Abstract
The prevalence of HIV-associated neurocognitive disorder (HAND) is increasing despite the widespread use of combination antiretroviral therapy (ART). Initial reports suggest that the use of antiretrovirals with good central nervous system (CNS) penetration leads to better neurocognitive outcomes, but this has not yet been confirmed in a large cohort study or randomised controlled trial. There is emerging evidence that high CNS concentrations of some antiretrovirals are potentially neurotoxic and may be associated with the development of HAND. Antiretroviral CNS exposure is ideally determined by determining the ratio of cerebrospinal fluid (CSF):plasma area under the curve of unbound drug, but usually only total drug concentrations are measured and the ratio of CSF:plasma drug concentration is done at a single time point, which can result in misclassifying CNS penetration ability. Efavirenz was previously thought to have poor CNS penetration, measured by the CSF:plasma ratio (0.87 %), but when unbound concentrations were measured it was found to have good CNS penetration (85 %). Indinavir and efavirenz are the only antiretroviral drugs for which CNS area under the concentration–time curves using unbound plasma and CSF concentrations has been calculated. Patient data to support the contribution of blood–brain barrier transporter polymorphisms to CNS antiretroviral concentrations are currently limited and lack power to detect true associations. Correlations between CNS antiretroviral exposure and effect is multifaceted, and to accurately predict CNS effects there is a need to develop a sophisticated intra-brain pharmacokinetic–pharmacodynamic–pharmacogenetic model that includes transporters as well as the influence of HIV.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
There are limited antiretroviral pharmacokinetic studies that adequately estimate CNS exposure calculating area under the concentration–time curve using total and unbound cerebrospinal fluid antiretroviral concentrations. |
Data on the clinical relevance and extent of the contribution of polymorphisms in genes encoding for blood–brain transporters to CNS antiretroviral exposure are limited due to the small number of studies and lack of power. |
Current understanding and categorizing of antiretroviral CNS penetration has not translated into better clinical outcomes and there is a need to develop a sophisticated intra-brain pharmacokinetic–pharmacodynamic–pharmacogenetic model that includes transporters as well as the influence of HIV. |
1 Introduction
The overall prevalence of all forms of HIV-associated neurocognitive disorders (HANDs) is increasing despite the widespread use of combination antiretroviral therapy (ART) [1]. While the incidence of severe disorders, such as HIV-dementia (HIV-D), has significantly reduced, milder forms of HAND are on the rise. This disease burden is, in large part, being driven by the longer life expectancy of treated individuals and the associated neurocognitive impairment due to cardiovascular disease and related degenerative diseases of aging [2]. HAND is associated with a range of functional impairments that can affect employment, driving and medication adherence [1, 3]. Proposed mechanisms of the development or progression of HAND in people receiving ART include persistent neurodegeneration and neurotoxicity from antiretroviral drugs [4]. In vitro data suggest that antiretroviral drugs cause neurotoxicity at therapeutic doses [5, 6]. Better central nervous system (CNS)-penetrating antiretroviral drugs were initially associated with better neurocognitive outcomes, but large cohort data suggest an associated increased risk of developing dementia [7, 8].
The association between viral replication and cerebrospinal fluid (CSF) antiretroviral concentrations has been the subject of intensive investigation. Physiochemical properties of the drug (size, lipophilicity, plasma protein binding, active transport into the CNS and metabolism in the CNS) can predict CNS drug exposure to some extent but pharmacokinetic studies are required for confirmation [9]. Pharmacokinetic studies of CNS penetration of drugs are usually done by sampling CSF, which is in close contact with brain extracellular fluid [10]. There are caveats when making inferences about CNS drug exposure using CSF drug concentrations [11, 12]. First, CSF acts as a slowly equilibrating compartment relative to plasma with reduced and delayed concentration peaks and an overall flatter profile shape of the area under the concentration–time curves (AUCs) [13]. CSF:plasma drug ratios, which are often used as a measure of CNS exposure, will therefore vary depending on the time of sampling. Estimation of CSF and plasma AUCs followed by calculating the ratio of exposure is a more robust method of estimating CNS drug penetration [11]; however, CSF AUC estimation is hampered by the difficulty in obtaining multiple CSF samples. Second, measuring total drug concentrations rather than unbound concentrations gives misleading information about CNS exposure as only unbound drug is able to act at the receptor site [14]. Efavirenz CSF penetration was thought to be limited based on total efavirenz concentrations, but efavirenz CSF penetration is excellent, with similar plasma and CSF unbound concentrations [14]. Third, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are both highly protein bound, with NNRTIs predominantly binding to α1-acid glycoprotein, while PIs bind to albumin [14, 15]. Antiretroviral entry into the CNS is therefore governed largely by multiple influx and efflux drug transporters at the blood–brain barrier and the blood–CSF barrier [16–19]. Drug exchange between blood, CSF and brain extracellular fluid does not occur freely, and drug concentration measurements made in any one of these compartments may not accurately reflect events in the other compartments [10, 20]. Fourth, genetic polymorphisms in relevant metabolizing enzymes and transporters at the different blood–brain interfaces may influence drug disposition and response [21, 22]. Last, HIV disease compromises the blood–brain barrier integrity which will influence drug exposure [23]. Healthy volunteer data may therefore not reflect drug exposure seen in HIV-infected patients.
A recent review in Clinical Pharmacokinetics discussed the pharmacokinetics and pharmacodynamics of antiretrovirals in the CNS [24]. We critically reviewed the pharmacokinetic data of antiretroviral drug exposure in the CNS with the focus on the quality of the CSF pharmacokinetic studies according to the different antiretroviral drug classes, which included a focus on total and unbound concentration analysis. We identified variables that influence CNS exposure, including the potential role of genetic polymorphisms on drug transporters and their influence on CNS antiretroviral exposure. Finally, we explored links between antiretroviral CNS pharmacokinetics and clinical outcomes.
1.1 Study Selection
We conducted a systematic search in the PubMed database from inception until 1 January 2015. Two reviewers (ED and JJ) independently identified studies that reported on the measurement of CSF antiretroviral concentrations in HIV-infected patients. Discrepancies between the two reviewers were mediated by a third reviewer (GM). We evaluated the quality of the data using the following criteria: a priori sample size calculation, CSF and plasma antiretroviral bound and unbound drug analysis, and estimation of CSF and plasma antiretroviral exposure using AUC. We evaluated pharmacodynamic or clinical outcomes if any were reported, and excluded studies that evaluated antiretroviral drug exposure in animal models.
1.2 Search Strategy
We conducted multiple searches on human antiretroviral pharmacokinetic studies in HIV-infected patients which measured drug concentrations in the CSF. For search 1 we used the following Medical Subject Heading (MeSH) terms: Search (HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv-1*[tiab] OR hiv-2*[tiab] OR hiv1[tiab] OR hiv2[tiab] OR hiv infect*[tiab] OR human immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR human immuno-deficiency virus[tiab] OR human immune-deficiency virus[tiab] OR ((human immun*[tiab]) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno-deficiency syndrome[tiab] OR acquired immune-deficiency syndrome[tiab] OR ((acquired immun*[tiab]) AND (deficiency syndrome[tiab])) OR “sexually transmitted diseases, Viral”[MeSH:NoExp]). For search 2 we used the following MeSH terms: Search (antiretroviral therapy, highly active[MeSH] OR anti-retroviral agents[MeSH] OR antiviral agents[MeSH:NoExp] OR ((anti[tiab]) AND (hiv[tiab])) OR antiretroviral*[tiab] OR ((anti[tiab]) AND (retroviral*[tiab])) OR HAART[tiab] OR ((anti[tiab]) AND (acquired immunodeficiency[tiab])) OR ((anti[tiab]) AND (acquired immuno-deficiency[tiab])) OR ((anti[tiab]) AND (acquired immune-deficiency[tiab])) OR ((anti[tiab]) AND (acquired immun*[tiab]) AND (deficiency[tiab])). For search 3 we used the following MeSH terms: Search (central nervous system[mh] OR central nervous system*[tiab] OR cerebrospinal fluid[mh] OR cerebrospinal fluid*[tiab]). For search 4 we used the following MeSH terms: Search (pharmacokinetics[mh] OR pharmacokinetics[tiab] OR transport*[tiab] OR penetra*[tiab] OR blood-brain barrier[mh] OR blood-brain barrier*[tiab]). We combined searches 1 and 2 and further refined the search by performing searches 3 and 4. The search strategy identified 505 articles that studied the CSF exposure of 18 different antiretroviral drugs. A meta-analysis was not possible due to study methodology heterogeneity. We opted to discuss each antiretroviral drug class critically, and conducted an additional search focused on human genetic polymorphisms and the association with CSF antiretroviral exposure.
2 Pharmacokinetics and Pharmacodynamics
Various pharmacodynamic markers for HIV CNS are used [25]. CSF inhibitory concentrations are frequently used in antiretroviral pharmacokinetic studies. Recently, CSF 95 % inhibitory quotients (IQ95) were proposed as an improved marker, with high CSF IQ95 being associated with better CSF viral suppression and a lower prevalence of CSF escape [26]. IQ95 is the ratio between the CSF concentration and the 95 % inhibitory concentration (IC95), and a ratio of more than 1 is considered adequate exposure. The relationship between IQ95 and the potential for neurotoxicity has not been investigated. Clinical neurocognitive endpoints and the relationship with antiretroviral pharmacokinetics has been best described by the CNS penetration-effectiveness (CPE) score hypothesis studies. The updated CPE score places antiretroviral drugs into four categories according to physiochemical drug properties, measured CSF drug concentrations, and efficacy as determined by CSF viral suppression and neurocognitive improvement [27]. Antiretrovirals with lower CPE scores are associated with higher CSF viral loads [8]. Antiretrovirals with higher CPE scores penetrate the CNS better and are thought to be more appropriate for patients with HIV-associated neurocognitive symptoms. In uncontrolled observational studies, higher CNS-penetrating antiretrovirals were associated with better CSF viral load suppression, while others also showed an association with improved neurocognitive outcomes compared with lower penetrating antiretrovirals [8, 28–30]. In a large cohort of nearly 62,000 patients followed-up for a median of 37 months, patients receiving drugs with a high CPE score were found to be at increased risk of developing dementia, with a hazard ratio of 1.74 (95 % confidence interval 1.15–2.65), compared with patients receiving ART with a lower CPE score [7]. Antiretroviral-mediated increase in the deposition of β-amyloid, as well as neurotoxicity, were cited as some of the reasons for the findings [6, 31]; however, this finding should be further studied as the association may have been confounded by the majority of patients switching from their original ART regimen, and initiation with a high CPE regimen may have been informed by patients presenting with neurocognitive symptoms. The association between higher CPE scores and better neurocognitive outcomes was not demonstrated in a recent randomised controlled trial, but the trial was underpowered and stopped early due to low accrual [32]. Current understanding and categorizing of antiretroviral CNS penetration has not translated into better clinical outcomes. In the following sections, we will review the pharmacokinetic data on which CNS penetration inferences are based on, and highlight the gaps in our knowledge.
2.1 Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
The nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have good CNS penetration, with the exception of tenofovir (see Table 1). Exposure of NRTIs in the CSF exceeds the in vitro inhibitory concentration to suppress 50 % viral replication (IC50), but no unbound data are available (see Table 2). However, CSF sampling measures extracellular drug concentrations and NRTIs require intracellular phosphorylation to be pharmacologically active, limiting efficacy conclusions from total or unbound NRTI concentrations [33]. Zidovudine penetrates the CNS well, with total intravenous CNS exposure of 75 % of that in plasma [34, 35]. Approximately 35 % of total abacavir plasma concentrations penetrate the CSF [36, 37]. Lamivudine, stavudine and tenofovir CSF AUCs have not been described (see Table 1). Only 5 % of tenofovir penetrates the CSF, most likely via active transport, therefore CSF concentrations are well below the in vitro IC50 to suppress viral replication for most patients [38].
2.2 Non-Nucleoside Reverse Transcriptase Inhibitors
Efavirenz is more than 99.5 % protein bound, with low total efavirenz cerebrospinal exposure of less than 1 % of that of plasma; however, unbound efavirenz concentrations reach equilibrium between the two compartments (see Table 3) [14, 39]. The equilibrium between unbound concentrations in CSF and plasma is in contrast to the PIs and suggests that unbound efavirenz easily penetrates the CNS and is not actively cleared from the CNS. Efavirenz is predominantly metabolized by cytochrome P450 (CYP) 2B6 into several metabolites, of which 8-hydroxy efavirenz is the main metabolite [40, 41]. Other metabolites include 7-hydroxy efavirenz and 8,14 hydroxy efavirenz [40]. Efavirenz metabolites do not seem to inhibit viral replication but may play a role in its adverse event profile, which predominantly involves the CNS [5, 14, 40, 42]. 8-hydroxy efavirenz has been hypothesized to be implicated in neurotoxicity [5]. Extensive metabolisers may generate more 8-hydroxy efavirenz and be predisposed to develop more neurotoxicity [43]. CSF 8-hydroxy efavirenz has in fact been associated with an increase in patient neurocognitive symptoms [44]; however, no association was found between 8-hydroxy efavirenz and CYP2B6 genotype or efavirenz plasma concentration in a small study of patients of mostly Asian origin [44]. The investigators postulated that 8-hydroxy efavirenz gets trapped in the CNS. Plasma 8-hydroxy efavirenz or CNS-metabolised 8-hydroxy efavirenz may undergo glucoronidation and be unable to cross the blood–brain barrier [44]. Total and unbound efavirenz exposure in the CSF is significantly higher than the IC50 required to suppress viral replication (see Table 4) [14, 39, 40, 45, 46]. Efavirenz has the highest IQ95 of the NNRTIs [26].
Limited CSF penetration data exist for nevirapine but its drug properties may allow for good CSF penetration [47–49]. Nevirapine is the least protein bound NNRTI (60 % protein binding) and has a low molecular weight of 266.6 g/mol. The effect of CSF penetration on viral suppression has not been studied.
Etravirine is extensively protein bound (96–99.9 %) in CSF and in plasma [50]. Total etravirine concentrations in the CSF are 1–4 % of total plasma etravirine concentrations, but less than 2 % of CSF total etravirine concentration is unbound [50, 51]. The unbound etravirine concentration is well below the in vitro IC50 to suppress viral replication but does not seem to affect its in vivo CSF viral activity (see Table 4) [50, 51]. Nguyen et al. [50] postulated that adequate intracellular etravirine rather than unbound extracellular etravirine is required for viral suppression.
2.3 Protease Inhibitors
The PIs have a molecular weight above 500 Da and are more than 90 % plasma protein bound, with the exception of indinavir, which is less than 60 % protein bound in plasma [13, 52]. The low protein binding of indinavir translates into higher total drug concentrations in the CSF than with other PIs. Only 6 % of indinavir in the CSF is bound to proteins [13, 52]. Unbound PI concentrations in the CSF do not reach equilibrium, even at steady-state [13, 52, 53]. The lack of equilibrium is likely explained by active removal of the PIs from the CSF by efflux pumps such as p-glycoprotein [13, 52].
Indinavir CSF exposure has been very well characterized, although it is no longer routinely used [54]. Table 5 summarizes the pharmacokinetic data of indinavir exposure at different dosing regimens. In vitro data suggest that unboosted indinavir reaches sufficient concentrations to inhibit wild-type virus in the majority of patients (see Table 6) [13, 55–57]. Ritonavir boosting to increase CSF concentrations specifically has been studied using indinavir [52]. Ritonavir increased plasma but not CSF unbound indinavir exposure [52]. Ritonavir has a minimal effect on p-glycoprotein at the blood–brain barrier level as low unbound concentrations reach the CNS in comparison to the gut and liver [52, 58]
Atazanavir, which has 86 % protein binding, is the PI that has the second highest proportion of unbound drug in the CSF [59]. Ritonavir added to atazanavir increases plasma total atazanavir concentrations by more than double, while CSF concentrations only increase slightly (see Table 5) [59]. The modelled estimate of total atazanavir penetration boosted with ritonavir in the CSF is 0.74 % of plasma concentrations [59]. CSF atazanavir failed to achieve concentrations above the in vitro IC50 in many patients (see Table 6). Unboosted atazanavir has the lowest IQ95 of the PIs [26]. Additional ritonavir increases the IQ95 of atazanavir similar to that of boosted lopinavir [26].
Nelfinavir manufacturing has been discontinued and no longer available as a treatment option. It is highly protein bound (99.7 ± 0.10 %) and reaches undetectable CSF concentrations, mostly when measured [57, 60–63]. Total nelfinavir CSF exposure in relation to plasma has not been adequately quantified despite sensitive methodology and instrumentation (see Table 5) [63, 64]. CSF nelfinavir concentrations are in the range of in vitro inhibitory concentrations of wild-type virus (see Table 6) [63, 64].
When boosted with ritonavir, lopinavir reaches therapeutic concentrations in plasma. Lopinavir is 97–99 % protein bound, with less than 0.5 % of total lopinavir concentrations reaching the CSF (see Table 5) [46, 60, 61, 65, 66]. Lopinavir total CSF concentrations exceed in vitro concentrations required to inhibit wild-type virus [46, 65, 66]. Data on lopinavir AUC exposure and CSF unbound concentrations are lacking.
Darunavir is only 6.5 % unbound in plasma and 97.2 % in CSF [53]. At the darunavir/ritonavir dose of 600/100 mg, total darunavir CSF concentrations are approximately 1 % of total plasma concentrations (see Table 5) [53, 67, 68]. Unbound darunavir CSF concentrations are significantly higher at 8.5 % of unbound plasma concentrations [53]. Darunavir has adequate CSF exposure (see Table 6) and the highest IQ95 of all the evaluated antiretrovirals [26].
The unbound plasma fraction of saquinavir is less than 1 % [69, 70]. CSF unbound concentrations are mostly unmeasurable, and when measured the unbound saquinavir CSF:plasma ratio is less than 1 % [69]. CSF concentrations are below the in vitro concentrations required to inhibit wild-type virus (see Table 6) [63, 69, 71].
2.4 Other Antiretroviral Drugs
The CSF concentrations of the fusion inhibitor enfuvirtide are not quantifiable due to negligible CSF penetration [72]. Although no unbound AUC penetration data are available, total CSF and plasma paired samples indicate that the entry inhibitor maraviroc and the integrase inhibitor raltegravir enter the CSF. Maraviroc achieves total CSF concentrations in excess of threefold the effective concentration to inhibit viral replication of 0.57 ng/ml [73]. In seven paired total CSF and plasma concentrations the median and range of plasma and CSF concentrations were 94.9 (21.4–478) and 3.63 (1.83–12.2) ng/ml, respectively, giving a median CSF/plasma ratio of 3 % (1–10) [73]. Raltegravir total CSF concentrations are approximately 6.0 % that of plasma, and exceed the concentration required to inhibit 50 % of viral replication in all patients but fail to exceed the IC95 in at least half of the patients (see Tables 7, 8) [74, 75].
3 Pharmacogenetic Data
A spectrum of transporters, classified into ATP-binding cassette (ABC) or solute-carrier (SLC) transporters, exist to facilitate or prevent the movement of molecules across the blood–CNS interface. Transport of ART out of the CNS is mediated by p-glycoprotein (also known as MDR-1 or ABCB1), the multidrug resistance-associated proteins (or MRPs, also known as ABCC) and breast cancer resistance protein (BCRP, also known as ABCG2) [17, 76, 77]. Limited data are available on the SLC superfamily at the blood–brain barrier, but they also seem to play an important role in the efflux of molecules [78]. Although CYP1B1 has been detected at the human blood–brain barrier, CYP3A4, CYP2C9 and CYP2D6 have not, and the impact of the enzymatic barrier on cerebral disposition of ART is probably negligible [18]. Genetic polymorphisms in ART blood–brain barrier transporters may therefore contribute to the difference in CNS ART exposure [19, 79]. Patient data to support the contribution of blood–brain barrier transporter polymorphisms to CNS antiretroviral concentrations are currently limited (see Table 9) and plagued by the lack of power to detect true associations [80].
4 Discussion and Conclusion
We reviewed the CNS pharmacokinetic, pharmacodynamic and pharmacogenetic data of ART. The movement of drug molecules into the CNS is complex, and extrapolation of CNS drug exposure from CSF drug concentrations oversimplifies the pharmacokinetics of CNS ART; however, CSF is the most accessible CNS matrix [10]. The majority of published ART CNS penetration studies measured CNS penetration by using single paired CSF–plasma concentration points to determine exposure. AUC accurately estimates exposure, which can only be determined by using multiple paired CSF–plasma concentrations in a patient or by combining samples from multiple patients using a population pharmacokinetic approach. Indinavir and efavirenz CNS penetration was characterized by measuring unbound plasma and CSF concentrations to calculate AUCs. The importance of measuring total and unbound drug concentrations is illustrated by efavirenz, where the CSF total concentration is a tiny fraction of plasma total concentration, while unbound concentrations in the two compartments are similar [14]. The unbound concentration of indinavir in the CSF is double that of the total concentration in the CSF [81]. Accurate inferences of ART CNS penetration without unbound AUC data in plasma and CSF compartments are limited.
Future studies should measure total and unbound antiretroviral concentrations and aim to calculate AUCs as a measure of exposure. High CPE score ART CNS exposure is a risk factor for HIV-D, suggesting that a therapeutic window does indeed exist for ART in the CNS where concentrations at the higher and lower spectrum lead to ART toxicity or viral replication, respectively [7, 27]. Laboratory evidence suggests that antiretrovirals are directly neurotoxic [5, 6]. Neurons challenged for a week with different concentrations of antiretrovirals, including therapeutic concentrations, underwent structural loss, as quantified using microtubule-associated protein-2 [6]. Neurotoxicity was most pronounced with abacavir, atazanavir, efavirenz, etravirine and nevirapine. Of particular interest is the inactive metabolite of efavirenz (8-hydroxy efavirenz), which was tenfold more toxic than efavirenz in rat neuronal cultures and has been associated with more CNS symptoms in patients [5, 44]. Future studies should quantify ART CNS therapeutic ranges not only to determine which antiretroviral drugs penetrate the CNS adequately to suppress viral replication but also which antiretroviral drugs penetrate the CNS to such an extent that they contribute to neurotoxicity. The impact of genetic polymorphisms in drug transport across membranes (including the blood–brain barrier) is well established for many drugs, including ART [21, 22, 82]. However, data on the clinical relevance and extent of the contribution of polymorphisms in genes encoding for blood–brain transporters to CNS antiretroviral exposure are limited due to the small number of studies and the lack of power. The invasiveness of lumbar punctures limits the sample size of CSF exposure studies. Correlations between CNS antiretrovira lexposure and effect is multifaceted. To accurately predict CNS effects there is a need to develop a sophisticated intra-brain pharmacokinetic–pharmacodynamic–pharmacogenetic model that includes transporters as well as the influence of HIV.
References
Heaton RK, Clifford DB, Franklin DR, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087–96.
Sacktor N, Robertson K. Evolving clinical phenotypes in HIV-associated neurocognitive disorders. Curr Opin HIV AIDS. 2014;9(6):517–20.
Andrade AS, Deutsch R, A Celano S, et al. Relationships among neurocognitive status, medication adherence measured by pharmacy refill records, and virologic suppression in HIV-infected persons. J Acquir Immune Defic Syndr. 2013;62(3):282–92.
Letendre S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top Antivir Med. 2011;19(4):137–42.
Tovar-y-Romo LB, Bumpus NN, Pomerantz D, et al. Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J Pharmacol Exp Ther. 2012;343(3):696–703.
Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol. 2012;18(5):388–99.
Caniglia EC, Cain LE, Justice A, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology. 2014;83(2):134–41.
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(1):65–70.
Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23(4):858–83.
De Lange ECM, Danhof M. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clin Pharmacokinet. 2002;41(10):691–703.
Enting RH, Hoetelmans RM, Lange JM, Burger DM, Beijnen JH, Portegies P. Antiretroviral drugs and the central nervous system. AIDS. 1998;12(15):1941–55.
Wynn HE, Brundage RC, Fletcher CV. Clinical implications of CNS penetration of antiretroviral drugs. CNS Drugs. 2002;16(9):595–609.
Haas DW, Stone J, Clough LA, et al. Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection. Clin Pharmacol Ther. 2000;68(4):367–74.
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.
Boffito M, Back DJ, Blaschke TF, et al. Protein binding in antiretroviral therapies. AIDS Res Hum Retrovir. 2003;19(9):825–35.
Ronaldson PT, Persidsky Y, Bendayan R. Regulation of ABC membrane transporters in glial cells: relevance to the pharmacotherapy of brain HIV-1 infection. Glia. 2008;56(16):1711–35.
Varatharajan L, Thomas SA. The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antivir Res. 2009;82(2):A99–109.
Eyal S, Hsiao P, Unadkat JD. Drug interactions at the blood-brain barrier: fact or fantasy? Pharmacol Ther. 2009;123(1):80–104.
Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005;6(8):591–602.
Groothuis DR, Levy RM. The entry of antiviral and antiretroviral drugs into the central nervous system. J Neurovirol. 1997;3:387–400.
Cropp CD, Yee SW, Giacomini KM. Genetic variation in drug transporters in ethnic populations. Clin Pharmacol Ther. 2008;84(3):412–6.
Rodríguez-Nóvoa S, Barreiro P, Jiménez-Nácher I, Soriano V. Overview of the pharmacogenetics of HIV therapy. Pharmacogenomics J. 2006;6(4):234–45.
Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Greenberg RN, Berger JR. Neuroimaging correlates of HIV-associated BBB compromise. J Neuroimmunol. 2004;157(1–2):140–6.
Calcagno A, Di Perri G, Bonora S. Pharmacokinetics and pharmacodynamics of antiretrovirals in the central nervous system. Clin Pharmacokinet. 2014;53:891–906.
Calcagno A, Cusato J, Simiele M, et al. High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis. J Antimicrob Chemother. 2014;69(1):241–5.
Calcagno A, Simiele M, Alberione MC, et al. Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control. Clin Infect Dis. 2014;60:311–7.
Letendre SL, Ellis RJ, Ances BM, McCutchan JA. Neurologic complications of HIV disease and their treatment. Top HIV Med. 2010;18(2):45–55.
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.
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.
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.
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.
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.
Bazzoli C, Jullien V, Le Tiec C, Rey E, Mentré F, Taburet A-M. Intracellular pharmacokinetics of antiretroviral drugs in HIV-infected patients, and their correlation with drug Action. Clin Pharmacokinet. 2010;49(1):17–45.
Rolinski B, Bogner JR, Sadri I, Wintergerst U, Goebel FD. Absorption and elimination kinetics of zidovudine in the cerebrospinal fluid in HIV-1-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;15(3):192–7.
Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317(4):185–91.
McDowell JA, Chittick GE, Ravitch JR, Polk RE, Kerkering TM, Stein DS. Pharmacokinetics of [14C]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.
McDowell JA, Lou Y, Symonds WS, Stein DS. Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000;44(8):2061–7.
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.
Yilmaz A, Watson V, Dickinson L, Back D. Efavirenz pharmacokinetics in cerebrospinal fluid and plasma over a 24-h dosing interval. Antimicrob Agents Chemother. 2012;56(9):4583–5.
Avery LB, VanAusdall JL, Hendrix CW, Bumpus NN. Compartmentalization and antiviral effect of efavirenz metabolites in blood plasma, seminal plasma, and cerebrospinal fluid. Drug Metab Dispos. 2013;41(2):422–9.
Di Iulio J, Fayet A, Arab-Alameddine M, et al. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genomics. 2009;19(4):300–9.
Kenedi CA, Goforth HW. A systematic review of the psychiatric side-effects of efavirenz. AIDS Behav. 2011;15(8):1803–18.
Decloedt EH, Maartens G. Neuronal toxicity of efavirenz: a systematic review. Expert Opin Drug Saf. 2013;12(6):841–6.
Winston A, Amin J, Clarke A, et al. Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. Clin Infect Dis. 2014. (Epub 11 Dec).
Best BM, Koopmans PP, Letendre SL, et al. Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J Antimicrob Chemother. 2011;66(2):354–7.
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.
Van Praag RME, van Weert ECM, van Heeswijk RPG, 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(3):896–9.
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.
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(12):1787–93.
Nguyen A, Rossi S, Croteau D, et al. Etravirine in CSF is highly protein bound. J Antimicrob Chemother. 2013;68(5):1161–8.
Tiraboschi JM, Niubo J, Vila A, Perez-Pujol S, Podzamczer D. Etravirine concentrations in CSF in HIV-infected patients. J Antimicrob Chemother. 2012;67(6):1446–8.
Haas DW, Johnson B, Nicotera J, et al. Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma. Antimicrob Agents Chemother. 2003;47(7):2131–7.
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.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2014 [Table 8, page 25]. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 21 Oct 2014.
Van Praag RM, Weverling GJ, Portegies P, et al. Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS. 2000;14(9):1187–94.
Letendre SL, Capparelli EV, Ellis RJ, McCutchan JA. Indinavir population pharmacokinetics in plasma and cerebrospinal fluid. The HIV Neurobehavioral Research Center Group. Antimicrob Agents Chemother. 2000;44(8):2173–5.
Polis MA, Suzman DL, Yoder CP, et al. Suppression of cerebrospinal fluid HIV burden in antiretroviral naive patients on a potent four-drug antiretroviral regimen. AIDS. 2003;17(8):1167–72.
Kalvass JC, Polli JW, Bourdet DL, et al. Why clinical modulation of efflux transport at the human blood-brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Ther. 2013;94(1):80–94.
Best BM, Letendre SL, Brigid E, et al. Low atazanavir concentrations in cerebrospinal fluid. AIDS. 2009;23(1):83–7.
Lafeuillade A, Solas C, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations. HIV Clin Trials. 2002;3(1):27–35.
Solas C, Lafeuillade A, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2003;47(1):238–43.
Aweeka F, Jayewardene A, Staprans S, et al. Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1–infected patients with and without AIDS dementia complex. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20(1):39–43.
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.
Karlström O, Ståhle L, Perrin L, Tegude H, Sönnerborg A. Efficacy of nelfinavir-based treatment in the central nervous system of HIV-1 infected patients. Scand J Infect Dis. 2006;38(5):371–4.
Capparelli EV, Holland D, Okamoto C, et al. Lopinavir concentrations in cerebrospinal fluid exceed the 50 % inhibitory concentration for HIV. AIDS. 2005;19(9):949–52.
DiCenzo R, DiFrancesco R, Cruttenden K, Donnelly J, Schifitto G. Lopinavir cerebrospinal fluid steady-state trough concentrations in HIV-infected adults. Ann Pharmacother. 2009;43(12):1972–7.
Yilmaz A, Izadkhashti A, Price RW, et al. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals. AIDS Res Hum Retrovir. 2009;25(4):457–61.
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.
Khaliq Y, Gallicano K, Venance S, Kravcik S, Cameron DW. Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 2000;68(6):637–46.
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.
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(5):371–5.
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(3):369–74.
Yilmaz A, Watson V, Else L, Gisslèn M. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS. 2009;23(18):2537–40.
Yilmaz A, Gisslén M, Spudich S, et al. Raltegravir cerebrospinal fluid concentrations in HIV-1 infection. PLoS One. 2009;4(9):e6877.
Johnson DH, Sutherland D, Acosta EP, Erdem H, Richardson D, Haas DW. Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study. PLoS One. 2013;8(12):5156–60.
Eilers M, Roy U, Mondal D. MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp Biol Med (Maywood). 2008;233(9):1149–60.
Cordon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci. 1989;86(2):695–8.
Kusuhara H, Sugiyama Y. Active efflux across the blood-brain barrier: role of the solute carrier family. NeuroRx. 2005;2(1):73–85.
Kim RB. Drug transporters in HIV therapy. Top HIV Med. 2003;11(4):136–9.
Johnson DH, Sutherland D, Acosta EP, Erdem H, Richardson D, Haas DW. Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study. PLoS One. 2013;8(12):e82672.
Haas DW, Clough LA, Johnson BW, et al. Evidence of a source of HIV type 1 within the central nervous system by ultraintensive sampling of cerebrospinal fluid and plasma. AIDS Res Hum Retrovir. 2000;16(15):1491–502.
Yasuda SU, Zhang L, Huang SM. The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther. 2008;84(3):417–23.
Capparelli EV, Letendre SL, Ellis RJ, Patel P, Holland D, Mccutchan JA. Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid. Antimicrob Agents Chemother. 2005;49(6):2504–6.
Van Leeuwen R, Katlama C, Kitchen V, et al. Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase I/II study. J Infect Dis. 1995;171(5):1166–71.
Mueller BU, Lewis LL, Yuen GJ, et al. Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 1998;42(12):3187–92.
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(9115):1547–51.
Haworth SJ, Christofalo B, Anderson RD, Dunkle LM. 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(3):235–8.
Hoetelmans RM, Kraaijeveld CL, Meenhorst PL, et al. Penetration of 3′-amino-3′-deoxythymidine, a cytotoxic metabolite of zidovudine, into the cerebrospinal fluid of HIV-1-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;15(2):131–6.
Martin C, Sönnerborg A, Svensson JO, Ståhle L. Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS. 1999;13(10):1227–32.
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.
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.
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.
Acknowledgments
Eric Decloedt, Bernd Rosenkranz, Gary Maartens and John Joska have no conflicts of interest to declare and no funding was received to prepare this manuscript. Eric Decloedt and John Joska received self-initiated research funding from the European and Developing Countries Clinical Trials Partnership (EDCTP Grant number SP.2011.41304.065) and the South African Medical Research Council.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Decloedt, E.H., Rosenkranz, B., Maartens, G. et al. Central Nervous System Penetration of Antiretroviral Drugs: Pharmacokinetic, Pharmacodynamic and Pharmacogenomic Considerations. Clin Pharmacokinet 54, 581–598 (2015). https://doi.org/10.1007/s40262-015-0257-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-015-0257-3