Thiazolidinediones could be an effective treatment for HIV-associated progressive multifocal leukoencephalopathy (2007)

HIV-associated progressive multi-focal leukoencephalopathy (PML) is a severe neurodegenerative disorder that leads to disability and death from fulminant damage to cerebral white matter. PML is caused by human polyoma JC virus, an almost ubiquitous virus normally kept in check by the immune system.1Chapagain M.L. Nguyen T. Bui T. Verma S. Nerurkar V.R. Comparison of real-time PCR and hemagglutination assay for quantitation of human polyomavirus JC.Virol J. 2006; 3: 3Crossref PubMed Scopus (20) Google Scholar PML had been common prior to the advent of highly active anti-retroviral therapy (HAART), and now some cases are being seen in the context of HAART failure2Langford T.D. Letendre S.L. Marcotte T.D. Ellis R.J. McCutchan J.A. Grant I. et al.Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy.AIDS. 2002; 16: 1019-1029Crossref PubMed Scopus (151) Google Scholar and also immune reconstitution syndrome, where a patient's HAART-restored immune system attacks brain tissue.3Vendrely A. Bienvenu B. Gasnault J. Thiebault J.B. Salmon D. Gray F. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy.Acta Neuropathol (Berl). 2005; 109: 449-455Crossref PubMed Scopus (146) Google Scholar Currently available treatments such as interferon are often ineffective4Nath A. Venkataramana A. Reich D.S. Cortese I. Major E.O. Progression of progressive multifocal leukoencephalopathy despite treatment with beta-interferon.Neurology. 2006; 66: 149-150Crossref PubMed Scopus (23) Google Scholar and new approaches are needed. I propose the hypothesis that thiazolidinediones (TZs) such as pioglitazone and rosiglitazone, currently used for treatment of type II diabetes, could potentially slow the course of PML and under the best of circumstances, induce a complete remission. Both basic science and clinical data lend support to the above idea. TZs have pleiotropic neuroprotective effects that can be demonstrated in several different animal models of neurodegeneration.5Pershadsingh H.A. Heneka M.T. Saini R. Amin N.M. Broeske D.J. Feinstein D.L. Effect of pioglitazone treatment in a patient with secondary multiple sclerosis.J Neuroinflammation. 2004; 1: 3Crossref PubMed Scopus (72) Google Scholar Neuroprotective effects are believed to be through anti-inflammatory mechanisms mediated by the peroxisome-activated gamma receptor.5Pershadsingh H.A. Heneka M.T. Saini R. Amin N.M. Broeske D.J. Feinstein D.L. Effect of pioglitazone treatment in a patient with secondary multiple sclerosis.J Neuroinflammation. 2004; 1: 3Crossref PubMed Scopus (72) Google Scholar TZ stimulation of the peroxisome-activated gamma receptor suppresses a multitude of inflammatory cytokines both in cultured cells and in vivo in animal models.5Pershadsingh H.A. Heneka M.T. Saini R. Amin N.M. Broeske D.J. Feinstein D.L. Effect of pioglitazone treatment in a patient with secondary multiple sclerosis.J Neuroinflammation. 2004; 1: 3Crossref PubMed Scopus (72) Google Scholar, 6Storer P.D. Xu J. Chavis J. Drew P.D. Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis.J Neuroimmunol. 2005; 161: 113-122Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 7Meier C.A. Chicheportiche R. Juge-Aubry C.E. Dreyer M.G. Dayer J.M. Regulation of the interleukin-1 receptor antagonist in THP-1 cells by ligands of the peroxisome proliferator-activated receptor gamma.Cytokine. 2002; 18: 320-328Crossref PubMed Scopus (61) Google Scholar Furthermore, pioglitazone has been shown to reduce activation of T lymphocytes from patients with multiple sclerosis,8Schmidt S. Moric E. Schmidt M. Sastre M. Feinstein D.L. Heneka M.T. Anti-inflammatory and antiproliferative actions of PPAR-gamma agonists on T lymphocytes derived from MS patients.J Leukoc Biol. 2004; 75: 478-485Crossref PubMed Scopus (90) Google Scholar and there is a published case report from 2004 of a 44-year-old woman with severe progressive multiple sclerosis, complicated by quadriparesis, ataxia, fatigue and cognitive decline, who had a significant clinical remission taking pioglitazone.5Pershadsingh H.A. Heneka M.T. Saini R. Amin N.M. Broeske D.J. Feinstein D.L. Effect of pioglitazone treatment in a patient with secondary multiple sclerosis.J Neuroinflammation. 2004; 1: 3Crossref PubMed Scopus (72) Google Scholar Large scale clinical trials with multiple sclerosis patients are undoubtedly underway now. Given that multiple sclerosis and PML are both demyelinating inflammation of the cerebral white matter, it would be logical to similarly initiate clinical trials in patients with HIV-associated PML. The trials could be either large randomized placebo controlled studies or ‘n of 1’ longitudinal studies like that for the patient with multiple sclerosis. TZs already show promise as a treatment for HAART-associated lipodystrophy9Hadigan C. Yawetz S. Thomas A. Havers F. Sax P.E. Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial.Ann Intern Med. 2004; 140: 786-794Crossref PubMed Scopus (176) Google Scholar, 10Calmy A. Hirschel B. Hans D. Karsegard V.L. Meier C.A. Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy.AIDS. 2003; 17: 770-772Crossref PubMed Scopus (47) Google Scholar so from an ethical standpoint potential benefits to patients would certainly justify open-label ‘n of 1’ studies, if they are done by HIV specialists who would insure no deleterious drug interactions with HAART medications. In conclusion, potential benefits of TZs for HIV-associated PML warrant further investigation. Conflict of interest: No conflict of interest to declare.