How much do antiretroviral drugs penetrate into the central nervous system?

The central nervous system can act as a compartment in which HIV can replicate independently from plasma, and also as a sanctuary in which, under suboptimal drug pressure, HIV antiretroviral genetic variants can occur. Continuous replication of HIV in brain can contribute to neurocognitive impairment. Therefore, reaching adequate concentrations of antiretrovirals in the central nervous system might be essential in providing neuroprotection and improving neurocognition. Antiretrovirals have a restricted entry into the brain, due to several factors: the unique structure of the blood-brain barrier, and the existence of efficient efflux mechanisms. However, there is a high variability of antiretrovirals in reaching therapeutic drug concentrations in cerebrospinal fluid, that depend on the characteristics of the antiretrovirals (molecular weight, lipophilicity, protein binding) and on their capacity to be substrate for efflux transporters. The review aims to discuss the main mechanisms that interfere with antiretroviral penetration into central nervous system, and to summarize the current data concerning the penetrability of different antiretrovirals into the cerebrospinal fluid. Abbreviations: ART = antiretroviral treatment; ARV = antiretrovirals; NRTI = nucleos(t)idic reverse-transcriptase inhibitors; NNRTI = non-nucleosidic reverse transcriptase inhibitors; INNRT = integrase inhibitors; CNS = central nervous system; BBB = blood-brain barrier; CMT = carrier-mediated transport; AET = active efflux transports; PGP = P-glycoprotein; MRP = multidrug resistance-associated proteins; SLC = solute carriers; OATP = organic anion transporting polypeptide; OAT = organic anion transporters; OCT = organic cation transporters; EFV = Efavirenz; IDV = Indinavir; ZDV = Zidovudine; d4T = Stavudine; ABC = Abacavir; ddI = Didanosine; 3TC = Lamivudine; TDF = Tenofovir; NVP = Nevirapine; PI = Protease inhibitors; APV = Amprenavir; NFV = Nelfinavir; SQV = Saquinavir; ATV = Ataznavir; TPV = Tipranavir; DRV = Darunavir; T20 = Enfuvirtide; RGV = Raltegravir

[1]  R. Tubiana,et al.  Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  D. de Jong,et al.  Therapy failure following selection of enfuvirtide-resistant HIV-1 in cerebrospinal fluid. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  L. Hagberg,et al.  Mode of coreceptor use by R5 HIV type 1 correlates with disease stage: a study of paired plasma and cerebrospinal fluid isolates. , 2009, AIDS research and human retroviruses.

[4]  G. Schifitto,et al.  Lopinavir Cerebrospinal Fluid Steady-State Trough Concentrations in HIV-Infected Adults , 2009, The Annals of pharmacotherapy.

[5]  M. Gisslén,et al.  Cold spots in hot spots: transcription start sites of active genes are spared from HIV vector integration , 2009, AIDS.

[6]  R. Price,et al.  Raltegravir Cerebrospinal Fluid Concentrations in HIV-1 Infection , 2009, PloS one.

[7]  V. Calvez,et al.  Presence of HIV-1 R5 Viruses in Cerebrospinal Fluid Even in Patients Harboring R5X4/X4 Viruses in Plasma , 2009, Journal of acquired immune deficiency syndromes.

[8]  L. Varatharajan,et al.  The transport of anti-HIV drugs across blood–CNS interfaces: Summary of current knowledge and recommendations for further research , 2009, Antiviral research.

[9]  R. Price,et al.  Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals. , 2009, AIDS research and human retroviruses.

[10]  M. Churchill,et al.  Tissue-Specific Sequence Alterations in the Human Immunodeficiency Virus Type 1 Envelope Favoring CCR5 Usage Contribute to Persistence of Dual-Tropic Virus in the Brain , 2009, Journal of Virology.

[11]  I. Grant,et al.  Low atazanavir concentrations in cerebrospinal fluid , 2009, AIDS.

[12]  N. Shaik,et al.  Interactions of pluronic block copolymers on P-gp efflux activity: experience with HIV-1 protease inhibitors. , 2008, Journal of pharmaceutical sciences.

[13]  T. Terasaki,et al.  Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) on Pharmacokinetics and Central Nervous System Penetration of Abacavir and Zidovudine in the Mouse , 2008, Drug Metabolism and Disposition.

[14]  O. Uthman,et al.  Adjunctive therapies for AIDS dementia complex. , 2008, The Cochrane database of systematic reviews.

[15]  X. Wu,et al.  Solid Lipid Nanoparticles Enhance the Delivery of the HIV Protease Inhibitor, Atazanavir, by a Human Brain Endothelial Cell Line , 2008, Pharmaceutical Research.

[16]  C. Yiannoutsos,et al.  Antiretroviral Treatment Effect on Immune Activation Reduces Cerebrospinal Fluid HIV-1 Infection , 2008, Journal of acquired immune deficiency syndromes.

[17]  D. Kuritzkes,et al.  Enfuvirtide Cerebrospinal Fluid (CSF) Pharmacokinetics and Potential use in Defining CSF HIV-1 Origin , 2008, Antiviral therapy.

[18]  B. Clotet,et al.  Expression and Functionality of Anti-Human Immunodeficiency Virus and Anticancer Drug Uptake Transporters in Immune Cells , 2008, Journal of Pharmacology and Experimental Therapeutics.

[19]  J. Nutt,et al.  Strategies to advance translational research into brain barriers , 2008, The Lancet Neurology.

[20]  B. Ances,et al.  Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders , 2008, International review of psychiatry.

[21]  R. Ellis,et al.  Lopinavir with Ritonavir Reduces the HIV RNA Level in Cerebrospinal Fluid , 2007 .

[22]  Ram Samudrala,et al.  Identification of potential HIV-1 targets of minocycline , 2007, Bioinform..

[23]  Mikko Niemi,et al.  Role of OATP transporters in the disposition of drugs. , 2007, Pharmacogenomics.

[24]  W. Haefeli,et al.  Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by Nucleoside, Nucleotide, and Non-Nucleoside Reverse Transcriptase Inhibitors , 2007, Drug Metabolism and Disposition.

[25]  J. Gibbs,et al.  The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses , 2006, Cerebrospinal Fluid Research.

[26]  G. Ippolito,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. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[27]  D. Berger.  Minocycline shown to have protection for the brain against HIV. Results of a preclinical study recently published in JAMA. , 2005, Positively aware : the monthly journal of the Test Positive Aware Network.

[28]  R. Ellis,et al.  Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV , 2005, AIDS.

[29]  R. Ellis,et al.  Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid , 2005, Antimicrobial Agents and Chemotherapy.

[30]  J. Clements,et al.  Neuroprotective and anti-human immunodeficiency virus activity of minocycline. , 2005, JAMA.

[31]  J. Ghersi-Egea,et al.  Factors affecting delivery of antiviral drugs to the brain , 2005, Reviews in medical virology.

[32]  Sheng-He Huang,et al.  Blood-brain barrier drug discovery for central nervous system infections. , 2005, Current drug targets. Infectious disorders.

[33]  D. Fuchs,et al.  Cerebrospinal fluid and plasma HIV-1 RNA levels and lopinavir concentrations following lopinavir/ritonavir regimen , 2004, Scandinavian journal of infectious diseases.

[34]  B. Brew,et al.  Independent Evolution of Human Immunodeficiency Virus (HIV) Drug Resistance Mutations in Diverse Areas of the Brain in HIV-Infected Patients, with and without Dementia, on Antiretroviral Treatment , 2004, Journal of Virology.

[35]  I. Grant,et al.  Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders , 2004, Annals of neurology.

[36]  D. Begley,et al.  ABC transporters and the blood-brain barrier. , 2004, Current pharmaceutical design.

[37]  Carla J. Reicks,et al.  The impact of HIV-associated neuropsychological impairment on everyday functioning , 2004, Journal of the International Neuropsychological Society.

[38]  S. Yao,et al.  The equilibrative nucleoside transporter family, SLC29 , 2004, Pflügers Archiv.

[39]  P. Gaillard,et al.  The role of drug transporters at the blood-brain barrier. , 2003, Annual review of pharmacology and toxicology.

[40]  S. A. Thomas,et al.  Effect of Transport Inhibitors and Additional Anti-HIV Drugs on the Movement of Lamivudine (3TC) across the Guinea Pig Brain Barriers , 2003, Journal of Pharmacology and Experimental Therapeutics.

[41]  D. Haas,et al.  Effects of Ritonavir on Indinavir Pharmacokinetics in Cerebrospinal Fluid and Plasma , 2003, Antimicrobial Agents and Chemotherapy.

[42]  C. Yoder,et al.  Suppression of cerebrospinal fluid HIV burden in antiretroviral naive patients on a potent four-drug antiretroviral regimen , 2003, AIDS.

[43]  C. Marra,et al.  Changes in CSF and plasma HIV-1 RNA and cognition after starting potent antiretroviral therapy , 2003, Neurology.

[44]  S. A. Thomas,et al.  Mechanisms by which 2′,3′‐dideoxyinosine (ddI) crosses the guinea‐pig CNS barriers; relevance to HIV therapy , 2003, Journal of neurochemistry.

[45]  H. Handoll,et al.  Interventions for replacing missing teeth: different times for loading dental implants. , 2004, The Cochrane database of systematic reviews.

[46]  H. von Giesen,et al.  Antiretroviral therapy regimens for neuro-AIDS. , 2002, Current drug targets. Infectious disorders.

[47]  John P. Moore,et al.  Increased CCR5 Affinity and Reduced CCR5/CD4 Dependence of a Neurovirulent Primary Human Immunodeficiency Virus Type 1 Isolate , 2002, Journal of Virology.

[48]  S. Jurriaans,et al.  Stable Concentrations of Zidovudine, Stavudine, Lamivudine, Abacavir, and Nevirapine in Serum and Cerebrospinal Fluid during 2 Years of Therapy , 2002, Antimicrobial Agents and Chemotherapy.

[49]  S. A. Thomas,et al.  The distribution of the anti‐HIV drug, 2′3′‐dideoxycytidine (ddC), across the blood–brain and blood–cerebrospinal fluid barriers and the influence of organic anion transport inhibitors , 2002, Journal of neurochemistry.

[50]  E. De Clercq,et al.  Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity , 2001, Journal of Virology.

[51]  S. A. Thomas,et al.  Transport characteristics of the anti-human immunodeficiency virus nucleoside analog, abacavir, into brain and cerebrospinal fluid. , 2001, The Journal of pharmacology and experimental therapeutics.

[52]  B. Brew,et al.  Varied tropism of HIV-1 isolates derived from different regions of adult brain cortex discriminate between patients with and without AIDS dementia complex (ADC): evidence for neurotropic HIV variants. , 2001, Virology.

[53]  D. Richman,et al.  Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients , 2000, AIDS.

[54]  D. Cooper,et al.  Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid , 2000, AIDS.

[55]  J. McCutchan,et al.  Indinavir Population Pharmacokinetics in Plasma and Cerebrospinal Fluid , 2000, Antimicrobial Agents and Chemotherapy.

[56]  P. Portegies,et al.  Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine , 2000, AIDS.

[57]  Hassan Mohammad Naif,et al.  Persistent CCR5 Utilization and Enhanced Macrophage Tropism by Primary Blood Human Immunodeficiency Virus Type 1 Isolates from Advanced Stages of Disease and Comparison to Tissue-Derived Isolates , 1999, Journal of Virology.

[58]  S. Morrison,et al.  An antibody-avidin fusion protein specific for the transferrin receptor serves as a delivery vehicle for effective brain targeting: initial applications in anti-HIV antisense drug delivery to the brain. , 1999, Journal of immunology.

[59]  K. Tashima,et al.  Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. , 1999, The Journal of infectious diseases.

[60]  Joseph W. Polli,et al.  Role of P-Glycoprotein on the CNS Disposition of Amprenavir (141W94), an HIV Protease Inhibitor , 1999, Pharmaceutical Research.

[61]  J. Eron,et al.  Antiretroviral-Drug Concentrations in Semen: Implications for Sexual Transmission of Human Immunodeficiency Virus Type 1 , 1999, Antimicrobial Agents and Chemotherapy.

[62]  A. Sönnerborg,et al.  Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. , 1999, AIDS.

[63]  D. Simpson,et al.  Human immunodeficiency virus-associated dementia: review of pathogenesis, prophylaxis, and treatment studies of zidovudine therapy. , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[64]  Takayuki Itoh,et al.  Microglia Express CCR5, CXCR4, and CCR3, but of These, CCR5 Is the Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates , 1999, Journal of Virology.

[65]  M. Yazdanian,et al.  In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. , 1998, Journal of pharmaceutical sciences.

[66]  D. Roden,et al.  The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. , 1998, The Journal of clinical investigation.

[67]  J. Sodroski,et al.  CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia , 1997, Nature.

[68]  J. Beijnen,et al.  Study on didanosine concentrations in cerebrospinal fluid , 1995, Pharmacy World and Science.

[69]  J. Beijnen,et al.  Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV , 1993, AIDS.

[70]  W H Oldendorf,et al.  Lipid Solubility and Drug Penetration of the Blood Brain Barrier , 1974, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[71]  H. Kusuhara,et al.  Active efflux across the blood-brain barrier: Role of the solute carrier family , 2011, NeuroRX.

[72]  I. Grant,et al.  Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. , 2008, Archives of neurology.

[73]  Inhibition of MRP 1 / ABCC 1 , MRP 2 / ABCC 2 , and MRP 3 / ABCC 3 by Nucleoside , Nucleotide , and Non-Nucleoside Reverse Transcriptase Inhibitors , 2007 .

[74]  Nitin K Saksena,et al.  Reservoirs of HIV-1 in vivo: implications for antiretroviral therapy. , 2003, AIDS reviews.

[75]  M. Avison,et al.  Interscience Conference on Antimicrobial Agents and Chemotherapy , 2001 .

[76]  S. Staprans,et al.  Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1--infected patients with and without AIDS dementia complex. , 1999, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[77]  U. de Girolami,et al.  Localization of HIV-1 co-receptors CCR5 and CXCR4 in the brain of children with AIDS. , 1998, The American journal of pathology.