Tenofovir in Progressive Multifocal Leukoencephalopathy

Abstract

Objectives

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the CNS caused by reactivation of the JC polyomavirus (JCV), typically in immunocompromised individuals. As no specific therapy against JCV exists, current management focuses on immune reconstitution. Recently, a potential therapeutic effect of tenofovir was reported.

Methods

We report 2 patients with PML who received tenofovir under a compassionate use protocol. Treatment was accompanied by MRI, clinical, and virologic monitoring.

Results

In both patients (serum and CSF), viral load was markedly reduced. In 1 patient, this was accompanied by temporary clinical stabilization and reduction in MRI lesion burden. The other patient further declined clinically, accompanied by progression of MRI lesion size and contrast enhancement. Dense lymphocytic infiltration on biopsy suggested predominant effects of alleviated immunosuppression rather than the direct antiviral drug effect. Both patients ultimately died of the disease.

Discussion

Despite virus reduction in both cases, sustained clinical improvement was not achieved. This suggests that viral load reduction alone is insufficient, and pathogenesis may be largely driven by the immune response to the infection. A combination of tenofovir with low-dose anti-inflammatory drugs may be a useful addition to PML therapy.

Introduction

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of JC polyoma virus (JCV). PML almost exclusively develops in immunocompromised states. Treatment therefore consists of treating the underlying disease and discontinuation of immunosuppression, where feasible. As observed in smaller studies, inhibition of programmed cell death protein-1 (PD-1) with pembrolizumab can enhance JCV-specific immunity, promoting viral control and neurologic improvement.^1-3 Adoptive T-cell transfer has shown promise for PML: registry-derived, partially HLA-matched virus-specific T cells led to clinical stabilization or improvement in 79%.⁴ Concurrent to improved immune function, symptoms may deteriorate with radiographic and biochemical evidence of enhanced inflammation at the edge of lesions, a phenomenon designated as “immune reconstitution inflammatory syndrome” (IRIS).

According to a recent report of a patient with fingolimod-associated PML,⁵ treatment with tenofovir alafenamide fumarate (TAF) in parallel to fingolimod cessation was associated with clinical stabilization and radiologic improvement of PML lesions. TAF is a prodrug of tenofovir with improved cellular uptake, resulting in good antiviral activity at lower doses and, thus, increased safety, widely used in HIV and hepatitis B treatment.⁶ We present 2 patients with PML, who were treated at the University of Leipzig Medical Center between November 2025 and January 2026. Both patients received TAF while awaiting approval for cost coverage of pembrolizumab or/and T-cell–based therapy.

Ethics Statement

Written informed consent for publication was obtained from the next of kin of both patients, who were deceased at the time of submission.

Case Descriptions

Case 1

A 71-year-old man was admitted to a secondary care hospital with a 10-day history of fatigue and psychomotor slowing; examination showed marked cognitive impairment without focal neurologic signs. Brain MRI displayed a nonenhancing focal lesion of the left capsula externa, claustrum, and putamen. CSF analysis revealed mild pleocytosis; bacterial and viral serology and autoantibody testing were negative. EEG showed increased frontocentral epileptogenicity, and lacosamide was started. Initially suspected seronegative autoimmune encephalitis was treated with IV methylprednisolone, resulting in transient improvement, followed by deterioration despite a second course.

Brain MRI performed 1 month after symptom onset displayed marked progression of preexisting lesions and new lesions in the mesencephalon and right hemisphere (Figure 1A). CSF analysis and brain biopsy (Figure 2) confirmed PML. JCV-specific T cells were detected in peripheral blood, and he was referred to our hospital for pembrolizumab therapy.

Figure 1. Serial MRI Imaging During TAF Treatment.

Baseline and (day 7) follow-up MRI of patients treated with tenofovir. (A) T2 FLAIR (fluid-attenuation inversion recovery) images from case #1 show demyelinating lesions in the peri-insular region of the left hemisphere and in the mesencephalon. (B) Follow-up imaging after 7 days of treatment demonstrates a reduction in the mesencephalic lesion (arrow), while the peri-insular lesions remained unchanged. No progression or expansion of lesion areas was observed. (C) T2 FLAIR images from case #2 show demyelinating lesions predominantly in the right cerebellar hemisphere. Contrast enhancement in MP Rage CE was detected in the same location. (D) Follow-up imaging after 7 days of treatment demonstrated progression of demyelinating lesions in the left cerebellar hemisphere (arrow) and increased contrast enhancement.

Figure 2. Histologic Analysis of Biopsy-Derived Tissue Samples.

Representative microphotographs of H&E-stained section of case #1 show edematous brain parenchyma with elevated cell density (A) and abundant accumulation of JCV in glial cells, as demonstrated by staining for the SV40 T antigen (B). By contrast, H&E-stained section of case #2 shows brain parenchyma with extensive lymphocytic infiltration, most prominent in a perivascular distribution, accompanied by diffuse macrophage infiltration (C), but only sparse (arrows) nuclear positivity for SV40 T antigen (D). Immunohistochemistry revealed diffuse infiltration of brain parenchyma of cytotoxic CD8⁺ T cells (E) and macrophages (F) by CD68 immunohistochemistry in case #1 and in case #2 (G and H). Scale bar lengths are indicated in each panel. JCV = JC polyomavirus.

On referral, roughly 2 months after symptom onset, the patient was unable to walk because of right-sided parkinsonism and pyramidal weakness. We initiated antiviral medication with 50 mg of TAF daily. On MRI at day 7 of antiviral therapy, the mesencephalic lesion appeared smaller, whereas the peri-insular lesions remained unchanged (Figure 1B). His condition temporarily stabilized. Thorough work-up could not identify primary or secondary immunodeficiency. CSF analysis on day 9 of TAF treatment showed the absence of JCV DNA. On the same day, we administered a single dose of 200 mg pembrolizumab.

On day 16 of TAF treatment (∼2.5 months after onset), the patient became unresponsive; EEG showed left hemispheric nonconvulsive status epilepticus (NCSE), which persisted despite sequential escalation of antiseizure therapy. TAF was replaced by 245 mg tenofovir disoproxil to allow for administration through the nasogastric tube, and mirtazapine was added. CSF on day 20 of TAF treatment remained negative for JCV DNA. NCSE resolved by day 23 of tenofovir treatment; brain MRI displayed slight regression of lesions.

The clinical course was further complicated by pneumogenic sepsis requiring broad-spectrum antibiotics, acute renal failure, and suspected syndrome of inadequate antidiuretic hormone secretion. Despite withdrawal of sedating medications and stable seizure control, the patient remained unconscious. Ultimately, the patient died under palliative care about 3 months after symptom onset, 40 days after initiation of TAF treatment.

Case 2

A 68-year-old woman presented to our hospital with sudden-onset dysarthria and mild upper-limb dysmetria. She had received long-term immunosuppressive treatment with methotrexate (MTX) due to rheumatoid arthritis. Initial brain MRI showed bilateral cerebellar lesions extending to the brain stem; gadolinium enhancement was observed in the larger right cerebellar lesion. CSF showed marginal pleocytosis (6/µL) with normal protein and lactate. JCV DNA was detected in CSF (2,000 genome equivalents [GE]/mL) and serum (46,100 GE/mL). We discontinued MTX; comprehensive work-up to detect additional immunosuppressive factors remained negative.

Twenty-three days after reported symptom onset, treatment with 50 mg TAF was initiated. Over 1 week, the patient developed severe upper limb ataxia and impaired dexterity. On day 7 of TAF treatment, follow-up MRI demonstrated progression of both lesion size and gadolinium enhancement (Figure 1, C and D). Conversely, serum (9,000 GE/mL, day 7) and CSF (650 GE/mL, day 14) JCV DNA levels were reduced. The number of virus-specific T cells was low, not supporting pembrolizumab treatment. Brain biopsy, performed to exclude CNS lymphoma, confirmed PML with concurrent IRIS (Figure 2). High-dose methylprednisolone (1 g/d for 3 days) did not result in clinical improvement.

Potential side effects of TAF treatment were gastrointestinal discomfort, loss of appetite, and hypophosphatemia. The patient experienced worsening ataxia, severe vertigo, and diplopia. On day 23 of TAF treatment, she became symptomatic with influenza A infection. TAF therapy was discontinued on day 26 considering apparent lack of efficacy. Following further clinical decline, the treatment strategy was changed to a palliative approach in accordance with the patient's wishes.

Discussion

We present 2 cases with compassionate use of TAF for treatment of PML. The clinical course of both individuals highlights the therapeutic complexity and pathophysiologic interplay between antiviral efficacy and neuroinflammatory sequelae in this condition. Both patients showed marked decreases in JCV DNA levels in serum and CSF, suggesting systemic antiviral activity of TAF. In case #1, this was paralleled by early radiologic improvement and temporary clinical stabilization. However, despite these encouraging findings, the patient's course was complicated by NCSE which ultimately contributed to fatal decline. Case #2 exhibited progressive neurologic decline without interim clinical or paraclinical stabilization following TAF initiation, despite the reduction in viral load. Of interest, a brain biopsy performed during TAF therapy revealed only sparse JCV positivity (SV40 T antigen staining, Figure 2D). Presumably, this was associated with the cessation of immunosuppression because the biopsy also demonstrated features of IRIS. Consistent with this, case #1 also showed marked T-cell infiltration at the lesion site before tenofovir treatment. Therefore, immune reconstitution (which admittedly cannot be defined in case #1) may have been the main driver of viral clearance, and the dissociation between virologic improvement and clinical decline points toward immune-mediated inflammatory injury, rather than ongoing viral replication, as the predominant contributor to the symptoms.

In contrast to the case of apparently successful tenofovir treatment in PML,⁵ both our patients eventually died despite JCV reduction in CSF and serum. Differences in disease triggers—fingolimod, MTX, or unknown immunosuppression, respectively—could have influenced immune reconstitution and viral control. In addition, higher initial JCV load in CSF in our patients likely played a critical role because these are associated with poorer prognosis.⁷ Finally, the presence of JCV-specific CD8⁺ cytotoxic T lymphocytes has similarly been linked to improved survival and treatment response.⁸

Despite a reduction in viral load in both cases, sustained clinical recovery was not achieved. These findings indicate that viral suppression alone does not ensure neurologic stabilization. Viral suppression in this context is likely attributable to immune reconstitution, potentially with additional direct antiviral effects of tenofovir. Although TAF may be considered as an adjunctive component within a multimodal treatment framework, its independent contribution remains uncertain, and potential benefits likely depend on carefully balanced modulation of the immune response. Whether combining specific antiviral medications with nonspecific anti-inflammatory agents (e.g., low-dose glucocorticoids) represents a suitable approach remains to be established and may warrant investigation.

Author Contributions

J. Lier: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. A. Mrestani: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. M. Braune: major role in the acquisition of data; analysis or interpretation of data. M. Hönemann: analysis or interpretation of data. J.O. Pelz: analysis or interpretation of data. J.-J. Rumpf: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. F. Then Bergh: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.

Study Funding

J. Lier and A. Mrestani both received funding from the University of Leipzig Clinician Scientist Program. A. Mrestani further received funding from the Jung Foundation for Science and Research through Jung Career Advancement Prize 2023. This work was also supported by the Open Access Publishing Fund of Leipzig University.

Disclosure

The authors report no relevant disclosures. Go toNeurology.org/NN for full disclosures.