A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study



      Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS.


      To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS.


      This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments.


      All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir.


      Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Baker D.
        • Marta M.
        • Giovannoni G.
        • Schmierer K.
        Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis.
        EBioMedicine. 2017; 16: 41-50
        • Balada E.
        • Ordi-Ros J.
        Vilardell-Torres M: molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity.
        Rev. Med. Virol. 2009; 19: 273-286
        • Berger J.R.
        • Sheremata W.A.
        • Resnick L.
        • et al.
        Multiple sclerosis –like illness occurring with human immunodeficiency virus infection.
        Neurology. 1989; 39: 324-329
        • Brudek T.
        • Christensen T.
        • Aagaard L.
        • Petersen T.
        • Hansen H.J.
        • Møller-Larsen A.
        B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity.
        Retrovirology. 2009; 6: 104
        • Charcot J.M.
        Histologie De La Sclerose En Plaques. 41. Gaz Hop, Paris1868 (554-5557-8, 566)
        • Chastain E.M.
        • Miller S.D.
        Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease.
        Immunol. Rev. 2012; 245: 227-238
        • Christensen T.
        Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses.
        Rev. Med. Virol. 2005; 15: 179-211
        • Christensen T.
        • Dissing Sørensen P.
        • Riemann H.
        • Hansen H.J.
        • Møller-Larsen A.
        Expression of sequence variants of endogenous retrovirus RGH in particle form in multiple sclerosis.
        Lancet. 1998; 352: 1033
        • Compston A.
        The 150th anniversary of the first depiction of the lesions of multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 1988; 51: 1249-1252
        • Gold J.
        • Goldacre R.
        • Maruszak H.
        • et al.
        HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study.
        J. Neurol. Neurosurg. Psychiatry. 2015; 86: 9-12
      1. Goodin D.S. The causal cascade to multiple sclerosis: a model for MS pathogenesis PLoS One 4 2009; e4565. February (2) 26.

        • Gourrand PA Harbo H.F.
        • Hauser S.E.
        • et al.
        The genetics of multiple sclerosis: an up-to-date review.
        Immunol. Rev. 2012; 248: 87-103
        • Grandi N.
        • Cadeddu M.
        • Blomberg J.
        • Tramontano E.
        Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes.
        Retrovirology. 2016; 13: 67
        • Haahr S.
        • Sommerlund M.
        • Møller-Larsen A.
        • Nielsen R.
        • Hansen H.J.
        Just another dubious virus in cells from a patient with multiple sclerosis?.
        Lancet. 1991; 337: 863-864
        • Hansen D.T.
        • Petersen T.
        • Christensen T.
        Retroviral envelope proteins: involvement in neuropathogenesis.
        J. Neurol. Sci. 2017; 380: 151-163
        • Kempkes B.
        • Robertson E.
        S. Epstein-Barr Virus latency: current and future perspectives.
        Curr. Opin. Virol. 2015; 14: 138-144
        • Kremer D.
        • Glanzman R.
        • Traboulsee A.
        • et al.
        Meeting report.
        Meeting report. 15. 2017: 18-23
      2. Liedthe M.D., Ryan Tomlin C., Lockhart S.M., et al. 2014. Longterm efficacy and safety of raltegravir in the management of HIV infection infect drug resist. 7, 73–84.

        • Mameli G.
        • Poddighe L.
        • Mei A.
        • Uleri E.
        • Sotgiu S.
        • Serra C.
        • Manetti R.
        • Dolei A.
        Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.
        PLoS One. 2012; 7: e44991
        • Maruszak H.
        • Brew B.J.
        • Giovannoni G.
        • Gold J.
        Could antiretroviral drugs be effective in multiple sclerosis? A case report.
        Eur. J. Neurol. 2011; 18: e110-e111
        • Møller-Larsen A.
        • Brudek T.
        • Petersen T.
        • Petersen E.L.
        • Aagaard M.
        • Hansen D.T.
        • Christensen T.
        Flow cytometric assay detecting cytotoxicity against human endogenous retrovirus antigens expressed on cultured multiple sclerosis cells.
        Clin. Exp. Immunol. 2013; 173: 398-410
        • Morandi E. Tanasescu R.
        • Tarlinton R.E.
        The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis.
        PLoS One. 2017; 12e0172415
        • Perron H.
        • Lolande B.
        • Gratacap B.
        • Laurent O.
        • et al.
        Isolation of retroviruses from patients with multiple sclerosis.
        Lancet. 1991; 337: 862-863
        • Punkosdy G.A.
        • Blain M Glass D.D.
        • et al.
        T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens.
        Proc. Natl. Acad. Sci. USA. 2011; 108: 3677-3682
        • Sormani M.P.
        • Miller D.H.
        • Couli G.
        • et al.
        Clinical trials of multiple sclerosis monitored with enhanced MRI; new sample size calculations based on large data sets.
        J. Neurol. Neurosurg. Psychiatry. 2001; 70: 494-499