Progressive Multifocal Leukoencephalopathy with Immune Reconstitution Inflammatory Syndrome (PML-IRIS): two case reports of successful treatment with mefloquine and a review of the literature.

Dear Editor, Failure of cell-mediated immunity allows reactivation of the ‘JC’ polyomavirus (JCV) in oligodendrocytes, and the development of progressive multifocal leukoencephalopathy (PML). This is most commonly associated with advanced human immunodefi ciency virus (HIV) infection, but is also described after biological therapies such as natalizumab, and rarely other conditions.1 In the early years of HIV treatment, PML frequently resulted in death irrespective of medical interventions. The development of antiretroviral therapy (ART) has greatly improved this prognosis. In the Swiss Cohort Study, incidence fell 4-fold and attributable 1-year mortality fell from 60% to 20%.2 Despite these advances, PML still has one of the highest mortality rates among acquired immune defi ciency syndrome (AIDS) defi ning illnesses. A rapid early mortality is observed, and less than half of survivors are expected to recover neurologically.3 While re-establishment of the immune system is important for successful outcomes, it can trigger an acute infl ammatory response to JCV or host antigens. This immune reconstitution infl ammatory syndrome (IRIS) exacerbates symptoms, though may not adversely affect mortality.4 Neither broad spectrum antiviral therapy with interferon alpha nor putative anti-JCV agents such as cytarabine and cidofovir have proved successful PML treatments.5,6 A cellbased screen of several thousand compounds for inhibition of JCV infection rates identifi ed the anti-malarial mefl oquine as a new theraputic candidate.7 Mefl oquine appeared to block JCV replication without signifi cant toxicity, and at concentrations achievable in the central nervous system (CNS). A number of case reports have since been published, reporting successful PML treatment with mefl oquine in HIV and non-HIV infected patients. A randomised, raterblinded study sponsored by Biogen Idec (Clinicaltrials.gov identifi er NCT00746941) to assess mefl oquine effi cacy in patients with PML was stopped in early 2011 after an analysis of the fi rst 24 participants randomised identifi ed no virologic benefi t, the primary endpoint.8 This study is yet to be published, and clearly caution must be adopted with continued off-label use of mefl oquine. However it is possible subgroups may benefi t. We report 2 cases of PMLIRIS in HIV-infected individuals with dramatic responses after mefl oquine treatment was started, and postulate an alternative mechanism of action.