title: A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes.
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.
authors.affiliation: Department of Neurology, Washington University in St. Louis, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, USA. cliffordd@neuro.wustl.edu
authors.forename: David B
authors.initials: DB
authors.lastname: Clifford
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: Paola
authors.initials: P
authors.lastname: Cinque
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Brew
authors.forename: Robert
authors.initials: R
authors.lastname: Zivadinov
authors.forename: Leonid
authors.initials: L
authors.lastname: Gorelik
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Zhao
authors.forename: Petra
authors.initials: P
authors.lastname: Duda
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use; D001921:Brain / Q000473:pathology; D004279:DNA, Viral / Q000134:cerebrospinal fluid; D005260:Female; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007577:JC Virus / Q000187:drug effects; D007968:Leukoencephalopathy, Progressive Multifocal / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D015767:Mefloquine / Q000627:therapeutic use*; D008875:Middle Aged; D016037:Single-Blind Method; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
chemical_list: D000962:Antimalarials; D000998:Antiviral Agents; D004279:DNA, Viral; D015767:Mefloquine