification of new targets remain key challenges in the development of effective targeted therapy in HAM/TSP.
A prospective uncontrolled trial of fermented milk drink containing viable Lactobacillus casei strain Shirota in the treatment of HTLV-1 associated myelopathy/tropical spastic paraparesis
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Ten patients with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) were treated in an uncontrolled preliminary trial by oral administration of viable Lactobacillus casei strain Shirota (LcS) containing fermented milk. HTLV-1 provirus load, motor function, neurological findings, and immunological parameters were evaluated after 4 weeks. Although LcS did not change the frequencies or absolute numbers of all the examined cell surface phenotypes of peripheral blood mononuclear cells, NK cell activity was significantly increased after 4 weeks of oral administration of LcS preparation. Improvements in spasticity (modified Ashworth Scale scores) and urinary symptoms were also seen after LcS treatment. No adverse effect was observed in all the 10 patients throughout the study period. Our results indicated that LcS may be a safe and beneficial agent for the treatment of HAM/TSP; therefore randomized controlled studies are warranted.

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Research articleLong term, high dose interferon-alpha treatment in HTLV-I-associated myelopathy/tropical spastic paraparesis: a combined clinical, virological and immunological study

Abstract

Curr. Opin. Neurobiol.

Lancet

Lancet

J. Neurol. Sci.

J. Neuroimmunol.

J. Neurol. Sci.

J. Neurol. Sci.

Virology

Brain Dev.

Lancet

Virology

J. Neurol. Sci.

J. Neuroimmunol.

Treatment of chronic hepatitis C with recombinant interferon alpha: a multicenter randomized, controlled trial

N. Engl. J. Med.

Long term recombinant interferon alpha treatment in MS with special emphasis to side effects

Multiple Sclerosis

Recombinant leukocyte interferon treatment of chronic hepatitis B

Hepatology

High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease

J. Exp. Med.

Biological and clinical significance of neutralizing and binding antibodies to interferon-alpha (IFN-α) during therapy for chronic hepatitis C

Clin. Exp. Immunol.

Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine

N. Engl. J. Med.

Serum levels of soluble interleukin-2 receptors and effects of interferon-α for patients with chronic hepatitis C virus

Dig. Dis. Sci.

Research article
Long term, high dose interferon-alpha treatment in HTLV-I-associated myelopathy/tropical spastic paraparesis: a combined clinical, virological and immunological study