A Potential Treatment for Progressive Multifocal Leukoencephalopathy

By Ulrike Kaunzner, MD

Synopsis: Fingolimod-associated progressive multifocal leukoencephalopathy in a 67-year-old woman with secondary progressive multiple sclerosis (MS) was treated off-label with tenofovir alafenamide fumarate (TAF), resulting in rapid radiologic improvement and clearance of John Cunningham virus (JCV) from cerebrospinal fluid. Although MS activity emerged after fingolimod withdrawal, TAF was well tolerated and the close temporal association with JCV clearance suggests a potential antiviral effect warranting further study.

Source: Torkildsen Ø, Bru ANS, Nerås Behzadi GI, Myhr KM. Successful treatment of progressive multifocal leukoencephalopathy with tenofovir alafenamide fumarate. Neurol Neuroimmunol Neuroinflamm. 2026;13(1):e200522.

Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic demyelinating disease of the central nervous system (CNS) caused by reactivation of John Cunningham virus (JCV), often with a fatal outcome. It primarily occurs in immunocompromised patients, including those receiving disease-modifying therapies (DMTs) for multiple sclerosis (MS). Prognosis remains poor, and no antiviral treatment has demonstrated proven efficacy. Current management largely focuses on restoring immune surveillance through discontinuation of DMTs, but this can trigger immune reconstitution inflammatory syndrome (IRIS) or rebound MS activity. Antiviral agents (such as cidofovir) have been studied with inconsistent results and substantial toxicity, leaving a critical therapeutic gap.

In this context, interest has grown in nucleotide analogues with improved safety profiles, including tenofovir alafenamide fumarate (TAF), a well-tolerated prodrug widely used in human immunodeficiency virus and hepatitis B infection. Although TAF has not been systematically evaluated in PML, its high intracellular concentrations and theoretical CNS penetration make it a biologically plausible candidate.

In the current case report, Torkildsen et al describe the use of TAF in a patient diagnosed with PML following fingolimod exposure. A 67-year-old woman with longstanding secondary progressive MS was treated with fingolimod after prior disease activity and gradual progression. After several years of relative stability, she developed accelerating cognitive decline and worsening gait in 2024. Brain magnetic resonance imaging (MRI) demonstrated new bilateral cerebellar T2/FLAIR hyperintensities without gadolinium enhancement or restricted diffusion. Cerebrospinal fluid (CSF) testing confirmed PML with JCV deoxyribonucleic acid (DNA) detected at 4,940 IU/mL, accompanied by elevated neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels.

Fingolimod was discontinued and the patient was started on off-label TAF at 50 mg daily. A higher dose was chosen for possible CNS penetration. MRI performed four days after treatment initiation demonstrated partial radiologic improvement. At three months, PML lesions had further regressed, and CSF JCV DNA became undetectable (< 1,000 IU/mL). At six months, viral clearance was sustained, with continued radiographic improvement of cerebellar lesions. Clinically, the patient remained stable, with an unchanged Expanded Disability Status Scale (EDSS) score of 8.5.

Commentary

This case report is important because of the rapid radiologic improvement observed within days of TAF initiation, which raises the possibility of antiviral activity, although spontaneous stabilization or immune reconstitution following fingolimod withdrawal cannot be excluded. Overall, TAF represents a possible therapeutic option in this otherwise devastating condition, given its favorable safety profile, high intracellular concentrations, and theoretical ability to reach CNS immune cells — in contrast to older nucleotide analogues such as cidofovir, which demonstrated inconsistent efficacy and significant toxicity. However, the evidence remains limited.

This is a single, uncontrolled case with relatively short follow-up, no measurement of CSF or serum tenofovir levels, and confounding MS rebound activity, making causality difficult to establish. Nonetheless, the combination of radiologic regression, virologic clearance, and excellent tolerability highlights TAF as a potentially valuable therapeutic candidate for PML. Given the absence of effective antiviral therapy for JCV and the substantial morbidity associated with PML, these findings justify further investigation. A prospective clinical trial or, at minimum, a multicenter observational cohort would be appropriate to evaluate TAF’s CNS penetration, optimal dosing, effects on JCV replication, clinical outcomes, and its potential role alongside immune reconstitution strategies, particularly in patients treated with DMTs associated with prolonged immunosuppression, where DMT cannot easily be withheld.

Ulrike W. Kaunzner, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.