Case Study Reports Positive Impact of Antiviral Therapy Tenofovir in MS, Warranting Further Research

Øivind Torkildsen, MD, PhD

A recently published case report of a patient with highly active multiple sclerosis (MS) who was also HIV positive showed that treatment with antiretrovirals (ART) containing tenofovir resulted in suppression of MS disease activity. Overall, these results suggest that the use of a potent inhibitor of Epstein-Barr virus (EBV) replication like tenofovir may be a potentially beneficial treatment option for MS.

The case study began in 2020, when investigators published a description of a 34-year-old woman with relapsing-remitting MS who was treated with a combination of ARTs containing tenofovir. At the time of her diagnosis in 2015, she began treatment with fingolimod (Gilenya; Novartis). Two years later, she was infected with HIV, where she began treatment with an integrase strand transfer inhibitor (INSTI)-based single-tablet regimen with 3 active agents consisting of a combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alanfenamide (TAF).

After 2 years of stable disease activity while on fingolimod, the therapy was discontinued. In 2019, she switched from TAF to tenofovir disoproxil fumarate (TDF), which is known to have less potency against EBV replication. After the switch, she had 1 gadolinium-enhancing lesion on MRI, but no new clinical relapses. In addition, she reported that 2 of her MS-related symptoms, pain and fatigue, decreased, and her neuropathic pain was completely resolved.

"Tenofovir has excellent safety and tolerability profile and is also used as a pre-exposure prophylaxis (PrEP) in high-risk individuals to prevent HIV infection, making it a particularly strong candidate as a drug for primary prevention of virally acquired diseases," lead author Øivind Torkildsen, MD, PhD, professor in the Department of Clinical Medicine at the University of Bergen, and colleagues, wrote. "Since EBV mainly resides in the latent phase in infected individuals, the observations on the use of TAF in patients with MS could help answer the question of whether lytic reactivation is necessary for disease activity in MS."

In the years following the initial publication in 2020, the patient demonstrated no new relapses, Expanded Disability Status Scale progression, or MRI lesions while on a combination of raltegravir, emtricitabine, and TDF. In 2022, she switched to a one-tablet dosing regimen consisting of dolutegravir and rilpivirin, a non-nucleoside-reverse transcription inhibitor with no known effect on EBV-replication, which subsequently worsened her condition 5 months later.

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Around that time, the patient began to show new signs of disease activity, including new gadolinium-enhancing lesions. Notably, she was hospitalized in October 2022 with an MRI-verified relapse and was subsequently treated with steroids. Months later, in June 2023, an MRI revealed new MS lesions, leading to the initiation of MS treatment with rituximab in June 2023.

"Since TAF and TDF mainly prevent the lytic reactivation of EBV, this could indicate that lytic reactivation is the primary driver of the disease process in MS. Several alternative explanations could also account for this potential effect. First, it is possible that the combined effect of CD4+ T cell repertoire depletion followed by sustained TAF-mediated suppression of the EBV-infected B cell compartment delayed priming and re-emergence of potentially pathogenic EBV-specific or autoreactive CD4+ T cells."

"We therefore cannot know if the remission was primary due to the effect of TAF on EBV lytic replication, and not due to HIV-mediated depletion of the CD4+ T cell compartment itself," the study authors added. "Secondly, an alternative hypothesis could be that TAF works primarily by inhibiting human endogenous retroviruses (HERV) which have been previously linked to MS disease pathogenesis."

Currently there is 1 study on TDF (NCT05957913) and 1 study on TAF (EUCT number: 2023–503,814–62–00) that are being performed in patients with MS, where the main goal is to determine the effect on EBV shedding. The first of these two, a phase 2b trial of 50 participants with EBV, is expected to conclude by the end of 2024. This study assesses tenofovir/emtricitabine (Truvada) in standard doses, with the primary outcome of change in EBV viral load.

REFERENCE
1. Torkildsen O, Myhr KM, Brugger-Synnes P, Bjornevik K. Antiviral therapy with tenofovir in MS. Mult Scler & Relat Disor. 2024;83:105436. doi:10.1016/j.msard.2024.105436