In the highly active antiretroviral therapy (HAART) era, the incidence and mortality of progressive multifocal leukoencephalopathy (PML) have significantly decreased in parallel with the improved immune status of the patients . Paradoxically, PML may develop or worsen despite potent HAART in the setting of an immune reconstitution inflammatory syndrome (IRIS) . Maraviroc, a CCR5 inhibitor, is a new antiviral drug with immunomodulating properties as a result of its ability to block the recruitment of CCR5+ cells . We report a case of paradoxical PML-IRIS whose improvement has been amazingly fast after maraviroc adjunction, suggesting that the immunomodulating properties of maraviroc may be beneficial in this context.
A 38-year-old HAART-naïve HIV-1-infected man was admitted on February 2009 for reduction of verbal fluency and cognitive impairment, without any paresis or need for support in everyday life. His CD4+ T-cell count was 55 cells/μl and plasma viral load 5.71 log10 copies/ml. HIV was wild-type and R5-tropic. Brain MRI showed nonenhancing T1 hypo-intense and T2 hyper-intense lesions in the right frontal lobe (Fig. 1). Cerebrospinal fluid (CSF) was positive for polyomavirus JC (JCV), and negative for other pathogens. HAART based on boosted lopinavir, lamivudine and zidovudine was started 5 days after admission.
One month later, his condition worsened sharply with mild cognitive slowing, aphasia, left hemiplegia and left facial palsy. He was confined to bed with deglutition impairment requiring gastrostomy. His CD4+ T-cells count was 379 cells/μl and plasma viral load was 3.6 log10 copies/ml. PCR for JCV was negative in the CSF. Brain MRI showed an increase in the size of frontal lesions without mass effect or gadolinium enhancement. Due to the fast clinical worsening and the strong immunological and virological responses, PML paradoxical IRIS was suspected. He received methylprednisolone (1 mg/kg/day) for 10 days without improvement. Enfuvirtide was added to his antiretroviral treatment , in association with maraviroc because of its supposed immunomodulating properties.
Two months later, the patient had a marked clinical improvement, with regression of speech disturbance and hemiparesia. He could walk with assistance and eat without the need for a tracheal fausse route. His plasma viral load was 1.8 log10 copies/ml and CD4+ T-cell count was 284 cells/μl. Brain MRI revealed a punctiform right frontal gadolinium enhancement and paradoxical enlargement frontal and parietal lesions (Fig. 1). Five months later, clinical improvement persists.
The lack of gadolinium enhancement on MRI at the time of worsening might challenge a diagnosis of PML-IRIS. However, its absence does not preclude it . This surrogate marker of PML-IRIS has inconsistently been reported , and its appearance may be delayed and dissociated from the clinical outcome [5–8]. Rapid clinical deterioration and strong immunological and virological responses followed by a delayed appearance of gadolinium enhancement were anyway highly suggestive of IRIS.
We hypothesize that the dramatic clinical improvement experienced by this patient shortly after the antiretroviral therapy change may be due to maraviroc. Although enfuvirtide may improve PML survival , a fast improvement was highly unexpected with enfuvirtide alone. A delayed steroids therapy effect was also unlikely. Lastly, spontaneous improvement due to the regulation of the restored immune system is usually slow and progressive .
Restoration of the JCV-specific cellular immune response is of paramount importance in PML outcome by controlling JCV replication in the central nervous system (CNS) . However, in the setting of immune recovery, an exuberant inflammatory response due to a strong cellular immune response mediated by JCV-specific CD8+ cytotoxic T lymphocytes could also contribute to worsen patient condition in the early phase of HAART . Chemokines and their receptors govern physiological and pathological leukocyte trafficking, and notably the recruitment of blood leukocytes into the CNS . CCR5 has been involved in lymphocytes and mononuclear phagocytes recruitment in the CNS in multiple sclerosis . An anti-CCL5 monoclonal antibody reduces T-cell and macrophage accumulation within the CNS and improves neurological function in a murine model of demyelination . Thus, CCR5 antagonists  might reduce the severity of neuro-inflammation and disease by targeting the CCR5+ leukocyte recruitment pathway to the CNS, explaining the improvement experienced by this patient. However, if a worsening neurologic disability was a consequence of immunosupression and active JCV infection, one needs to be cautious when using a drug that blunts CNS leukocyte trafficking. In our patient, CSF was negative for JCV by PCR while worsening, suggesting that JCV replication was already under control.
In conclusion, we report a case of paradoxical PML-IRIS with an unusually fast improvement after maraviroc adjunction. We propose that maraviroc could be beneficial in the management of paradoxical PML-IRIS by modulating CNS leukocyte trafficking and attenuating any deleterious inflammatory response, and is deserving of further studies.
1. Engsig FN, Hansen AB, Omland LH, Kronborg G, Gerstoft J, Laursen AL, et al
. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis 2009; 199:77–83.
2. Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection. Clinical manifestations and treatment with steroids. Neurology 2009; 72:1458–1464.
3. Desmetz C, Lin YL, Mettling C, Portales P, Rabesandratana H, Clot J, Corbeau P. The strength of the chemotactic response to a CCR5 binding chemokine is determined by the level of cell surface CCR5 density. Immunology 2006; 119:551–561.
4. Gasnault J, Hendel Chavez H, Darasteanu I, Dulioust A, Lancar R, Dembele B, et al.
Recovery of anti-JCV specific T cell responses and better survival on intensified antiretroviral therapy in HIV-1 infected patients with progressive multifocal leukoencephalopathy: the ANRS 125 trial. WEAB204, IAS 2007.
5. Collazos J, Mayo J, Martinez E, Blanco MS. Contrast-enhancing progressive multifocal leukoencephalopathy as an immune reconstitution event in AIDS patients. AIDS 1999; 13:1426–1428.
6. Kotecha N, George MJ, Smith TW, Corvi F, Litofsky NS. Enhancing progressive multifocal leukoencephalopathy: an indicator of improved immune status? Am J Med 1998; 105:541–543.
7. Travis J, Varma A, duPlessis D, Turnbull I, Vilar FJ. Immune reconstitution associated with progressive multifocal leukoencephalopathy in human immunodeficiency virus: a case discussion and review of the literature. Neurologist 2008; 14:321–326.
8. Giudici B, Vaz B, Bossolasco S, Casari S, Brambilla AM, Luke W, et al
. Highly active antiretroviral therapy and progressive multifocal leukoencephalopathy: effects on cerebrospinal fluid markers of JC virus replication and immune response. Clin Infect Dis 2000; 30:95–99.
9. Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004; 17:365–370.
10. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003; 9(Suppl 1):25–31.
11. Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003; 3:569–581.
12. Trebst C, Staugaitis SM, Tucky B, Wei T, Suzuki K, Aldape KD, et al
. Chemokine receptors on infiltrating leucocytes in inflammatory pathologies of the central nervous system (CNS). Neuropathol Appl Neurobiol 2003; 29:584–595.
13. Glass WG, Hickey MJ, Hardison JL, Liu MT, Manning JE, Lane TE. Antibody targeting of the CC chemokine ligand 5 results in diminished leukocyte infiltration into the central nervous system and reduced neurologic disease in a viral model of multiple sclerosis. J Immunol 2004; 172:4018–4025.
14. MacArthur RD, Novak RM. Reviews of antiinfective agents: maraviroc: the first of a new class of antiretroviral agents. Clin Infect Dis 2008; 47:236–241.