Advertisement

Clinical Pharmacokinetics

, Volume 53, Issue 10, pp 891–906 | Cite as

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

  • Andrea CalcagnoEmail author
  • Giovanni Di Perri
  • Stefano Bonora
Review Article

Abstract

HIV-positive patients may be effectively treated with highly active antiretroviral therapy and such a strategy is associated with striking immune recovery and viral load reduction to very low levels. Despite undeniable results, the central nervous system (CNS) is commonly affected during the course of HIV infection, with neurocognitive disorders being as prevalent as 20–50 % of treated subjects. This review discusses the pathophysiology of CNS infection by HIV and the barriers to efficacious control of such a mechanism, including the available data on compartmental drug penetration and on pharmacokinetic/pharmacodynamic relationships. In the reviewed articles, a high variability in drug transfer to the CNS is highlighted with several mechanisms as well as methodological issues potentially influencing the observed results. Nevirapine and zidovudine showed the highest cerebrospinal fluid (CSF) to plasma ratios, although target concentrations are currently unknown for the CNS. The use of the composite CSF concentration effectiveness score has been associated with better virological outcomes (lower HIV RNA) but has been inconsistently associated with neurocognitive outcomes. These findings support the CNS effectiveness of commonly used highly antiretroviral therapies. The use of antiretroviral drugs with increased CSF penetration and/or effectiveness in treating or preventing neurocognitive disorders however needs to be assessed in well-designed prospective studies.

Keywords

Atazanavir Darunavir Raltegravir Maraviroc Etravirine 
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

Conflict of interest

No funding has been received for the preparation of this review.

A. Calcagno has received travel grants or speaker’s honoraria from Abbott, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD) and Janssen-Cilag. S. Bonora has received grants, travel grants and consultancy fees from Abbott, Boehringer-Inghelheim, BMS, Gilead-Sciences, GlaxoSmithKline (GSK), MSD, Pfizer and Janssen-Cilag. G. Di Perri has received grants, travel frants and consultancy fees from Abbott, Boehringer-Inghelheim, BMS, Gilead-Sciences, GSK, MSD, Pfizer, Roche and Tibotec (Johnson & Johnson).

References

  1. 1.
    Valcour V, Chalermchai T, Sailasuta N, et al. Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis. 2012;206(2):275–82.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Gannon P, Khan MZ, Kolson DL. Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol. 2011;24(3):275–83.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Zhou L, Saksena NK. HIV associated neurocognitive disorders. Infect Dis Rep. 2013;5(Suppl 1):e8.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Clifford DB, Ances BM. HIV-associated neurocognitive disorder. Lancet Infect Dis. 2013;13(11):976–86.PubMedGoogle Scholar
  5. 5.
    Bonnet F, Amieva H, Marquant F, et al. Cognitive disorders in HIV-infected patients: are they HIV-related? AIDS. 2013;27(3):391–400.PubMedGoogle Scholar
  6. 6.
    Burdo TH, Lackner A, Williams KC. Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev. 2013;254(1):102–13.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Carroll-Anzinger D, Kumar A, Adarichev V, Kashanchi F, Al-Harthi L. Human immunodeficiency virus-restricted replication in astrocytes and the ability of gamma interferon to modulate this restriction are regulated by a downstream effector of the Wnt signaling pathway. J Virol. 2007;81(11):5864–71.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Masliah E, Heaton RK, Marcotte TD, et al. Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC group. The HIV Neurobehavioral Research Center. Ann Neurol. 1997;42:963–72.PubMedGoogle Scholar
  9. 9.
    Glass JD, Fedor H, Wesselingh SL, McArthur JC. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol. 1995;38:755–62.PubMedGoogle Scholar
  10. 10.
    Anthony IC, Bell JE. The neuropathology of HIV/AIDS. Int Rev Psychiatry. 2008;20:15–24.PubMedGoogle Scholar
  11. 11.
    Kaul M. HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol. 2009;22(3):315–20.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Williams DW, Eugenin EA, Calderon TM, Berman JW. Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol. 2012;91(3):401–15.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Nakagawa S, Castro V, Toborek M. Infection of human pericytes by HIV-1 disrupts the integrity of the blood–brain barrier. J Cell Mol Med. 2012;16(12):2950–7.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Abdulle S, Hagberg L, Gisslén M. Effects of antiretroviral treatment on blood–brain barrier integrity and intrathecal immunoglobulin production in neuroasymptomatic HIV-1-infected patients. HIV Med. 2005;6(3):164–9.PubMedGoogle Scholar
  15. 15.
    Abdulle S, Hagberg L, Svennerholm B, Fuchs D, Gisslén M. Continuing intrathecal immunoactivation despite two years of effective antiretroviral therapy against HIV-1 infection. AIDS. 2002;16(16):2145–9.PubMedGoogle Scholar
  16. 16.
    Calcagno A, Alberione MC, Romito A, Imperiale D, Ghisetti V, Audagnotto S, et al. Prevalence and predictors of blood brain barrier damage in the HAART Era. J Neurovirol. Epub 2014 Jun 28. Google Scholar
  17. 17.
    Shen L, Siliciano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J Allergy Clin Immunol. 2008;122(1):22–8.PubMedGoogle Scholar
  18. 18.
    Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A. 2014;111(6):2307–12.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R. Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog. 2009;5(4):e1000395.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Zhang Y, Wei F, Liang Q, et al. High levels of divergent HIV-1 quasispecies in patients with neurological opportunistic infections in China. J Neurovirol. 2013;19(4):359–66.PubMedGoogle Scholar
  21. 21.
    Edén A, Fuchs D, Hagberg L, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. 2010;202(12):1819–25.PubMedCentralPubMedGoogle Scholar
  22. 22.
    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;50(5):773–8.PubMedGoogle Scholar
  23. 23.
    Peluso MJ, Ferretti F, Peterson J, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS. 2012;26(14):1765–74.PubMedGoogle Scholar
  24. 24.
    Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789–99.PubMedGoogle Scholar
  25. 25.
    Heaton R, Franlin D, Woods S, et al. Asymptomatic mild HIV-associated neurocognitive disorder increases risk for future symptomatic decline: a CHARTER longitudinal study [abstract]. 19th Conference on Retroviruses and Opportunistic Infections (CROI); 5–8 Mar 2012; Seattle.Google Scholar
  26. 26.
    Blackstone K, Moore DJ, Heaton RK, et al. Diagnosing symptomatic HIV-associated neurocognitive disorders: self-report versus performance-based assessment of everyday functioning. J Int Neuropsychol Soc. 2012;18(1):79–88.PubMedGoogle Scholar
  27. 27.
    Cysique LA, Brew BJ. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol. 2011;17(2):176–83.PubMedGoogle Scholar
  28. 28.
    Winston A, Arenas-Pinto A, Stöhr W, et al. Neurocognitive function in HIV infected patients on antiretroviral therapy. PLoS One. 2013;8(4):e61949.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Spudich S. HIV and neurocognitive dysfunction. Curr HIV/AIDS Rep. 2013;10(3):235–43. doi: 10.1007/s11904-013-0171-y.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Varatharajan L, Thomas SA. The transport of anti-HIV drugs across blood–CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res. 2009;82(2):A99–109.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Kumar AM, Borodowsky I, Fernandez B, Gonzalez L, Kumar M. Human immunodeficiency virus type 1 RNA Levels in different regions of human brain: quantification using real-time reverse transcriptase-polymerase chain reaction. J Neurovirol. 2007;13(3):210–24.PubMedGoogle Scholar
  32. 32.
    Fox E, Bungay PM, Bacher J, et al. Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey. J Pharmacol Exp Ther. 2002;301(3):1003–11.PubMedGoogle Scholar
  33. 33.
    Liu X, Van Natta K, Yeo H, et al. Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos. 2009;37(4):787–93.PubMedGoogle Scholar
  34. 34.
    Blaney SM, Daniel MJ, Harker AJ, Godwin K, Balis FM. Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates. Antimicrob Agents Chemother. 1995;39(12):2779–82.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Caruso A, Alvarez-Sánchez R, Hillebrecht A, et al. PK/PD assessment in CNS drug discovery: prediction of CSF concentration in rodents for P-glycoprotein substrates and application to in vivo potency estimation. Biochem Pharmacol. 2013;85(11):1684–99.PubMedGoogle Scholar
  36. 36.
    de Lange EC. Utility of CSF in translational neuroscience. J Pharmacokinet Pharmacodyn. 2013;40(3):315–26.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Eisfeld C, Reichelt D, Evers S, Husstedt I. CSF penetration by antiretroviral drugs. CNS Drugs. 2013;27(1):31–55.PubMedGoogle Scholar
  38. 38.
    Enting RH, Hoetelmans RM, Lange JM, et al. Antiretroviral drugs and the central nervous system. AIDS. 1998;12:1941–55.PubMedGoogle Scholar
  39. 39.
    Soulas C, Conerly C, Kim WK, et al. Recently infiltrating MAC387(+) monocytes/macrophages a third macrophage population involved in SIV and HIV encephalitic lesion formation. Am J Pathol. 2011;178:2121–35.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Minogue AM, Jones RS, Kelly RJ, McDonald CL, Connor TJ, Lynch MA. Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice. Neurobiol Aging. 2014;35(6):1442–52.PubMedGoogle Scholar
  41. 41.
    Vinikoor MJ, Napravnik S, Floris-Moore M, Wilson S, Huang DY, Eron JJ. Incidence and clinical features of cerebrovascular disease among HIV-infected adults in the Southeastern United States. AIDS Res Hum Retroviruses. 2013;29(7):1068–74.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Singer EJ, Valdes-Sueiras M, Commins DL, Yong W, Carlson M. HIV stroke risk: evidence and implications. Ther Adv Chronic Dis. 2013;4(2):61–70.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Croteau D, Best B, Clifford D, et al. Older age is associated with higher ARV concentrations in CSF in HIV+ individuals [abstract]. 19th Conference on Retroviruses and Opportunistic Infections (CROI); 5–8 Mar 2012; Seattle.Google Scholar
  44. 44.
    Moss DM, Siccardi M, Back DJ, Owen A. Predicting intestinal absorption of raltegravir using a population-based ADME simulation. J Antimicrob Chemother. 2013;68(7):1627–34.PubMedGoogle Scholar
  45. 45.
    Marshall DW, Brey RL, Butzin CA, et al. Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection. Arch Neurol. 1988;45:954–8.PubMedGoogle Scholar
  46. 46.
    Petito CK, Cash KS. Blood–brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol. 1992;32:658–66.PubMedGoogle Scholar
  47. 47.
    Andersson LM, Hagbwerg L, Fuchs D, Svennerholm B, Gisslen M. Increased blood brain-barrier permeability in neuroasymptomatic HIV-1-infected individuals-correlation with cerebrospinal fluid HIV-1 RNA and neopterin levels. J Neurovirol. 2001;7:542–7.PubMedGoogle Scholar
  48. 48.
    Marchi N, Betto G, Fazio V, et al. Blood–brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema. Epilepsia. 2009;50(4):664–77.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Yilmaz A, Gisslén M, Spudich S, et al. Raltegravir cerebrospinal fluid concentrations in HIV-1 infection. PLoS One. 2009;4(9):e6877.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Calcagno A, Bonora S, Simiele M, et al. Tenofovir and emtricitabine cerebrospinal fluid-to-plasma ratios correlate to the extent of blood–brain barrier damage. AIDS. 2011;25(11):1437–9.PubMedGoogle Scholar
  51. 51.
    Calcagno A, Cusato J, Simiele M, et al. High interpatient variability of raltegravir cerebrospinal fluid concentrations in HIV-positive patients: a pharmacogenetic analysis. J Antimicrob Chemother. 2014;69(1):241–5.PubMedGoogle Scholar
  52. 52.
    Marzolini C, Mueller R, Li-Blatter X, Battegay M, Seelig A. The brain entry of HIV-1 protease inhibitors is facilitated when used in combination. Mol Pharm. 2013;10(6):2340–9.PubMedGoogle Scholar
  53. 53.
    Avery LB, Zarr MA, Bakshi RP, Siliciano RF, Hendrix CW. Increasing extracellular protein concentration reduces intracellular antiretroviral drug concentration and antiviral effect. AIDS Res Hum Retroviruses. 2013;29(11):1434–42.PubMedGoogle Scholar
  54. 54.
    Yilmaz A, Ståhle L, Hagberg L, et al. Cerebrospinal fluid and plasma HIV-1 RNA levels and lopinavir concentrations following lopinavir/ritonavir regimen. Scand J Infect Dis. 2004;36(11–12):823–8.PubMedGoogle Scholar
  55. 55.
    Croteau D, Best BM, Letendre S, et al. Lower than expected maraviroc concentrations in cerebrospinal fluid exceed the wild-type CC chemokine receptor 5-tropic HIV-1 50 % inhibitory concentration. AIDS. 2012;26(7):890–3.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Croteau D, Rossi SS, Best BM, et al. Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90 % inhibitory concentration. J Antimicrob Chemother. 2013;68(3):684–9.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci. 2003;21(3–4):79–96.PubMedGoogle Scholar
  58. 58.
    Avery LB, Sacktor N, McArthur JC, Hendrix CW. Protein-free efavirenz concentrations in cerebrospinal fluid and blood plasma are equivalent: applying the law of mass action to predict protein-free drug concentration. Antimicrob Agents Chemother. 2013;57(3):1409–14.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Delille CA, Pruett ST, Marconi VC, et al. Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations. J Clin Pharmacol. 2014;54(9):1063–71. doi: 10.1002/jcph.298.
  60. 60.
    Nguyen A, Rossi S, Croteau D, et al. Etravirine in CSF is highly protein bound. J Antimicrob Chemother. 2013;68(5):1161–8.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Stępień KM, Tomaszewski M, Tomaszewska J, Czuczwar SJ. The multidrug transporter P-glycoprotein in pharmacoresistance to antiepileptic drugs. Pharmacol Rep. 2012;64(5):1011–9.PubMedGoogle Scholar
  62. 62.
    Kannan P, John C, Zoghbi SS, et al. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin Pharmacol Ther. 2009;86(4):368–77.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Bleasby K, Castle JC, Roberts CJ, et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica. 2006;36(10–11):963–88.PubMedGoogle Scholar
  64. 64.
    Hartkoorn RC, Kwan WS, Shallcross V, et al. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics. 2010;20(2):112–20.PubMedGoogle Scholar
  65. 65.
    Kaddoumi A, Choi SU, Kinman L, et al. Inhibition of P-glycoprotein activity at the primate blood–brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid. Drug Metab Dispos. 2007;35(9):1459–62.PubMedGoogle Scholar
  66. 66.
    Calcagno A, Yilmaz A, Cusato J, et al. Determinants of darunavir cerebrospinal fluid concentrations: impact of once-daily dosing and pharmacogenetics. AIDS. 2012;26(12):1529–33.PubMedGoogle Scholar
  67. 67.
    Zakeri-Milani P, Valizadeh H. Intestinal transporters: enhanced absorption through P-glycoprotein-related drug interactions. Expert Opin Drug Metab Toxicol. 2014;10(6):859-71. Google Scholar
  68. 68.
    Lepist EI, Phan TK, Roy A, et al. Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. Antimicrob Agents Chemother. 2012;56(10):5409–13.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Sánchez Martín A, Cabrera Figueroa S, Cruz Guerrero R, et al. Impact of pharmacogenetics on CNS side effects related to efavirenz. Pharmacogenomics. 2013;14(10):1167–78.PubMedGoogle Scholar
  70. 70.
    Wyen C, Hendra H, Siccardi M, et al. Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. J Antimicrob Chemother. 2011;66(9):2092–8.PubMedGoogle Scholar
  71. 71.
    Saitoh A, Sarles E, Capparelli E, et al. CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children. AIDS. 2007;21(16):2191–9.PubMedGoogle Scholar
  72. 72.
    Best BM, Letendre SL, Brigid E, et al. Low atazanavir concentrations in cerebrospinal fluid. AIDS. 2009;23(1):83–7.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Capparelli EV, Letendre SL, Ellis RJ, et al. Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid. Antimicrob Agents Chemother. 2005;49(6):2504–6.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Yilmaz A, Watson V, Else L, Gisslèn M. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS. 2009;23(18):2537–40.PubMedGoogle Scholar
  75. 75.
    Melica G, Canestri A, Peytavin G, et al. Maraviroc-containing regimen suppresses HIV replication in the cerebrospinal fluid of patients with neurological symptoms. AIDS. 2010;24(13):2130–3.PubMedGoogle Scholar
  76. 76.
    Tiraboschi JM, Niubo J, Curto J, Podzamczer D. Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients. J Acquir Immune Defic Syndr. 2010;55(5):606–9.PubMedGoogle Scholar
  77. 77.
    Burger DM, Kraaijeveld CL, Meenhorst PL, et al. Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV. AIDS. 1993;7:1581–7.PubMedGoogle Scholar
  78. 78.
    Lane HC, Falloon J, Walker RE, et al. Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. A phase II randomized, placebo-controlled trial. Ann Intern Med. 1989;111:41–50.PubMedGoogle Scholar
  79. 79.
    Elovaara I, Poutiainen E, Lahdevirta J, et al. Zidovudine reduces intrathecal immunoactivation in patients with early human immunodeficiency virus type 1 infection. Arch Neurol. 1994;51:943–50.PubMedGoogle Scholar
  80. 80.
    Balis FM, Pizzo PA, Eddy J, et al. Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. J Pediatr. 1989;114:880–4.PubMedGoogle Scholar
  81. 81.
    Hagberg L, Andersson M, Chiodi F, et al. Effect of zidovudine on cerebrospinal fluid in patients with HIV infection and acute neurological disease. Scand J Infect Dis. 1991;23:681–5.PubMedGoogle Scholar
  82. 82.
    Tozzi V, Narciso P, Galgani S, et al. Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex. AIDS. 1993;7:683–92.PubMedGoogle Scholar
  83. 83.
    Sidtis JJ, Gatsonis C, Price RW, et al. Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group. Ann Neurol. 1993;33:343–9.PubMedGoogle Scholar
  84. 84.
    McDowell JA, Chittick GE, Ravitch JR, et al. Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study. Antimicrob Agents Chemother. 1999;43:2855–61.PubMedCentralPubMedGoogle Scholar
  85. 85.
    McDowell JA, Lou Y, Symonds WS, et al. Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000;44:2061–7.PubMedCentralPubMedGoogle Scholar
  86. 86.
    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:e13.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Antinori A, Perno CF, Giancola ML, et al. Efficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma. Clin Infect Dis. 2005;41:1787–93.PubMedGoogle Scholar
  88. 88.
    Burger DM, Kraayeveld CL, Meenhorst PL, et al. Study on didanosine concentrations in cerebrospinal fluid. Implications for the treatment and prevention of AIDS dementia complex. Pharm World Sci. 1995;17:218–21.PubMedGoogle Scholar
  89. 89.
    Gisslén M, Norkrans G, Svennerholm B, et al. The effect on human immunodeficiency virus type 1 RNA levels in cerebrospinal fluid after initiation of zidovudine or didanosine. J Infect Dis. 1997;175:434–7.PubMedGoogle Scholar
  90. 90.
    Best B, Letendre S, Capparelli E, et al. Efavirenz and emtricitabine concentrations consistently exceed wild-type IC50 in cerebrospinal fluid: CHARTER findings [abstract]. 16th Conference on Retroviruses and Opportunistic Infections (CROI); 8–11 Feb 2009; Montreal.Google Scholar
  91. 91.
    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;351:1547–51.PubMedGoogle Scholar
  92. 92.
    Blaschke A, Capparelli E, Ellis R, et al. A population model-based approach for determining lamivudine (3TC) cerebrospinal fluid (CSF) penetration in HIV-infected adults [abstract]. 7th Conference on Retroviruses and Opportunistic Infections (CROI); 30 Jan–2 Feb 2000; San Francisco.Google Scholar
  93. 93.
    Haworth SJ, Christofalo B, Anderson RD, et al. A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;17:235–8.PubMedGoogle Scholar
  94. 94.
    Brady KA, Boston RC, Aldrich JL, et al. Stavudine entry into cerebrospinal fluid after single and multiple doses in patients infected with human immunodeficiency virus. Pharmacotherapy. 2005;25:10–7.PubMedGoogle Scholar
  95. 95.
    Zhang L, Price R, Aweeka F, et al. Making the most of sparse clinical data by using a predictive-model-based analysis, illustrated with a stavudine pharmacokinetic study. Eur J Pharm Sci. 2001;12:377–85.PubMedGoogle Scholar
  96. 96.
    Best BM, Letendre SL, Koopmans P, et al. Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir. J Acquir Immune Defic Syndr. 2012;59(4):376–81.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Takasawa K, Terasaki T, Suzuki H, et al. Distributed model analysis of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine distribution in brain tissue and cerebrospinal fluid. J Pharmacol Exp Ther. 1997;282:1509–17.PubMedGoogle Scholar
  98. 98.
    Anthonypillai C, Gibbs JE, Thomas SA. The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses. Cerebrospinal Fluid Res. 2006;3:1.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Tashima KT, Caliendo AM, Ahmad M, et al. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. J Infect Dis. 1999;180:862–4.PubMedGoogle Scholar
  100. 100.
    Best BM, Koopmans PP, Letendre SL, et al. Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J Antimicrob Chemother. 2010;66:354–7.PubMedCentralPubMedGoogle Scholar
  101. 101.
    van Praag RM, van Weert EC, van Heeswijk RP, et al. Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob Agents Chemother. 2002;46:896–9.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals. AIDS. 2001;15:1089–95.PubMedGoogle Scholar
  103. 103.
    Mora-Peris B, Watson V, Vera JH, et al. Rilpivirine exposure in plasma and sanctuary site compartments after switching from nevirapine-containing combined antiretroviral therapy. J Antimicrob Chemother. 2014;69(6):1642-7.Google Scholar
  104. 104.
    Kravcik S, Gallicano K, Roth V, et al. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr. 1999;21:371–5.PubMedGoogle Scholar
  105. 105.
    Sadler BM, Chittick GE, Polk RE, et al. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J Clin Pharmacol. 2001;41:386–96.PubMedGoogle Scholar
  106. 106.
    Murphy R, Currier J, Gerber J, et al. Antiviral activity and pharmacokinetics of amprenavir with or without zidovudine/3TC in the cerebrospinal fluid of HIV-infected adults [abstract]. 7th Conference on Retroviruses and Opportunistic Infections (CROI); 30 Jan–2 Feb 2000; San Francisco.Google Scholar
  107. 107.
    Saumoy M, Tiraboschi J, Gutierrez M, et al. Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy (the FONT study). HIV Med. 2011;12:438–41.PubMedGoogle Scholar
  108. 108.
    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;25:457–61.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Capparelli EV, Holland D, Okamoto C, et al. Lopinavir concentrations in cerebrospinal fluid exceed the 50 % inhibitory concentration for HIV. AIDS. 2005;19:949–52.PubMedGoogle Scholar
  110. 110.
    DiCenzo R, DiFrancesco R, Cruttenden K, et al. Lopinavir cerebrospinal fluid steady-state trough concentrations in HIV-infected adults. Ann Pharmacother. 2009;43:1972–7.PubMedGoogle Scholar
  111. 111.
    Lafeuillade A, Solas C, Halfon P, et al. Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations. HIV Clin Trials. 2002;3:27–35.PubMedGoogle Scholar
  112. 112.
    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;45:1511–7.Google Scholar
  113. 113.
    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;6:63.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Moyle GJ, Sadler M, Buss N. Plasma and cerebrospinal fluid saquinavir concentrations in patients receiving combination antiretroviral therapy. Clin Infect Dis. 1999;28:403–4.PubMedGoogle Scholar
  115. 115.
    Gisolf EH, Enting RH, Jurriaans S, et al. Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine. AIDS. 2000;14:1583–9.PubMedGoogle Scholar
  116. 116.
    Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998;101:289–94.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Yilmaz A, Price RW, Gisslén M. Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother. 2012;67(2):299–311.PubMedGoogle Scholar
  118. 118.
    Price RW, Parham R, Kroll JL, et al. Enfuvirtide cerebrospinal fluid (CSF) pharmacokinetics and potential use in defining CSF HIV-1 origin. Antivir Ther. 2008;13:369–74.PubMedCentralPubMedGoogle Scholar
  119. 119.
    van Lelyveld SF, Nijhuis M, Baatz F, et al. Therapy failure following selection of enfuvirtide-resistant HIV-1 in cerebrospinal fluid. Clin Infect Dis. 2010;50:387–90.PubMedGoogle Scholar
  120. 120.
    Zhou XJ, Havlir DV, Richman DD, et al. Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. AIDS. 2000;14(18):2869–76.PubMedGoogle Scholar
  121. 121.
    Letendre SL, Capparelli EV, Ellis RJ, McCutchan JA. Indinavir population pharmacokinetics in plasma and cerebrospinal fluid. Antimicrob Agents Chemother. 2000;44(8):2173–5.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Letendre S, Mills A, Tashima K, et al. Distribution and antiviral activity in cerebrospinal fluid (CSF) of the integrase inhibitor, dolutegravir (DTG): ING116070 week 16 results [abstract]. 20th Conference on Retroviruses and Opportunistic Infections (CROI); 3–6 Mar 2013; Atlanta.Google Scholar
  123. 123.
    Croteau D, Letendre S, Best BM, et al. Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1. Antimicrob Agents Chemother. 2010;54(12):5156–60.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Staprans S, Marlowe N, Glidden D, et al. Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS. 1999;13:1051–61.PubMedGoogle Scholar
  125. 125.
    Ellis RJ, Gamst AC, Capparelli E, et al. Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology. 2000;54:927–36.PubMedGoogle Scholar
  126. 126.
    Eggers C, Hertogs K, Sturenburg HJ, et al. Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration. AIDS. 2003;17:1897–906.PubMedGoogle Scholar
  127. 127.
    Mellgren A, Antinori A, Cinque P, et al. Cerebrospinal fluid HIV-1 infection usually responds well to antiretroviral treatment. Antivir Ther. 2005;10:701–7.PubMedGoogle Scholar
  128. 128.
    Gisslen M, Norkrans G, Svennerholm B, et al. HIV-1 RNA detectable with ultrasensitive quantitative polymerase chain reaction in plasma but not in cerebrospinal fluid during combination treatment with zidovudine, lamivudine and indinavir. AIDS. 1998;12:114–6.PubMedGoogle Scholar
  129. 129.
    Letendre S, McClernon D, Ellis R, et al. Persistent HIV in the central nervous system during treatment is associated with worse ART penetration and cognitive impairment [abstract]. 16th Conference on Retroviruses and Opportunistic Infections (CROI); 8–11 Feb 2009; Montreal.Google Scholar
  130. 130.
    Yilmaz A, Yiannoutsos CT, Fuchs D, et al. Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation. 2013;10:62.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Masters MC, Ances BM. Role of neuroimaging in HIV-associated neurocognitive disorders. Semin Neurol. 2014;34(1):89–102.PubMedGoogle Scholar
  132. 132.
    Garvey LJ, Pavese N, Politis M, et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS. 2014;28(1):67–72.PubMedGoogle Scholar
  133. 133.
    Robertson KR, Su Z, Margolis DM, et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology. 2010;74(16):1260–6.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Grund B, Wright EJ, Brew BJ, et al. Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect. J Neurovirol. 2013;19(4):383–92.PubMedCentralPubMedGoogle Scholar
  135. 135.
    Acosta EP, Limoli KL, Trinh L, et al. Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data. Antimicrob Agents Chemother. 2012;56(11):5938–45.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Calcagno A, Simiele M, Alberione MC, et al. Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-positive patients. Clin Infect Dis. 2014. In Press.Google Scholar
  137. 137.
    Ellis RJ, Moore DJ, Childers ME, et al. Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol. 2002;59(6):923–8.PubMedGoogle Scholar
  138. 138.
    Edén A, Hagberg L, Svennerholm B, et al. Longitudinal follow up of Detectable HIV 1 RNA in cerebrospinal fluid in subjects on suppressive antiretroviral therapy [abstract]. 19th Conference on Retroviruses and Opportunistc Infections (CROI); 5–8 Mar 2012; Seattle.Google Scholar
  139. 139.
    Wendel KA, McArthur JC. Acute meningoencephalitis in chronic human immunodeficiency virus (HIV) infection: putative central nervous system escape of HIV replication. Clin Infect Dis. 2003;37(8):1107–11.PubMedGoogle Scholar
  140. 140.
    Bogoch II, Davis BT, Venna N. Reversible dementia in a patient with central nervous system escape of human immunodeficiency virus. J Infect. 2011;63(3):236–9.PubMedGoogle Scholar
  141. 141.
    Bingham R, Ahmed N, Rangi P, et al. HIV encephalitis despite suppressed viraemia: a case of compartmentalized viral escape. Int J STD AIDS. 2011;22(10):608–9.PubMedGoogle Scholar
  142. 142.
    Khoury MN, Tan CS, Peaslee M, Koralnik IJ. CSF viral escape in a patient with HIV-associated neurocognitive disorder. J Neurovirol. 2013;19(4):402–5.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Cusini A, Vernazza PL, Yerly S, et al. Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid. J Acquir Immune Defic Syndr. 2013;62(1):28–35.PubMedGoogle Scholar
  144. 144.
    Perez Valero I, Letendre S, Ellis R, et al. Prevalence and risk factors for HIV CSF viral escape: results from the CHARTER and HNRP cohorts. J Int AIDS Soc. 2012;15(Suppl 4):18189.Google Scholar
  145. 145.
    Gisslén M, Norkrans G, Svennerholm B, Hagberg L. The effect on human immunodeficiency virus type 1 RNA levels in cerebrospinal fluid after initiation of zidovudine or didanosine. J Infect Dis. 1997;175(2):434–7.PubMedGoogle Scholar
  146. 146.
    Bunupuradah T, Chetchotisakd P, Jirajariyavej S, et al. Neurocognitive impairment in patients randomized to second-line lopinavir/ritonavir-based antiretroviral therapy vs. lopinavir/ritonavir monotherapy. J Neurovirol. 2012;18(6):479–87.PubMedGoogle Scholar
  147. 147.
    Santos JR, Muñoz-Moreno JA, Moltó J, et al. Virological efficacy in cerebrospinal fluid and neurocognitive status in patients with long-term monotherapy based on lopinavir/ritonavir: an exploratory study. PLoS One. 2013;8(7):e70201.PubMedCentralPubMedGoogle Scholar
  148. 148.
    Pérez-Valero I, González-Baeza A, Estébanez M, et al. Neurocognitive impairment in patients treated with protease inhibitor monotherapy or triple drug antiretroviral therapy. PLoS One. 2013;8(7):e69493.PubMedCentralPubMedGoogle Scholar
  149. 149.
    Perez-Valero I, Bayon C, Cambron I, Gonzalez A, Arribas JR. Protease inhibitor monotherapy and the CNS: peace of mind? J Antimicrob Chemother. 2011;66(9):1954–62.PubMedGoogle Scholar
  150. 150.
    Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. 2010;24:2365–74.PubMedGoogle Scholar
  151. 151.
    Vernazza P, Daneel S, Schiffer V, et al. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. AIDS. 2007;21(10):1309–15.PubMedGoogle Scholar
  152. 152.
    Du Pasquier RA, Jilek S, Kalubi M, et al. Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy. AIDS. 2013;27(2):203–10.PubMedGoogle Scholar
  153. 153.
    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;5:98.PubMedCentralPubMedGoogle Scholar
  154. 154.
    Yilmaz A, Verhofstede C, D’Avolio A, et al. Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr. 2010;55(5):590–6.PubMedGoogle Scholar
  155. 155.
    Dahl V, Lee E, Peterson J, et al. Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis. 2011;204(12):1936–45.PubMedCentralPubMedGoogle Scholar
  156. 156.
    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;65:65–70.PubMedCentralPubMedGoogle Scholar
  157. 157.
    Hammond ER, Crum RM, Treisman GJ, et al. The cerebrospinal fluid HIV risk score for assessing central nervous system activity in persons with HIV. Am J Epidemiol. 2014;180(3):297–307.PubMedGoogle Scholar
  158. 158.
    Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73(5):342–8.PubMedCentralPubMedGoogle Scholar
  159. 159.
    Tozzi V, Balestra P, Salvatori MF, et al. Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive disorders. J Acquir Immune Defic Syndr. 2009;52(1):56–63.PubMedGoogle Scholar
  160. 160.
    Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS. 2009;23(11):1359–66.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Winston A, Duncombe C, Li PC, et al. Does choice of combination antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatment-naive, HIV-1-infected individuals commencing cART? A randomized, controlled study. Clin Infect Dis. 2010;50(6):920–9.PubMedGoogle Scholar
  162. 162.
    Smurzynski M, Wu K, Letendre S, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. 2011;25(3):357–65.PubMedCentralPubMedGoogle Scholar
  163. 163.
    Arendt G, Orhan E, Nolting T. Retrospective analysis of the HAART CNS penetration effectiveness (CPE) index on neuropsychological performance of a big neuro-AIDS cohort [abstract]. 18th Conference on Retroviruses and Opportunistic Infections (CROI); 27 Feb–2 Mar 2011; Boston.Google Scholar
  164. 164.
    Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials. 2011;12(6):333–8.PubMedGoogle Scholar
  165. 165.
    Rourke SB, Carvalhal A, Zypurski A, et al. CNS penetration effectiveness of cART and neuropsychological outcomes: cross-sectional results from the OHTN Cohort Study [abstract]. 19th Conference on Retroviruses and Opportunistic Infections; 5–8 Mar 2012; Seattle.Google Scholar
  166. 166.
    Robertson K, Jiang H, Kumwenda J, et al. Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: AIDS Clinical Trials Group study a5199, the International Neurological Study. Clin Infect Dis. 2012;55(6):868–76.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Ciccarelli N, Fabbiani M, Colafigli M, et al. Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected patients with controlled plasma viraemia. Antivir Ther. 2013;18(2):153–60.PubMedGoogle Scholar
  168. 168.
    Kahouadji Y, Dumurgier J, Sellier P, et al. Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score. HIV Med. 2013;14(5):311–5.PubMedGoogle Scholar
  169. 169.
    Ellis RJ, Letendre S, Vaida F, et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin Infect Dis. 2014;58(7):1015–22.PubMedGoogle Scholar
  170. 170.
    Vassallo M, Durant J, Biscay V, et al. Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? AIDS. 2014;28(4):493–501.PubMedGoogle Scholar
  171. 171.
    Antinori A, Lorenzini P, Giancola ML, et al. Antiretroviral CNS penetration-effectiveness (CPE) 2010 ranking predicts CSF viral suppression only in patients with undetectable HIV-1 RNA in plasma [abstract]. 18th Conference on Retroviruses and Opportunistic Infections (CROI); 27 Feb–2 Mar 2011; Boston.Google Scholar
  172. 172.
    Giancola ML, Lorenzini P, Cingolani A, et al. virological response in cerebrospinal fluid to antiretroviral therapy in a large Italian cohort of HIV-infected patients with neurological disorders. AIDS Res Treat. 2012;2012:708456.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Rawson T, Muir D, Mackie NE, et al. Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting. J Infect. 2012;65(3):239–45.PubMedGoogle Scholar
  174. 174.
    Pinnetti C, Lorenzini P, Forbici F, et al. CSF viral escape in patients without neurological disorders: prevalence and associated factors [abstract]. 20th Conference on Retroviruses and Opportunistic Infections (CROI); 3–6 Mar 2014; Boston.Google Scholar
  175. 175.
    Casado JL, Marín A, Moreno A, Iglesias V, Perez-Elías MJ, Moreno S, Corral I. Central nervous system antiretroviral penetration and cognitive functioning in largely pretreated HIV-infected patients. J Neurovirol. 2014;20(1):54–61.PubMedGoogle Scholar
  176. 176.
    Fabbiani M, Grima P, Milanini B, et al. Central nervous system penetration effectiveness score better correlates with cognitive performance of HIV+ patients after accounting for drug susceptibility of plasma virus [abstract]. 19th Conference on Retroviruses and Opportunistic Infections (CROI); 5–8 Mar 2012; Seattle.Google Scholar
  177. 177.
    Antinori A, Marcotullio S, Ammassari A, et al. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2011. New Microbiol. 2012;35(2):113–59.PubMedGoogle Scholar
  178. 178.
    Cysique LA, Waters EK, Brew BJ. Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research. BMC Neurol. 2011;11:148.PubMedCentralPubMedGoogle Scholar
  179. 179.
    Aquaro S, Svicher V, Schols D, et al. Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies. J Leukoc Biol. 2006;80(5):1103–10.PubMedGoogle Scholar
  180. 180.
    Shikuma CM, Nakamoto B, Shiramizu B, et al. Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV. Antivir Ther. 2012;17(7):1233–42.PubMedCentralPubMedGoogle Scholar
  181. 181.
    Gray LR, Tachedjian G, Ellett AM, et al. The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes. PLoS One. 2013;8(4):e62196.PubMedCentralPubMedGoogle Scholar
  182. 182.
    Kallianpur KJ, Shikuma C, Kirk GR, et al. Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter. Neurology. 2013;80(19):1792–9.PubMedCentralPubMedGoogle Scholar
  183. 183.
    Valcour VG, Ananworanich J, Agsalda M, et al. HIV DNA reservoir increases risk for cognitive disorders in cART-naïve patients. PLoS One. 2013;8(7):e70164.PubMedCentralPubMedGoogle Scholar
  184. 184.
    Rusconi S, Vitiello P, Adorni F, et al. Maraviroc as intensification strategy in HIV-1 positive patients with deficient immunological response: an Italian randomized clinical trial. PLoS One. 2013;8(11):e80157.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Soulié C, Tubiana R, Simon A, et al. Presence of HIV-1 R5 viruses in cerebrospinal fluid even in patients harboring R5X4/X4 viruses in plasma. J Acquir Immune Defic Syndr. 2009;51(1):60–4.PubMedGoogle Scholar
  186. 186.
    Garvey L, Nelson M, Latch N, et al. CNS effects of a CCR5 inhibitor in HIV-infected subjects: a pharmacokinetic and cerebral metabolite study. J Antimicrob Chemother. 2012;67(1):206–12.PubMedGoogle Scholar
  187. 187.
    Vera JH, Garvey LJ, Allsop JM, et al. Alterations in cerebrospinal fluid chemokines are associated with maraviroc exposure and in vivo metabolites measurable by magnetic resonance spectroscopy. HIV Clin Trials. 2012;13(4):222–7.PubMedGoogle Scholar
  188. 188.
    Cui L, Locatelli L, Xie MY, Sommadossi JP. Effect of nucleoside analogs on neurite regeneration and mitochondrial DNA synthesis in PC-12 cells. J Pharmacol Exp Ther. 1997;280:1228–34.PubMedGoogle Scholar
  189. 189.
    Werth JL, Zhou B, Nutter LM, Thayer SA. 2′,3′-Dideoxycytidine alters calcium buffering in cultured dorsal root ganglion neurons. Mol Pharmacol. 1994;45:1119–24.PubMedGoogle Scholar
  190. 190.
    Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol. 2012;18(5):388–99.PubMedCentralPubMedGoogle Scholar
  191. 191.
    Akay C, Cooper M, Odeleye A, et al. Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol. 2014;20(1):39–53.PubMedCentralPubMedGoogle Scholar
  192. 192.
    Friis-Møller N, Thiébaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil. 2010;17(5):491–501.PubMedGoogle Scholar
  193. 193.
    Cruse B, Cysique LA, Markus R, Brew BJ. Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy. J Neurovirol. 2012;18:264–76.PubMedGoogle Scholar
  194. 194.
    Ortiz G, Koch S, Romano JG, Forteza AM, Rabinstein AA. Mechanisms of ischemic stroke in HIV-infected patients. Neurology. 2007;68:1257–61.PubMedGoogle Scholar
  195. 195.
    Soontornniyomkij V, Umlauf A, Chung SA, et al.HIV protease inhibitor exposure predicts cerebral small vessel disease. AIDS. 2014;28(9):1297-306.Google Scholar
  196. 196.
    Green DA, Masliah E, Vinters HV, et al. Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS. 2005;19(4):407–11.PubMedGoogle Scholar
  197. 197.
    Giunta B, Ehrhart J, Obregon DF, et al. Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders. Mol Brain. 2011;4(1):23.PubMedCentralPubMedGoogle Scholar
  198. 198.
    Ciccarelli N, Fabbiani M, Di Giambenedetto S, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology. 2011;76(16):1403–9.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Andrea Calcagno
    • 1
    Email author
  • Giovanni Di Perri
    • 1
  • Stefano Bonora
    • 1
  1. 1.Unit of Infectious Diseases, Department of Medical SciencesUniversity of TorinoTorinoItaly

Personalised recommendations