Advertisement

CNS Drugs

, Volume 26, Issue 2, pp 123–134 | Cite as

HIV-Associated Neurological Disorders

A Guide to Pharmacotherapy
  • Ik L. Tan
  • Justin C. McArthurEmail author
Review Article

Abstract

In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorder (HAND) continues to be a common and significant morbidity among individuals infected with HIV. The term HAND encompasses a spectrum of progressively severe CNS involvement, ranging from asymptomatic neurocognitive impairment and minor neurocognitive disorder through to the most severe form of HIV-associated dementia (HAD). While the incidence of HAD has declined significantly with HAART, the milder forms of HAND persist. In addition, HAND now develops in individuals with less advanced immunosuppression. The reasons for the persistence of milder forms of HAND in individuals treated with HAART are not entirely known. There are several hypotheses to explain this phenomenon that include the legacy effect, a failure of antiretroviral agents to reverse neurological damage, poor access of antiretroviral agents to the CNS, chronic systemic immune activation associated with microbial translocation products, sustained CNS inflammation, the improved survival of HIV-seropositive individuals and the possible contribution from aging, amyloid deposition and other co-morbidities. In contrast, the incidence of HIV-associated CNS opportunistic processes including progressive multifocal leukoencephalopathy, tuberculosis, CNS toxo-plasmosis, cytomegalovirus encephalitis, cryptococcosis and primary CNS lymphoma has declined dramatically with the introduction of HAART. This review briefly summarizes our current understanding of HAND and the pathological mechanisms involved, namely direct injury from HIV-1 and viral proteins, indirect neurotoxicity from proinflammatory cytokines and chronic, sustained immune activation in the CNS. To date, only HAART has been shown to benefit HAND despite numerous controlled trials of adjunctive ‘anti-inflammatory’ agents. Although HAART has a profound impact on the incidence and severity of HAND, there exists a ‘therapeutic gap’ as even HAART that is effective at inducing durable virological suppression may only partially reverse HAND. In addition, there may be potential CNS adverse effects of antiretroviral agents. There is an ongoing multicentre clinical trial to investigate the role of the CNS Penetration-Effectiveness index, an indicator of drug permeability and availability in the CNS, to help guide the choice of antiretroviral agents in the treatment of HAND. With recent recommendations for earlier treatment intervention with HAART for HIV-1 infection, it remains to be seen the effects of this on HAND. There is an urgent need to better define the therapeutic guidelines for the prevention and treatment of HAND.

Keywords

Progressive Multifocal Leukoencephalopathy Progressive Multifocal Leukoencephalopathy Maraviroc Asymptomatic Neurocognitive Impairment Chronic Immune Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was supported by the JHU NIMH Center for novel therapeutics for HIV cognitive disorders (1P30MH075673). Dr Justin C. McArthur has recently received research grants from Biogen Idec, and book royalties from Oxford University Press. Dr Ik Lin Tan has no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    The Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008 Jul 26; 372(9635): 293–9Google Scholar
  2. 2.
    Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010 Jun 1; 24(9): 1243–50PubMedGoogle Scholar
  3. 3.
    Cysique LA, Maruff P, Brew BJ. Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: a combined study of two cohorts. J Neurovirol 2004 Dec; 10(6): 350–7PubMedGoogle Scholar
  4. 4.
    McArthur JC, Brew BJ, Nath A. Neurological complications of HIV infection. Lancet Neurol 2005 Sep; 4(9): 543–55PubMedGoogle Scholar
  5. 5.
    McArthur JC, Steiner J, Sacktor N, et al. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 2010 Jun; 67(6): 699–714PubMedGoogle Scholar
  6. 6.
    Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007 Oct 30; 69(18): 1789–99PubMedGoogle Scholar
  7. 7.
    McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol 2004 Dec; 157(1–2): 3–10PubMedGoogle Scholar
  8. 8.
    Luther VP, Wilkin AM. HIV infection in older adults. Clin Geriatr Med 2007 Aug; 23(3): 567–83, viiPubMedGoogle Scholar
  9. 9.
    Sevigny JJ, Albert SM, McDermott MP, et al. Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 2004 Dec 14; 63(11): 2084–90PubMedGoogle Scholar
  10. 10.
    Cysique LA, Maruff P, Brew BJ. Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology 2006 May 9; 66(9): 1447–50PubMedGoogle Scholar
  11. 11.
    Clifford DB. HIV-associated neurocognitive disease continues in the antiretroviral era. Top HIV Med 2008 Jun–Jul; 16(2): 94–8PubMedGoogle Scholar
  12. 12.
    Brew BJ. Benefit or toxicity from neurologically targeted antiretroviral therapy? Clin Infect Dis 2010 Mar 15; 50(6): 930–2PubMedGoogle Scholar
  13. 13.
    Dore GJ, McDonald A, Li Y, et al. Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 2003 Jul 4; 17(10): 1539–45PubMedGoogle Scholar
  14. 14.
    Cunningham AL, Naif H, Saksena N, et al. HIV infection of macrophages and pathogenesis of AIDS dementia complex: interaction of the host cell and viral genotype. J Leukoc Biol 1997 Jul; 62(1): 117–25PubMedGoogle Scholar
  15. 15.
    Rabkin JG, Chesney MA. Adhering to complex regimens for HIV. GMHC Treat Issues 1998 Apr; 12(4): 8–11PubMedGoogle Scholar
  16. 16.
    Hinkin CH, Castellon SA, Durvasula RS, et al. Medication adherence among HIV+ adults: effects of cognitive dysfunction and regimen complexity. Neurology 2002 Dec 24; 59(12): 1944–50PubMedGoogle Scholar
  17. 17.
    Heaton RK, Marcotte TD, Mindt MR, et al. The impact of HIV-associated neuropsychological impairment on everyday functioning. J Int Neuropsychol Soc 2004 May; 10(3): 317–31PubMedGoogle Scholar
  18. 18.
    Ellis RJ, Deutsch R, Heaton RK, et al. Neurocognitive impairment is an independent risk factor for death in HIV infection: San Diego HIV Neurobehavioral Research Center Group. Arch Neurol 1997 Apr; 54(4): 416–24PubMedGoogle Scholar
  19. 19.
    Tozzi V, Balestra P, Galgani S, et al. Neurocognitive performance and quality of life in patients with HIV infection. AIDS Res Hum Retroviruses 2003 Aug; 19(8): 643–52PubMedGoogle Scholar
  20. 20.
    Davis LE, Hjelle BL, Miller VE, et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 1992 Sep; 42(9): 1736–9PubMedGoogle Scholar
  21. 21.
    Rumbaugh JA, Nath A. Developments in HIV neuropathogenesis. Curr Pharm Des 2006; 12(9): 1023–44PubMedGoogle Scholar
  22. 22.
    Schouten J, Cinque P, Gisslen M, et al. HIV-1 infection and cognitive impairment in the cART era: a review. AIDS 2010 Mar 13; 25(5): 561–75Google Scholar
  23. 23.
    Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol 2005 Jan; 5(1): 69–81PubMedGoogle Scholar
  24. 24.
    Price RW, Brew B, Sidtis J, et al. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 1988 Feb 5; 239(4840): 586–92PubMedGoogle Scholar
  25. 25.
    Churchill MJ, Wesselingh SL, Cowley D, et al. Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol 2009 Aug; 66(2): 253–8PubMedGoogle Scholar
  26. 26.
    Kaul M, Lipton SA. Mechanisms of neuroimmunity and neurodegeneration associated with HIV-1 infection and AIDS. JNeuroimmune Pharmacol 2006 Jun; 1(2): 138–51Google Scholar
  27. 27.
    Wiley CA, Achim C. Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome. Ann Neurol 1994 Oct; 36(4): 673–6PubMedGoogle Scholar
  28. 28.
    Brew BJ, Rosenblum M, Cronin K, et al. AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations. Ann Neurol 1995 Oct; 38(4): 563–70PubMedGoogle Scholar
  29. 29.
    Green DA, Masliah E, Vinters HV, et al. Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS 2005 Mar 4; 19(4): 407–11PubMedGoogle Scholar
  30. 30.
    Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006 Dec; 12(12): 1365–71PubMedGoogle Scholar
  31. 31.
    Price RW, Spudich S. Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 2008 May 15; 197 Suppl. 3: S294–306PubMedGoogle Scholar
  32. 32.
    Spudich SS, Nilsson AC, Lollo ND, et al. Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis 2005; 5: 98PubMedGoogle Scholar
  33. 33.
    Hagberg L, Dotevall L, Norkrans G, et al. Cerebrospinal fluid neopterin concentrations in central nervous system infection. J Infect Dis 1993 Nov; 168(5): 1285–8PubMedGoogle Scholar
  34. 34.
    Brew BJ, Bhalla RB, Paul M, et al. Cerebrospinal fluid beta 2-microglobulin in patients with AIDS dementia complex: an expanded series including response to zidovudine treatment. AIDS 1992 May; 6(5): 461–5PubMedGoogle Scholar
  35. 35.
    Clifford DB, Fagan AM, Holtzman DM, et al. CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology 2009 Dec 8; 73(23): 1982–7PubMedGoogle Scholar
  36. 36.
    Ancuta P, Kamat A, Kunstman KJ, et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 2008; 3(6):e2516PubMedGoogle Scholar
  37. 37.
    Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol 2006 Mar; 7(3): 235–9PubMedGoogle Scholar
  38. 38.
    Kaul M. HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol 2009 Jun; 22(3): 315–20PubMedGoogle Scholar
  39. 39.
    Perry VH, Newman TA, Cunningham C. The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 2003 Feb; 4(2): 103–12PubMedGoogle Scholar
  40. 40.
    Bashir RM, Harris NL, Hochberg FH, et al. Detection of Epstein-Barr virus in CNS lymphomas by in-situ hybridization. Neurology 1989 Jun; 39(6): 813–7PubMedGoogle Scholar
  41. 41.
    Tan IL, McArthur JC. HIV-associated central nervous system diseases in the era of combination antiretroviral therapy. Eur J Neurol 2011 Mar; 18(3): 371–2PubMedGoogle Scholar
  42. 42.
    Garvey L, Winston A, Walsh J, et al. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol 2011 Mar; 18(3): 527–34PubMedGoogle Scholar
  43. 43.
    d’Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 2004 Mar; 55(3): 320–8PubMedGoogle Scholar
  44. 44.
    Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001 Dec 1; 98(12): 3406–12PubMedGoogle Scholar
  45. 45.
    Heaton RK, Grant I, Butters N, et al. The HNRC 500: neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J Int Neuropsychol Soc 1995 May; 1(3): 231–51Google Scholar
  46. 46.
    Sacktor N. The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol 2002 Dec; 8 Suppl. 2: 115–21PubMedGoogle Scholar
  47. 47.
    Heaton RK, Clifford DB, Franklin Jr DR, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010 Dec 7; 75(23): 2087–96PubMedGoogle Scholar
  48. 48.
    Janssen RS, Nwanyanwu OC, Selik RM, et al. Epidemiology of human immunodeficiency virus encephalopathy in the United States. Neurology 1992 Aug; 42(8): 1472–6PubMedGoogle Scholar
  49. 49.
    Bhaskaran K, Mussini C, Antinori A, et al. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol 2008 Feb; 63(2): 213–21PubMedGoogle Scholar
  50. 50.
    Letendre SL, McCutchan JA, Childers ME, et al. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol 2004 Sep; 56(3): 416–23PubMedGoogle Scholar
  51. 51.
    Tozzi V, Balestra P, Galgani S, et al. Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment. AIDS 1999 Oct 1; 13(14): 1889–97PubMedGoogle Scholar
  52. 52.
    Robertson KR, Robertson WT, Ford S, et al. Highly active antiretroviral therapy improves neurocognitive functioning. J Acquir Immune Defic Syndr 2004 May 1; 36(1): 562–6PubMedGoogle Scholar
  53. 53.
    Marra CM, Lockhart D, Zunt JR, et al. Changes in CSF and plasma HIV-1 RNA and cognition after starting potent antiretroviral therapy. Neurology 2003 Apr 22; 60(8): 1388–90PubMedGoogle Scholar
  54. 54.
    Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009 Apr 30; 360(18): 1815–26PubMedGoogle Scholar
  55. 55.
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Bethesda (MD): Department of Health and Human Services, 2011 Jan 10: 1–166Google Scholar
  56. 56.
    Rumbaugh JA, Steiner J, Sacktor N, et al. Developing neuroprotective strategies for treatment of HIV-associated neurocognitive dysfunction. Futur HIV Ther 2008; 2(3): 271–80PubMedGoogle Scholar
  57. 57.
    Gavegnano C, Schinazi RF. Antiretroviral therapy in macrophages: implication for HIV eradication. Antivir Chem Chemother 2009; 20(2): 63–78PubMedGoogle Scholar
  58. 58.
    Sidtis JJ, Gatsonis C, Price RW, et al. Zidovudine treatment of the AIDS dementia complex: results of a placebocontrolled trial. AIDS Clinical Trials Group. Ann Neurol 1993 Apr; 33(4): 343–9Google Scholar
  59. 59.
    Portegies P, de Gans J, Lange JM, et al. Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. BMJ 1989 Sep 30; 299(6703): 819–21PubMedGoogle Scholar
  60. 60.
    Brew BJ, Halman M, Catalan J, et al. Factors in AIDS dementia complex trial design: results and lessons from the abacavir trial. PLoS Clin Trials 2007; 2(3): e13PubMedGoogle Scholar
  61. 61.
    Foudraine NA, Hoetelmans RM, Lange JM, et al. Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine.Lancet 1998 May 23; 351(9115): 1547–51PubMedGoogle Scholar
  62. 62.
    Martin C, Sonnerborg A, Svensson JO, et al. Indinavirbased treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS 1999 Jul 9; 13(10): 1227–32PubMedGoogle Scholar
  63. 63.
    Letendre SL, van den Brande G, Hermes A, et al. Lopinavir with ritonavir reduces the HIV RNA level in cerebrospinal fluid. Clin Infect Dis 2007 Dec 1; 45(11): 1511–7Google Scholar
  64. 64.
    Yilmaz A, Fuchs D, Hagberg L, et al. Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study. BMC Infect Dis 2006; 6: 63PubMedGoogle Scholar
  65. 65.
    Price RW, Yiannoutsos CT, Clifford DB, et al. Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS 1999 Sep 10; 13(13): 1677–85Google Scholar
  66. 66.
    Ferrando S, van Gorp W, McElhiney M, et al. Highly active antiretroviral treatment in HIV infection: benefits for neuropsychological function. AIDS 1998 May 28; 12(8): F65–70PubMedGoogle Scholar
  67. 67.
    Letendre SL, Cherner M, Ellis RJ, et al. The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance: biological correlates of disease. AIDS 2005 Oct; 19Suppl. 3: S72–8PubMedGoogle Scholar
  68. 68.
    Morgello S, Estanislao L, Ryan E, et al. Effects of hepatic function and hepatitis C virus on the nervous system assessment of advanced-stage HIV-infected individuals. AIDS 2005 Oct; 19Suppl. 3: S116–22PubMedGoogle Scholar
  69. 69.
    Perry W, Carlson MD, Barakat F, et al. Neuropsychological test performance in patients co-infected with hepatitis C virus and HIV. AIDS 2005 Oct; 19 Suppl. 3: S79–84PubMedGoogle Scholar
  70. 70.
    McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 1993 Nov; 43(11): 2245–52Google Scholar
  71. 71.
    Valcour V, Yee P, Williams AE, et al. Lowest ever CD4 lymphocyte count (CD4 nadir) as a predictor of current cognitive and neurological status in human immunodeficiency virus type 1 infection: the Hawaii Aging with HIV Cohort. J Neurovirol 2006 Oct; 12(5): 387–91PubMedGoogle Scholar
  72. 72.
    Valcour V, Sithinamsuwan P, Letendre S, et al. Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep 2010 Mar; 8(1): 54–61Google Scholar
  73. 73.
    Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008 Jan; 65(1): 65–70PubMedGoogle Scholar
  74. 74.
    Letendre SL, Ellis RJ, Ances BM, et al. Neurologic complications of HIV disease and their treatment. Top HIV Med 2010 Apr–May; 18(2): 45–55PubMedGoogle Scholar
  75. 75.
    Lanoy E, Guiguet M, Bentata M, et al. Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score. Neurology 2011 Feb 15; 76(7): 644–51PubMedGoogle Scholar
  76. 76.
    Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 2009 Jul 17; 23(11): 1359–66PubMedGoogle Scholar
  77. 77.
    Letendre SL, FitSimons C, Ellis R, et al. Correlates of CSF viral loads in 1,221 volunteers of the CHARTER cohort [abstract no. 172]. 17th Conference on Retroviruses and Opportunistic Infections (CROI); 2010 Feb 16–19; San Francisco (CA)Google Scholar
  78. 78.
    McGee B, Smith N, Aweeka F. HIV pharmacology: barriers to the eradication of HIV from the CNS. HIV Clin Trials 2006 May–Jun; 7(3): 142–53PubMedGoogle Scholar
  79. 79.
    Yilmaz A, Gisslen M, Spudich S, et al. Raltegravir cerebrospinal fluid concentrations in HIV-1 infection. PLoS One 2009; 4(9): e6877PubMedGoogle Scholar
  80. 80.
    Yilmaz A, Izadkhashti A, Price RW, et al. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals. AIDS Res Hum Retroviruses 2009 Apr; 25(4): 457–61PubMedGoogle Scholar
  81. 81.
    Yilmaz A, Watson V, Else L, et al. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS 2009 Nov 27; 23(18): 2537–40PubMedGoogle Scholar
  82. 82.
    Smurzynski M, Wu K, Letendre S, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS 2011 Jan 28; 25(3): 357–65PubMedGoogle Scholar
  83. 83.
    Sacktor N, Tarwater PM, Skolasky RL, et al. CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 2001 Aug 14; 57(3): 542–4PubMedGoogle Scholar
  84. 84.
    Cysique LA, Maruff P, Brew BJ. Antiretroviral therapy in HIV infection: are neurologically active drugs important? Arch Neurol 2004 Nov; 61(11): 1699–704PubMedGoogle Scholar
  85. 85.
    Giancola ML, Lorenzini P, Balestra P, et al. Neuroactive antiretroviral drugs do not influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2006 Mar; 41(3): 332–7PubMedGoogle Scholar
  86. 86.
    University of California, San Diego. Clinical trial of CNS-targeted HAART [Clinicaltrials.gov identifier NCT00624195]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Nov 7]
  87. 87.
    Cunningham R, Silbergleit R. Viral myocarditis presenting with seizure and electrocardiographic findings of acute myocardial infarction in a 14-month-old child. Ann Emerg Med 2000 Jun; 35(6): 618–22PubMedGoogle Scholar
  88. 88.
    Cinque P, Presi S, Bestetti A, et al. Effect of genotypic resistance on the virological response to highly active antiretroviral therapy in cerebrospinal fluid. AIDS Res Hum Retroviruses 2001 Mar 20; 17(5): 377–83PubMedGoogle Scholar
  89. 89.
    Canestri A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis 2010 Mar 1; 50(5): 773–8PubMedGoogle Scholar
  90. 90.
    Kraft-Terry SD, Buch SJ, Fox HS, et al. A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron 2009 Oct 15; 64(1): 133–45PubMedGoogle Scholar
  91. 91.
    Nowacek A, Gendelman HE. NanoART, neuroAIDS and CNS drug delivery. Nanomedicine (Lond) 2009 Jul; 4(5): 557–74Google Scholar
  92. 92.
    Cysique LA, Brew BJ. Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review. Neuropsychol Rev 2009 Jun; 19(2): 169–85PubMedGoogle Scholar
  93. 93.
    Dalakas MC, Semino-Mora C, Leon-Monzon M. Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2′3′-dideoxycytidine (ddC). Lab Invest 2001 Nov; 81(11): 1537–44PubMedGoogle Scholar
  94. 94.
    Nolan D, Mallal S. Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms. Antivir Ther 2004 Dec; 9(6): 849–63PubMedGoogle Scholar
  95. 95.
    Cespedes MS, Aberg JA. Neuropsychiatric complications of antiretroviral therapy. Drug Saf 2006; 29(10): 865–74PubMedGoogle Scholar
  96. 96.
    Rihs TA, Begley K, Smith DE, et al. Efavirenz and chronic neuropsychiatric symptoms: a cross-sectional case control study. HIV Med 2006 Nov; 7(8): 544–8PubMedGoogle Scholar
  97. 97.
    Robertson KR, Su Z, Margolis DM, et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010 Apr 20; 74(16): 1260–6PubMedGoogle Scholar
  98. 98.
    Childer ME, Woods SP, Letendre S, et al. Cognitive functioning during highly active antiretroviral therapy interruption in human immunodeficiency virus type 1 infection. J Neurovirol 2008 Nov; 14(6): 550–7Google Scholar
  99. 99.
    Kirk JB, Goetz MB. Human immunodeficiency virus in an aging population, a complication of success. J Am Geriatr Soc 2009 Nov; 57(11): 2129–38PubMedGoogle Scholar
  100. 100.
    Valcour V, Shikuma C, Shiramizu B, et al. Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology 2004 Sep 14; 63(5): 822–7PubMedGoogle Scholar
  101. 101.
    Shelburne 3rd SA, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002 May; 81(3): 213–27Google Scholar
  102. 102.
    Gray F, Bazille C, Adle-Biassette H, et al. Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol 2005; 11 Suppl. 3: 16–22PubMedGoogle Scholar
  103. 103.
    Venkataramana A, Pardo CA, McArthur JC, et al. Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients. Neurology 2006 Aug 8; 67(3): 383–8PubMedGoogle Scholar
  104. 104.
    Johnson T, Nath A. Immune reconstitution inflammatory syndrome and the central nervous system. Curr Opin Neurol 2011 Jun; 24(3): 284–90PubMedGoogle Scholar
  105. 105.
    Zhao Y, Navia BA, Marra CM, et al. Memantine for AIDS dementia complex: open-label report of ACTG 301. HIV Clin Trials 2010 Jan–Feb; 11(1): 59–67PubMedGoogle Scholar
  106. 106.
    Schifitto G, Navia BA, Yiannoutsos CT, et al. Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS 2007 Sep 12; 21(14): 1877–86PubMedGoogle Scholar
  107. 107.
    Navia BA, Dafni U, Simpson D, et al. A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 1998 Jul; 51(1): 221–8PubMedGoogle Scholar
  108. 108.
    Sacktor N, Schifitto G, McDermott MP, et al. Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study. Neurology 2000 Jan 11; 54(1): 233–5PubMedGoogle Scholar
  109. 109.
    The Dana Consortium on the Therapy of HIV Ddementia and Related Cognitive Disorders. A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment: Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Neurology 1998 Mar; 50(3): 645–51Google Scholar
  110. 110.
    Schifitto G, Yiannoutsos CT, Ernst T, et al. Selegiline and oxidative stress in HIV-associated cognitive impairment. Neurology 2009 Dec 8; 73(23): 1975–81PubMedGoogle Scholar
  111. 111.
    Zink CF, Pagnoni G, Chappelow J, et al. Human striatal activation reflects degree of stimulus saliency. Neuroimage 2006 Feb 1; 29(3): 977–83PubMedGoogle Scholar
  112. 112.
    Szeto GL, Brice AK, Yang HC, et al. Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells. J Infect Dis 2010 Apr 15; 201(8): 1132–40PubMedGoogle Scholar
  113. 113.
    Probasco JC, Spudich SS, Critchfield J, et al. Failure of atorvastatin to modulate CSF HIV-1 infection: results of a pilot study. Neurology 2008 Aug 12; 71(7): 521–4PubMedGoogle Scholar
  114. 114.
    Ances BM, Letendre SL, Alexander T, et al. Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders. Int Rev Psychiatry 2008 Feb; 20(1): 89–93PubMedGoogle Scholar
  115. 115.
    University of Pennsylvania. Modulation of monocyte activation by atorvastatin in HIV infection [Clinicaltrials.gov identifier NCT01263938]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Nov 7]
  116. 116.
    University of Hawaii. Maraviroc intensification and peripheral blood monocyte HIV DNA levels [Clinical-Trials.gov identifier NCT00987948]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Nov 7]
  117. 117.
    Johns Hopkins University. Study of paroxetine and fluconazole for the treatment of HIV associated neurocognitive disorder (Paraflu) [ClinicalTrials.gov identifier NCT01354314]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Nov 7]
  118. 118.
    De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 2008 Sep 12; 22(14): 1759–67PubMedGoogle Scholar
  119. 119.
    Huang SS, Skolasky RL, Dal Pan GJ, et al. Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol 1998 Jun; 4(3): 324–32PubMedGoogle Scholar
  120. 120.
    Vollmer-Haase J, Young P, Ringelstein EB. Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997 May 10; 349(9062): 1366PubMedGoogle Scholar
  121. 121.
    Royal 3rd W, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003 Jun; 9(3): 411–9PubMedGoogle Scholar
  122. 122.
    De Luca A, Giancola ML, Cingolani A, et al. Clinical and virological monitoring during treatment with intrathecal cytarabine in patients with AIDS-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 1999 Mar; 28(3): 624–8PubMedGoogle Scholar
  123. 123.
    Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection: AIDS Clinical Trials Group 243 Team. N Engl J Med 1998 May 7; 338(19): 1345–51PubMedGoogle Scholar
  124. 124.
    Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009 Nov 10; 73(19): 1551–8PubMedGoogle Scholar
  125. 125.
    Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol 2009 Feb; 66(2): 255–8PubMedGoogle Scholar
  126. 126.
    Biogen Idec. Study to explore the effect of mefloquine in subjects with progressive multifocal leukoencephalopathy (PML) [ClinicalTrials.gov identifier NCT00746941]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Nov 7]]
  127. 127.
    Berger JR, Pall L, Lanska D, et al. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 1998 Feb; 4(1): 59–68PubMedGoogle Scholar
  128. 128.
    Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003; 9 Suppl. 1: 47–53PubMedGoogle Scholar
  129. 129.
    Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010 Apr; 9(4): 425–37PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  1. 1.Department of Neurology, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of Pathology, Department of Medicine, School of Medicine and Department of Epidemiology, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations