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      A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes

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          Abstract

          Immune reconstitution has improved outcomes for progressive multifocal leukoencephalopathy (PML), a potentially lethal brain disease caused by JC virus (JCV). However, an antiviral treatment to control JCV is needed when immune reconstitution is delayed or not possible. On the basis of in vitro efficacy, this study evaluated the effect of mefloquine on PML and factors that may predict PML outcomes. This 38-week, open-label, randomized, parallel-group, proof-of-concept study compared patients with PML who received standard of care (SOC) with those who received SOC plus mefloquine (250 mg for 3 days, then 250 mg weekly). Patients randomized to SOC could add mefloquine treatment at week 4. The primary endpoint was change from baseline to weeks 4 and 8 in JCV DNA copy number (load) in cerebrospinal fluid (CSF). Exploratory analyses evaluated factors that might correlate with clinical outcome. The majority of enrolled patients were HIV positive. Preplanned interim data analyses suggested that the study was unlikely to successfully demonstrate a significant difference between groups; therefore, the study was terminated prematurely. There was no significant difference between groups in CSF JCV DNA loads or clinical/MRI findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome.

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          Progressive multifocal leukoencephalopathy and other forms of JC virus disease.

          Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the JC virus (JCV). PML usually occurs via reactivation of JCV when an immune system becomes compromised. A diagnosis of PML is normally made on the basis of distinguishing neurological features at presentation, characteristic brain MRI changes and the presence of JCV DNA in cerebrospinal fluid. PML has a 3 month mortality rate of 20-50%, so prompt intervention is essential. Currently, reconstitution of the immune system affords the best prognosis for this condition. When PML is first suspected, and where possible, immunosuppressant or immunomodulatory therapy should be suspended or reduced. If PML is associated with a protein therapy that has a long half-life the use of plasma exchange to accelerate the removal of the drug from the circulation may aid the restoration of immune system function. Rapid improvements in immune function, however, might lead to transient worsening of the disease. In this Review, we critically appraise the controversies surrounding JCV infection, and provide practical management guidelines for PML.
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            Identification and characterization of mefloquine efficacy against JC virus in vitro.

            Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEDelta), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
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              Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name?

              Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn's disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus-host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease.
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                Author and article information

                Contributors
                +1-314-7478423 , +1-314-7478427 , cliffordd@neuro.wustl.edu
                Journal
                J Neurovirol
                J. Neurovirol
                Journal of Neurovirology
                Springer US (Boston )
                1355-0284
                1538-2443
                4 June 2013
                4 June 2013
                2013
                : 19
                : 351-358
                Affiliations
                [ ]Department of Neurology, Washington University in St. Louis, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110 USA
                [ ]Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg 10/ 7C-103, 10 Center Drive, Bethesda, MD 20892 USA
                [ ]Department of Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d’Ancona 20, 20127 Milan, Italy
                [ ]Departments of Neurology and HIV Medicine, St Vincent’s Hospital and University of New South Wales, Sydney, Australia
                [ ]Department of Neurology, Buffalo Neuroimaging Analysis Center, Buffalo, NY USA
                [ ]Department of Research, Biogen Idec Inc., Weston, MA USA
                [ ]Pharmaceutical Product Development, LLC, 7901 E. Riverside Drive, Austin, TX 78744 USA
                [ ]Department of Medical Research, Biogen Idec Inc., Weston, MA USA
                [ ]Department of Neurology, Level 4, Xavier Building, St. Vincent’s Hospital, Victoria Street Darlinghurst, 20120 Sydney, Australia
                [ ]Jacobs Neurological Institute, 100 High Street, Buffalo, NY 14203 USA
                [ ]Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142 USA
                Article
                173
                10.1007/s13365-013-0173-y
                3758507
                23733308
                afa15bf6-006b-428c-829b-5a02c508f5a4
                © The Author(s) 2013

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 23 March 2013
                : 3 May 2013
                : 7 May 2013
                Categories
                Article
                Custom metadata
                © Journal of NeuroVirology, Inc. 2013

                Microbiology & Virology
                mefloquine,leukoencephalopathy,progressive multifocal,jc virus,magnetic resonance imaging

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