review article pharmacokinetic, pharmacogenetic, and other

Review ArticlePharmacokinetic Pharmacogenetic and Other FactorsInfluencing CNS Penetration of Antiretrovirals

Jacinta Nwamaka Nwogu12 Qing Ma345 Chinedum Peace Babalola12

Waheed Adeola Adedeji6 Gene D Morse345 and Babafemi Taiwo7

1Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ibadan Ibadan Nigeria2Centre for Drug Discovery Development and Production Faculty of Pharmacy University of Ibadan Ibadan Nigeria3School of Pharmacy and Pharmaceutical Sciences and New York State Center of Excellence in Bioinformatics and Life SciencesUniversity at Buffalo 701 Ellicott Street Buffalo NY 14203 USA4Pharmacy Practice (Medicine and Pediatrics) School of Pharmacy and Pharmaceutical Sciences University at Buffalo285 Kapoor Hall Buffalo NY 14214 USA5Center for Integrated Global Biomedical Sciences University at Buffalo Buffalo NY 14203 USA6Department of Clinical Pharmacology University College Hospital Ibadan Nigeria7Division of Infectious Diseases Center for Global Health Feinberg School of Medicine Northwestern University645 N Michigan Avenue Suite 900 Chicago IL USA

Correspondence should be addressed to Jacinta Nwamaka Nwogu jacintaamakagmailcom

Received 22 April 2016 Accepted 21 August 2016

Academic Editor Soraya Seedat

Copyright copy 2016 Jacinta Nwamaka Nwogu et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Neurological complications associated with the human immunodeficiency virus (HIV) are a matter of great concern Whileantiretroviral (ARV) drugs are the cornerstone of HIV treatment and typically produce neurological benefit some ARV drugs havelimited CNS penetration while others have been associated with neurotoxicity CNS penetration is a function of several factorsincluding sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters Other factors are related topharmacokinetics and pharmacogenetics of the specificARV agent ormediated by drug interactions local inflammation and bloodflow In this review we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasison those commonly used in sub-Saharan Africa We also summarize some key associations between ARV drug penetration CNSefficacy and neurotoxicity

1 Introduction

Human immunodeficiency virus (HIV) remains a leadingcause of morbidity and mortality especially in sub-SaharanAfrica where 70 of the people living with HIV globally liveHIV penetrates the central nervous system (CNS) within afew days of infection [1ndash4] establishing residence in macro-phages and microglia cells and producing CNS inflamma-tion that may lead to neuronal injury and neurologicalcomplications Combination antiretroviral therapy (ART) forHIV effectively suppresses plasma HIV viremia [5ndash7] and asa result considerably increases life expectancy [8] ART also

confers neurological benefit in most individuals by suppress-ing CNS viral replication and inflammation However upto 40 of individuals exhibit neurocognitive impairmentdespite successful suppression of plasma viremia [9] Poten-tial explanations for this include poor penetration of ARVdrugs into the CNS whichmay allow continuedHIV replica-tion and inflammation in that compartment [10] In additionsome antiretroviral drugs may be neurotoxic In this reviewarticle we provide an overview of the various factors influ-encing the CNS penetration of antiretroviral drugs Theseinclude general factors such as drug transporters the blood-brain barrier and blood-cerebrospinal fluid barrier and host

Hindawi Publishing CorporationAIDS Research and TreatmentVolume 2016 Article ID 2587094 13 pageshttpdxdoiorg10115520162587094

2 AIDS Research and Treatment

specific factors that are driven by pharmacokinetics andpharmacogenetics Other factors include physicochemicalproperties of the antiretroviral drug local cerebral bloodflowand chronic inflammation We also summarize associationsbetween antiretroviral drug penetrations CNS efficacy andneurotoxicity

2 Data Collection Methods

We conducted a comprehensive query of PubMed andGoogle Scholar Search terms used included pharmacoge-netics Africa antiretrovirals zidovudine efavirenz teno-fovir saquinavir raltegravir enfuvirtide bevirimat nevi-rapine ritonavir maraviroc zalcitabine delavirdine ampre-navir indinavir didanosine nelfinavir lopinavir stavudineatazanavir fosamprenavir abacavir tipranavir emtricitabinedarunavir lamivudine Central Nervous System blood flowpenetratlowast HIV blood brain barrier CSF CSF concentrationtransporters P-gp ABCB1 protein binding plasma con-centration and drug interaction Additional references wereobtained from the reference lists in the articles identifiedusing this search method Only articles published in Englishlanguage were reviewed

3 Commonly Used Antiretroviral Drugs inSub-Saharan Africa

The World Health Organization (WHO) recommends thatthe first-line ART should consist of a nonnucleoside reversetranscriptase inhibitor (NNRTI) and two nucleos(t)idereverse transcriptase inhibitors (NRTIs) one of which shouldbe zidovudine (ZDV) or tenofovir disoproxil fumarate(TDF) Efavirenz (EFV) is the preferred NNRTI in ARTregimens in sub-Saharan Africa [11 12] although somepatients are treated with nevirapine- (NVP-) based ART [13ndash15] Other NRTIs commonly used as first-line treatment arelamivudine (3TC) and emtricitabine (FTC) Both didanosine(ddI) and stavudine (d4T) are rarely used these days becauseof their toxicities [16 17] The WHO recommendation forsecond-line ART consists of a ritonavir-boosted proteaseinhibitor (PI) plus two or three NRTIs one of which shouldbe ZDV or TDF depending on what was used in first-linetherapy Atazanavir with ritonavir (ATVr) and lopinavirritonavir (LPVr) are the preferred PIs Saquinavir (SQV)has fallen out of favor partly because it has a high pill-burden while indinavir (IDV) has a high risk of toxicity andfosamprenavir (FPV) is relatively expensive Although theintegrase strand transfer inhibitor raltegravir is an optionfor second-line therapy when combined with a boosted PIintegrase inhibitors are typically reserved for third-line regi-mens Other components of third-line therapy include drugslikely to have anti-HIV activity such as the second-generationNNRTI etravirine and the boosted PI darunavirritonavir(DRVr) both of which are rarely available due to relativelyhigh costs [18] Dolutegravir (DTG) a newer integrase strandtransfer inhibitor is not yet available in sub-Saharan Africabut has the potential to gain attention in this region in the nextfew years due to its attractive safety efficacy and resistance

profile DTG was demonstrated to be superior in first-lineART to EFV [19 20] and DRVr [21] in large randomizedtrials

4 CNS Penetration of DifferentAntiretroviral Drugs

Penetration of antiretrovirals into the CNS is critical tooptimize suppression of the CSF HIV viral load and overallreplication in the CNS It has been suggested that the useof antiretroviral compounds with poor penetration into theCNS may be associated with an increased risk of cognitivedecline This is however controversial as shown by the pro-posed CNS Penetration-Effectiveness (CPE) ranking systemwhich categorizes antiretrovirals into three groups (lowintermediate and high CNS penetration) [10] or four groups[22] based on their chemical properties concentration in theCSF and effectiveness in reducing the CSF viral load Studiesevaluating associations between CPE score and neurocog-nitive outcomes have produced inconsistent results [23ndash25]although lower CPE ranking correlatedwith higherHIV viralloads in CSF [10] Studies on CNS penetration of commonlyused antiretrovirals and their CPE rankings are shown inTable 1 Of note the same antiretroviral drug displays vari-ations in CSF concentration (varying penetrating abilities)in different patients within the same study and in differentstudies This likely reflects the multifactorial determinants ofCNS drug penetration

5 Factors Affecting CNS Penetration ofAntiretroviral Drugs

51 General Factors

511 Blood-Brain Barrier and Blood-CSF Barrier The blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) arenormal anatomical structures that evolved to protect the CNSfrom toxic substances In HIV-infected individuals howeverthese barriers also limit penetration and potentially efficacyof some antiretrovirals in the brain The BBB is formedby brain capillary endothelial cells fused together by tightjunctions hence characterized by lack of fenestration and thepaucity of pinocytosis [26 27] On the other hand BCSFBwhich separates CSF and blood consists of the choroid plexusand the arachnoidmembraneThe choroid plexus epitheliumis involved in numerous exchange processes that increase theCSF concentrations of nutrients and hormones and decreasethe CSF concentrations of potentially deleterious compoundsand metabolites [28] These characteristics restrict the pen-etration of large or hydrophilic molecules through the BBBand BCSFB selectively permitting penetration of small andlipophilic moleculesThus antiretrovirals such as NVP ZDVEFV and FTC with physicochemical properties that supportpenetration have an advantage in penetrating the BBB bysimple diffusion Any condition which compromises the BBBandor BCSFBwill likely increase the rate of entrance of drugsinto the brain [29]

AIDS Research and Treatment 3

Table 1 Cerebrospinal fluid concentration of some antiretrovirals as a percentage of plasma concentration and their CPE ranking

Antiretroviral drug Sample sizeCSF concentration as a percentage of

plasma concentration () References Revised CPE rank [22]Median (range) Mean (SD)

Zidovudine50 60 (4ndash262) [133]

418 2 (0ndash674) [134]5 96 (8) [135]

Abacavir 54 36 [136] 33a 35 (31ndash44) [137]

Lamivudine 55 23 (0ndash490) [134] 2Stavudine 31 20 (0ndash204) [134] 2

Didanosine 4 27 (14) [135] 25 Undetected [134]

Tenofovir 38 57 (3ndash10)b [84] 1

Efavirenz

69 05 (026ndash076)b [138]

311 Undetected [134]

26 071 (037)c in600mg [139]

11 13 (08ndash16)b [140]Nevirapine 16 63 (41ndash77) [134] 4

Indinavir

19 17 (886)c [141]

32216 (04ndash228) or 6

usingAUC ratio

[142]

Lopinavirr 26 023 (012ndash075) [88] 312 085 (047) [143]

Nelfinavir6 Not detected in

CSF [144]1

9 Not detected inCSF [134]

Ritonavir 8 000 (000ndash52) [134] 1

Darunavirr 14 05d [145] 314 09 (03ndash18) [87]

Atazanavir9 112 (05ndash139) [146]

28 14 (06ndash34)b [140]13 3d [145]

Raltegravir41 17 (18ndash338)b [140]

324 3 (1ndash61) [147]35 206 (05ndash133) [148]

Dolutegravir 12 0546 (0480) [149] NA

Maraviroc7 30 (1ndash10) [150]

312 22 (04ndash17) [151]

12 101 (029) 420(122)e [143]

aSubjects with multiple plasma and CSF samples bmedian (IQR) cmean (coefficient of variation) dgeometric mean e Maraviroc CSFunbound plasmaratio and NA = not available The ranks assigned to the antiretrovirals in Table 1 are based on revised ranking system proposed by Letendre et al and notCSFplasma ratio from the authors findings in the table Higher CPE score means higher CNS penetration

512 Drug Transporters Transporters are membrane pro-teins that facilitate the movement of molecules into or out ofcells They can be categorized in different ways includingefflux and influx transporters or the adenosine triphosphate

binding cassette (ABC) and solute carrier (SLC) transportersThe CNS penetration of antiretroviral drugs that are sub-strates of drug transporters is partly dependent on the level ofexpression of the transporters Due to the substrate specificity


of these transporters drugs that possess significant similari-ties to them are transported into or out of cells Efflux andinflux transporters can play a critical role in determiningdrug concentrations in the systemic circulation and in cellsHowever the overall rate constant for efflux of drug from thebrain is approximately 75-fold higher and from CSF is 8-foldhigher than the respective rate constants for influx [30] Thisimplies that efflux of drugs out of cells occursmore frequentlywhen compared to drug influx into the cells due to ubiqui-tous expression of efflux transporters The emphasis is on theABC transporters for example permeability-glycoprotein(P-gp) and multidrug resistance-associated proteins (MRPs)because of their effect on the CNS penetration of someantiretrovirals

The brain penetration of antiretrovirals that are substratesof transport proteins is partly affected by these transportersThe efflux pumps (P-gp MRPs and breast cancer resistanceprotein (BCRP)) are present at the BBB and have been shownto extrude substrate drugs from this site Thus they limitPIs from penetrating the CNS [31ndash36] due to their affinityfor these transporters The most important efflux transporterinfluencing the brain penetration of antiretrovirals is P-gp because of its multiple binding sites for substrates andinhibitors [37 38] Apart from PIs P-gp limits brain pene-tration of the NRTIs abacavir and ZDV [32 39] and can alsoefflux some structurally unrelated hydrophobic molecules

The expression and functionality of P-gp can be mod-ulated by inhibition and induction which can affect thepharmacokinetics efficacy safety or tissue levels of P-gp sub-strates [40] For example PIs (substrates of P-gp) generallyhave poor brain penetration but their penetrability may beenhanced by coadministration with specific P-gp inhibitorsuch as ritonavir [36] Consistent with this a study innonhuman primates reported that P-gp inhibition at the BBBsignificantly enhanced the distribution of nelfinavir into thebrain [41] A previous study showed that patients withHIV encephalitis have higher brain P-gp levels comparedto patients without HIV encephalitis [42] suggesting thatpatients with HIV encephalitis may be predisposed to lowerCNS penetration of substrate drugs In addition MRP hasbeen reported to contribute to the poor brain penetrationsof PIs [43]

52 Host Specific Factors

521 Pharmacogenetics Pharmacogenetics is the disciplinethat analyses the genetic basis for the interindividual varia-tion in the body disposition of drugs [44] Pharmacogeneticshas found application in the treatment of numerous diseasesincludingHIV infection Since pharmacogenetics can predictdrug exposure hence response to therapy or risk of toxicityit is of particular importance for the drugs that have a narrowtherapeutic index andor metabolic pathways affected bypolymorphisms in the drug metabolizing enzymes

Cytochrome P450 2B6 has received much attention inHIV therapy due to its ubiquitous role in the metabolism ofantiretroviral drugs CYP2B6 is highly polymorphic [45 46]and is characterized by wide interindividual variability inexpression and activity [47] Both EFV and NVP are mainly

Table 2 Some reported frequencies of CYP2B6 polymorphism indifferent African populations

Population Frequency () Number ofsubjects Reference

African American 20 50 [48]African American 36 85 [49]African American 34 93 [152]Tanzanians 36 95 [153]Malawians and31 (15) 26 [60]Ghanaians 46 42 [152]Ghanaians 25 800 [78]Ethiopians and455 (87) 262 [45]Ivory coast 38 41 [152]Sierra Leone 36 52 [152]Senegal 60 10 [152]Guinea 48 21 [152]West Africa 42 166 [152]West Africa 50 153 [49]Yoruba (Ibadan Nigeria) 35 78 [49]South Africa and41 (23) 80 [154]Xhosa (South Africa) andand17 109 [155]CMA (South Africa) andand9 67 [155]Botswana 366 101 [156]Zimbabwe 49 71 [76]Uganda 356 121 [63]Uganda 29 7 males [13]Mozambique 7 78 [14]andGT (TT) and andandloss of function CYP2B6lowast18

metabolized by CYP2B6 with African populations havinghigher poor metabolizer frequency [48 49] hence poten-tially prone to development of adverse reactions with theseagents Indeed previous studies have reported significantassociations of some CYP2B6 variants with elevated plasmaEFV [50ndash55] which is relevant to CNS EFV levelseffectssince higher plasma concentration may result in higher CNSpenetration In linewith thisWinston and Puls in their studythough with a small sample size reported an association ofCSF EFV concentrationwithCYP2B6 genotype [56] FurtherCYP2B6 polymorphism also affects NVP plasma levels [57ndash59] NVP concentrations increased by 92 with the presenceofCYP2B6 516T allele anddecreased by 31with the presenceof 11986211988411987531198605lowast3 in Malawians [60] However another studyreported that CYP2B6 516983 genotypes had no effect onNVP concentrations [61] Table 2 shows the wide variabilityin poor metabolizer frequencies in different African pop-ulations as reported in different studies This observationsuggests that results from one African population should notbe extrapolated to other African populations since Africansare very heterogenic with respect to drug disposition andpharmacogenetics This is in line with recommended multi-national clinical trial across sub-Saharan Africa in order tovalidate the EFV dose recommendation [53]


Table 3 Some drugs that are affected by host pharmacogenetics and the resultant effect

Antiretroviral drug Enzyme involved EffectEfavirenz CYP2B6 Increase in efavirenz concentrations and increased risk of discontinuation [50ndash56]

Nevirapine CYP2B6 Increase in nevirapine plasma concentrations and increase hypersensitivity adverseeffect associated with nevirapine [57ndash60]

Atazanavir UGT1A1 Hyperbilirubinemia (indirect plasma bilirubin increase) and jaundice [157ndash160]Tenofovir ABCC2 ABCC4 Renal function decline [161ndash163]Abacavir HLA-Blowast5701 Hypersensitivity associated with abacavir [164ndash167]

In addition polymorphisms in drug transporter genescan influence penetration of substrate drugs into the CNSIllustratively polymorphism in ABCB1 was shown to influ-ence plasma concentrations of NFV [62] and of EFV [63 64]It was also reported that ABCB1 c3435CgtT contributed toNVP-induced hepatotoxicity risk [14] On the contrary CSFRAL concentrations did not differ by ABCB1 3435CgtT geno-type in healthy volunteers [65] Significant variability inABCB1 genes has been reported in black South Africans[66] Hence antiretroviral CNS penetrationmay vary in suchpopulation

The evidences to date suggest that genetic profile couldbe put into consideration prior to initiation of a givenantiretroviral agent especially those for which their primarymetabolism is by enzyme(s) with genetic polymorphismThemost relevant drug in this respect in sub-Saharan Africa isEFV However much work still needs to be done to translatethe potential of EFV pharmacogenetics into clinical practiceOther common antiretroviral drugs used in sub-SaharanAfricawhich are also affected by pharmacogenetics have beenhighlighted in Table 3

Pharmacogenetics and Efavirenz Despite the efficacy of EFVin viral suppression neuropsychiatric side effects are com-mon [57 67ndash72] and some patients on EFV-based therapydiscontinue treatment as a result of neurotoxicity and otheradverse effects [67 73 74] Some of these cases are possiblyassociated with CYP2B6 polymorphisms that predispose tohigher drug concentrations [75] Accordingly it has beensuggested that a lower dose of EFV should be given to patientswith poor metabolizer genotype compared to fast metab-olizers with functional CYP2B6 alleles [53 76] Of notepatients carrying 11986211988411987521198616lowast6lowast18 showed extremely highplasma EFV concentrations compared to those carryingeither 11986211988411987521198616lowast1lowast1 or 11986211988411987521198616lowast6lowast6 and 11986211988411987521198616lowast6lowast6patients also had higher plasma EFV concentrations thanpatients with 11986211988411987521198616lowast1lowast1 genotype [77] In another study11986211988411987521198616lowast6lowast16 was again associated with increased plasmaEFV concentration [52] These results showed that efavirenzplasma concentration may partly depend on CYP2B6 geno-type

CYP2A6 polymorphism (CYP2A6 248TgtG) has also beenreported to be associated with high EFV plasma level ina Ghanaian cohort study [78] Cytochrome P450 2A6 hasminor contribution to the metabolism of EFV [79] Howeverthis pathwaymay become increasingly important for individ-uals with poormetabolizerCYP2B6 genes DualCYP2B6 and

CYP2A6 slow metabolism may lead to extremely high EFVexposure [79]

While it has been proposed that pharmacogenetic testingto identify patients carrying poormetabolizer genotypes mayhelp optimize EFV dosing and minimize potential neurotox-icity from high EFV concentration routine pharmacogenetictesting is not currently recommended However the findingthat EFV 400mg once daily dose is virologically noninferiorand better tolerated than current 600mg dosing [80] shouldmotivate consideration of the lower dose for routine use

53 Pharmacokinetics and Drug Specific Factors

531 Drug Characteristics

(a) Molecular Weight and Lipophilicity The physicochemicalproperties of antiretroviral drugs influence their entry intothe CNS Many drugs cross cellular membranes by simplediffusion in which drug molecules diffuse freely acrossmembrane from the area where the concentration is high tothe area of lower concentration The rate of penetration of adrug into the brain by simple diffusion depends on its lipidsolubility and size [81] Antiretrovirals with very high molec-ular weight tend to have relatively poor CNS penetrationFor example enfuvirtide a fusion inhibitor with molecularmass above 4000Da penetrates poorly into the CNS [82]On the other hand abacavir andZDVwithmolecular weightsof 286332 gmol and 267242 gmol respectively are betterpositioned to penetrate the CNS

The lipophilic nature of the BBB preferentially allowspenetration of low molecular weight molecules with optimallipophilicity Oilwater partition coefficient is a useful toolin predicting the lipid solubility of neutral molecules Thehigher the partition coefficient the greater the lipophilicityand the better the brain penetration of the drug That meansdrugs with lower partition coefficient will not easily penetratethe BBB by simple diffusion However the optimal partitioncoefficient for good membrane penetration is about 100 [26]Therefore drugs with very high partition coefficients (1000)will also have lower diffusion capacity because it is difficultfor highly lipophilic drugs (lipid soluble) to diffuse from thelipid layer of the BBB into the brain extracellular fluid [26]For acidic and basic drugs the degree of ionization whichis pH dependent determines lipid solubility For exampleweakly acidic drugs will exist in more unionized form atlower pH and themore a given drug exists in unionized formthe better the membrane permeability is In contrast weakly


Table 4 Summary of the factors affecting antiretroviral drug CNS penetrations

General factors Pharmacokineticspharmacogenetics Other factors

(i) Blood-Brain barrier (BBB)(ii) Blood-CSF barrier (BCSFB)(iii) Drug transporter

(i) Drug-drug interactions(ii) Drug-herb interactions(iii) Enzyme inhibitioninduction(iv) Polymorphism in drug metabolizing enzyme(v) Drug-protein binding(vi) Molecular weight of the antiretroviral drug

(i) Local cerebral blood flow(ii) Presence of chronic inflammation

basic drugs will exist in more ionized form at lower pHTo illustrate the impact of this using Henderson-Hasselbalchequation NVP which is a weakly basic drug with pKa of 28[83] will exist largely in unionized form in plasma (pH ofabout 74) and this may be a contributing factor to good CNSpenetration of NVP

(b) Protein BindingDrugs especially lipophilic ones bind tocirculating proteins which are usually albumin acid glyco-proteins globulins and lipoproteins Different antiretroviraldrugs vary in the extent to which they bind to proteinOnly the unbound antiretroviral drugs are available to crossmembrane Nucleoside analogues like ZDV 3TC ddI d4Tand abacavir havemolecularweights less than 500Da and lowprotein binding allowing better CNS penetration Howeverhaving a low molecular weight and low protein binding isnot enough to ensure high CNS penetration For exampletenofovir has low molecular weight (287213 gmol) and lowprotein binding and was reported to have low CNS pen-etration [84] Contrary to most nucleoside analogues PIshave high molecular weights (gt500Da) and protein binding(greater than 90) with the exception of IDV [26 85 86]and are also substrates of efflux transporters Molecularweightgt 500Da and protein binding gt 90 generally impedemembrane penetration of drugs [26] the characteristics thatmay contribute to the low brain penetration of PIs Of notemany antiretrovirals exert substantial antiviral activity in theCNS even when the CSF concentration is low comparedto plasma levels provided the CSF levels exceed efficacythresholds This is the case with some boosted PIs such asDRVr [87] and LPVr [88] Similarly EFV is over 99boundto protein [89] and has sufficient concentration in the CSF forviral suppression and induction of adverse events in that com-partment Generally several factors combine to determinethe CNS penetration and effects of different antiretroviraldrugs These factors have been summarized in Table 4

532 Drug Interaction HIV infection is associated withseveral opportunistic infections [90 91] as well as other coin-fections and comorbidities As a result many HIV patientsreceiving ART also use concomitant medications for otherconditions thus predisposing to drug-drug interactionsPharmacokinetic interactions occur when the precipitantdrug (the drug causing the interaction) alters the concentra-tions of the object drug (affected drug) Many drug inter-actions occur as a result of enzyme induction or inhibitionwhichmay lead to decrease or increase in the plasma concen-tration (and presumably CNS levels) of the object drug The

interactions are sometimes more complex with some drugssimultaneously inhibiting and inducing multiple enzymaticpathways or with two drugs exhibiting bidirectional interac-tions Some drugs can also increase the brain uptake of otherdrugs from the blood through enzyme inhibition For exam-ple ketoconazole increasedCSF concentration of ritonavir by178 [92]

Tuberculosis is themost common opportunistic infectionduring HIV infection [93] Several drug-drug interactionsbetween antiretrovirals and antituberculosis agents havebeen reported with the most dramatic ones occurring withrifampin a potent CYP 450 inducer Illustratively the plasmaconcentration of NVP was reduced by 373 [94] and themedian AUC was reduced from 562 to 328microgmL perhour (minus416) when coadministered with rifampin [95]Thisis mainly because rifampin induces the enzyme CYP2B6which is responsible for the biotransformation of NVP Theinteractions between rifampin and EFV are also substantialand may necessitate an increase in EFV dose when coad-ministered while interactions between rifampin and boostedPIs are so consequential that coadministration is generallycontraindicated [96ndash103] Interactions may occur with otherantituberculosis drugs for example isoniazid is a potentinhibitor of both CYP2C19 and CYP3A4 [104] Thereforeconcomitant administration of drugs that are substrate toboth CYP2C19 and CYP3A4 like NFV may lead to clinicallyimportant drug-drug interaction

Importantly several drug interactions that may facilitateCNS penetration of antiretrovirals occur via inhibition ofthe efflux transporters that are involved in limiting brainpenetration of drugs As such CNS penetration of some anti-retrovirals may be enhanced by coadministering suitableefflux inhibitor such as ritonavir [87] an inhibitor of effluxtransporter and CYP 450 enzymes [105] Nicotine signifi-cantly increased SQV blood-to-brain transfer in rats throughinhibition of efflux transporters [106] Most clinically impor-tant drug-drug interactions can be explained in part bymodulation of important transportersrsquo activity

Use of traditional medicine is a common practice espe-cially in Africa where patients often simultaneously seektreatment from both conventional and traditional healthprovidersTheWHO estimated that up to 80 of the Africanpopulation uses traditional medicine [107] Some medicinalplants have been identified as having antiretroviral properties[91 108 109] While the antiretroviral efficacy of such herbalproducts has not been demonstrated in well conducted ran-domized clinical trials patients may resort to their use due to


limited access to recommended antiretroviral drugs intoler-ance to the conventionalmedicine or cultural factors Henceherbal use is common among people onART [110 111] Unfor-tunately many HIV patients do not disclose this to theirantiretroviral prescribers

Many traditional medicines have complex metabolicpathways including CYP 450 enzymes [112] and may perpe-trate clinically important drug interactions For example anin vitro study identified the potential for clinically significantdrug interactions for both H hemerocallidea and Suther-landia (two African plants used for the treatment of HIV)through inhibition of CYP3A4 and P-glycoprotein expression[113] When these plants are taken together with antiretro-virals this may lead to increased plasma concentration andCNS penetration of the substrate antiretroviral drugs Thismay particularly enhance CNS penetration of PIs becausethey are substrates of both CYP3A4 and P-gp There is apaucity of data on the metabolism of medicinal plants ingeneral However clinical studies and case reports involvingmany antiretroviral-herb pharmacokinetic interactions havebeen reviewed [114]

54 Other Factors

541 Chronic Inflammation Thepresence of chronic inflam-mation in HIV patients may compromise the BBB and affectthe pattern of antiretroviral penetration into the CNS Inone study 246 of patients treated with ART and 386 ofuntreated patients were found to have BBB alteration [115]The percentage difference between treated and untreatedindividuals was not significant suggesting that BBB impair-ment persists in someHIVpatients even duringART Consis-tent with this other studies found persistent BBB impairmentin some patients despite CSF viral load reduction after anti-retroviral therapy [116 117]

Alteration in the cells (eg pericytes astrocytes andendothelial cells) that provide support to the BBB can alsoaffect CNS penetration of antiretrovirals and this is commoninHIV infection Brain pericytes for example are positionedwithin the neurovascular unit to support BBB maintenance[118] Brain pericyte coverage was found to be diminished inHIV-infected patients and this was associated with pericytedysfunction in chronic neuroinflammation These changeswere accompanied by shrinking of tight junction proteinand presence of phosphorylated occludin indicative of BBBcompromise [119] Using a set of adult viable pericyte defi-cient mouse mutants it was shown that pericyte deficiencyincreases the permeability of the BBB to water and a range oflow molecular mass and high-molecular-mass tracers [120]These data suggest enhanced CNS penetration of antiretrovi-rals in HIV positive individuals with persistent CNS inflam-mation compared to HIV negative individuals On the con-trary in vitro experiments showed that chronic inflammationcan upregulate P-gp expression and activity and so tightenthe BBB to CNS-acting drugs that are P-gp substrates [121]Therefore the presence of chronic inflammation with sub-sequent disruption of BBB and the supporting cells in thebrain may be an important determinant of CNS penetrationof antiretroviral drugs

542 Local Cerebral Blood Flow The brain receives 15ndash20of the cardiac output making it one of the most perfusedorgans in the body [122] Factors that regulate the cerebralblood flow (CBF) include the net pressure gradient acrossthe cerebral vascular beds (the most important of which isthe mean arterial blood pressure) and the cerebral vascularresistance These together with the autoregulation processallow the brain to control the cerebral blood perfusion [123]The antiretroviral drug distribution to the brain follows thepattern of other drugsrsquo distribution to the brain [124] suchthat the initial rapid phase in drug distribution reflects thecardiac output and regional blood flow and the brain beingone of the highly perfused organs in the body receives mostof the drug few minutes after absorption Subsequent phasesof drug distribution are affected by several variables suchas the local cerebral perfusion lipid solubility of the drugintegrity of tight junctions in the brain arrangement of theperivascular glial cells drug binding to plasma protein andthe diffusion gradient [124]

A reduction in resting cerebral blood flow has beendemonstrated in HIV patients and linked to development ofHAND [125] Additionally anaemia is a common haemato-logical disorder among patients with HIVAIDS [126ndash128]and when severe it may compromise cerebral perfusion Pre-mature atherosclerosis among patients with HIVAIDS mayalso adversely affect cerebral perfusion and CNS penetrationof antiretroviral drugs [129ndash132] On the other hand inflam-mation of the brain and the meninges that may complicateHIV infection increases the cerebral blood flow and poten-tially drug access to the CNS

6 Conclusion

Antiretroviral drug concentrations in the CNS reflect inter-play of several factors that promote drug entry and others thatlimit entry The balance achieved varies between individualsand for each drug Since manifestations of HAND remainapparent in many patients despite suppression of plasmaviremia optimizing CNS permeability of antiretroviralsshould be an integral part of antiretroviral drug developmentThe ideal agents would have optimal CNS efficacy whilebeing free of neurotoxicity Research is needed to furtherunderstand the effect of antiretroviral CNS penetration onHAND and to discover appropriate interventions

Disclosure

Thecontent is solely the responsibility of the authors and doesnot necessarily represent the official views of the NationalInstitutes of Health

Competing Interests

The authors declare that there is no conflict of interestsregarding publication of this paper


Acknowledgments

Research training for this publication was supported bythe Fogarty International Center and National Instituteof Mental Health of the National Institutes of Healthunder Award no D43TW009608 It was also supportedby the National Institutes of Health under the followingaward numbers Dr Gene D Morse was supported by1UL1TR001412 and D43TW010313 Dr Qing Ma was sup-ported by K08MH098794

References

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[2] G Schnell R W Price R Swanstrom and S Spudich ldquoCom-partmentalization and clonal amplification of HIV-1 variantsin the cerebrospinal fluid during primary infectionrdquo Journal ofVirology vol 84 no 5 pp 2395ndash2407 2010

[3] G Tambussi A Gori B Capiluppi et al ldquoNeurological symp-toms during primary Human Immunodeficiency Virus (HIV)infection correlate with high levels of HIV RNA in cere-brospinal fluidrdquo Clinical Infectious Diseases vol 30 no 6 pp962ndash965 2000

[4] L E Davis B L Hjelle V E Miller et al ldquoEarly viralbrain invasion in iatrogenic human immunodeficiency virusinfectionrdquo Neurology vol 42 no 9 pp 1736ndash1739 1992

[5] A DrsquoArminioMonforte P Cinque AMocroft et al ldquoChangingincidence of central nervous system diseases in the EuroSIDAcohortrdquo Annals of Neurology vol 55 no 3 pp 320ndash328 2004

[6] A Mocroft C Katlama A M Johnson et al ldquoAIDS acrossEurope 1994ndash98 the EuroSIDA studyrdquoThe Lancet vol 356 no9226 pp 291ndash296 2000

[7] M Egger B Hirschel P Francioli et al ldquoImpact of newantiretroviral combination therapies inHIV infected patients inSwitzerland prospective multicentre studyrdquoTheBritishMedicalJournal vol 315 no 7117 pp 1194ndash1199 1997

[8] A Mocroft B Ledergerber C Katlama et al ldquoDecline in theAIDS and death rates in the EuroSIDA study an observationalstudyrdquoThe Lancet vol 362 no 9377 pp 22ndash29 2003

[9] L Nabha L Duong and J Timpone ldquoHIV-associated neu-rocognitive disorders perspective on management strategiesrdquoDrugs vol 73 no 9 pp 893ndash905 2013

[10] S Letendre J Marquie-Beck E Capparelli et al ldquoValidationof the CNS penetration-effectiveness rank for quantifyingantiretroviral penetration into the central nervous systemrdquoArchives of Neurology vol 65 no 1 pp 65ndash70 2008

[11] World Health Organization ldquoConsolidated guidelines on gen-eral HIV care and the use of antiretroviral drugs for treatingand preventing HIV infection recommendations for a pub-lic health approachrdquo 2013 httpappswhointirisbitstream106658532119789241505727 engpdf

[12] G Meintjes J Black F Conradie et al ldquoAdult antiretroviraltherapy guidelines 2014rdquo Southern African Journal of HIVMedicine vol 15 no 4 pp 121ndash143 2014

[13] S R Penzak G Kabuye P Mugyenyi et al ldquoCytochrome P4502B6 (CYP2B6) G516T influences nevirapine plasma concentra-tions in HIV-infected patients in Ugandardquo HIV Medicine vol8 no 2 pp 86ndash91 2007

[14] C Ciccacci P Borgiani S Ceffa et al ldquoNevirapine-inducedhepatotoxicity and pharmacogenetics a retrospective study in apopulation from Mozambiquerdquo Pharmacogenomics vol 11 no1 pp 23ndash31 2010

[15] D F Carr M Chaponda E M Cornejo Castro et al ldquoCYP2B6c983TgtC polymorphism is associated with nevirapine hyper-sensitivity in Malawian and Ugandan HIV populationsrdquo TheJournal of Antimicrobial Chemotherapy vol 69 no 12 pp 3329ndash3334 2014

[16] V Phan S Thai K Choun L Lynen and J van GriensvenldquoIncidence of treatment-limiting toxicity with stavudine-basedantiretroviral therapy in Cambodia a retrospective cohortstudyrdquo PLoS ONE vol 7 no 1 Article ID e30647 2012

[17] R Subbaraman S K Chaguturu K H Mayer T P Flaniganand N Kumarasamy ldquoAdverse effects of highly active antiretro-viral therapy in developing countriesrdquo Clinical Infectious Dis-eases vol 45 no 8 pp 1093ndash1101 2007

[18] B Simmons A Hill N Ford K Ruxrungtham and J Anan-woranich ldquoPrices of second-line antiretroviral treatment formiddle-income countries inside versus outside sub-SaharanAfricardquo Journal of the International AIDS Society vol 17 no 4supplement 3 Article ID 19604 2014

[19] S Walmsley A Baumgarten J Berenguer et al ldquoBrief reportdolutegravir plus abacavirlamivudine for the treatment ofHIV-1 infection in antiretroviral therapy-naive patients week96 and week 144 results from the single randomized clinicaltrialrdquo Journal of Acquired ImmuneDeficiency Syndromes vol 70no 5 pp 515ndash519 2015

[20] S L Walmsley A Antela N Clumeck et al ldquoDolutegravir plusAbacavir-Lamivudine for the treatment of HIV-1 infectionrdquoTheNew England Journal of Medicine vol 369 no 19 pp 1807ndash18182013

[21] B Clotet J Feinberg J Van Lunzen et al ldquoOnce-daily dolute-gravir versus darunavir plus ritonavir in antiretroviral-naiveadults with HIV-1 infection (FLAMINGO) 48 week resultsfrom the randomised open-label phase 3b studyrdquo The Lancetvol 383 no 9936 pp 2222ndash2231 2014

[22] S L Letendre R J Ellis B M Ances and J A McCutchanldquoNeurologic complications of HIV disease and their treatmentrdquoTopics in HIV Medicine vol 18 no 2 pp 45ndash55 2010

[23] K Robertson H Jiang J Kumwenda et al ldquoImproved neu-ropsychological and neurological functioning across three anti-retroviral regimens in diverse resource-limited settings aidsclinical trials group study A5199 the international neurologicalstudyrdquo Clinical Infectious Diseases vol 55 no 6 pp 868ndash8762012

[24] C M Marra Y Zhao D B Clifford et al ldquoImpact of combina-tion antiretroviral therapy on cerebrospinal fluid HIV RNA andneurocognitive performancerdquo AIDS vol 23 no 11 pp 1359ndash1366 2009

[25] N Ciccarelli M Fabbiani M Colafigli et al ldquoRevised centralnervous system neuropenetration-effectiveness score is asso-ciated with cognitive disorders in HIV-infected patients withcontrolled plasma viraemiardquoAntiviralTherapy vol 18 no 2 pp153ndash160 2013

[26] RH Enting RMWHoetelmans JMA LangeDM BurgerJ H Beijnen and P Portegies ldquoAntiretroviral drugs and thecentral nervous systemrdquo AIDS vol 12 no 15 pp 1941ndash19551998

[27] P Ballabh A Braun and M Nedergaard ldquoThe blood-brainbarrier an overview structure regulation and clinical impli-cationsrdquo Neurobiology of Disease vol 16 no 1 pp 1ndash13 2004


[28] E C M de Lange ldquoPotential role of ABC transporters as adetoxification system at the blood-CSF barrierrdquoAdvanced DrugDelivery Reviews vol 56 no 12 pp 1793ndash1809 2004

[29] WM Scheld RGDaceyH RWinn J EWelsh J A Jane andM A Sande ldquoCerebrospinal fluid outflow resistance in rabbitswith experimental meningitis Alterations with penicillin andmethylprednisolonerdquo The Journal of Clinical Investigation vol66 no 2 pp 243ndash253 1980

[30] R E Galinsky B L Hoesterey and B D Anderson ldquoBrain andcerebrospinal fluid uptake of zidovudine (AZT) in rats afterintravenous injectionrdquo Life Sciences vol 47 no 9 pp 781ndash7881990

[31] L Bousquet C Roucairol A Hembury et al ldquoComparison ofABC transporter modulation by atazanavir in lymphocytes andhuman brain endothelial cells ABC transporters are involvedin the atazanavir-limited passage across an in vitro humanmodel of the blood-brain barrierrdquo AIDS Research and HumanRetroviruses vol 24 no 9 pp 1147ndash1154 2008

[32] M Eilers U Roy and D Mondal ldquoMRP (ABCC) transporters-mediated efflux of anti-HIV drugs saquinavir and zidovu-dine from human endothelial cellsrdquo Experimental Biology andMedicine vol 233 no 9 pp 1149ndash1160 2008

[33] O Janneh R CHartkoorn E Jones et al ldquoCulturedCD4T cellsand primary human lymphocytes express hOATPs intracellularaccumulation of saquinavir and lopinavirrdquo British Journal ofPharmacology vol 155 no 6 pp 875ndash883 2008

[34] C J Bachmeier T J Spitzenberger W F Elmquist and D WMiller ldquoQuantitative assessment of HIV-1 protease inhibitorinteractions with drug efflux transporters in the blood-brainbarrierrdquo Pharmaceutical Research vol 22 no 8 pp 1259ndash12682005

[35] S Park and P J Sinko ldquoP-glycoprotein and mutlidrug resis-tance-associated proteins limit the brain uptake of saquinavirin micerdquoThe Journal of Pharmacology and Experimental Thera-peutics vol 312 no 3 pp 1249ndash1256 2005

[36] J W Polli J L Jarrett S D Studenberg et al ldquoRole of P-glycoprotein on the CNS disposition of amprenavir (141W94)anHIV protease inhibitorrdquo Pharmaceutical Research vol 16 no8 pp 1206ndash1212 1999

[37] I Carrier M Julien and P Gros ldquoAnalysis of catalytic car-boxylate mutants E552Q and E1197Q suggests asymmetricATP hydrolysis by the two nucleotide-binding domains of P-glycoproteinrdquo Biochemistry vol 42 no 44 pp 12875ndash128852003

[38] Y Zhou M M Gottesman and I Pastan ldquoStudies of humanMDR1-MDR2 chimeras demonstrate the functional exchange-ability of a major transmembrane segment of the multidrugtransporter and phosphatidylcholine flippaserdquo Molecular andCellular Biology vol 19 no 2 pp 1450ndash1459 1999

[39] NGiri N Shaik G Pan et al ldquoInvestigation of the role of breastcancer resistance protein (BcrpAbcg2) on pharmacokineticsand central nervous system penetration of abacavir and zidovu-dine in the mouserdquo Drug Metabolism and Disposition vol 36no 8 pp 1476ndash1484 2008

[40] S-F Zhou ldquoStructure function and regulation of P-glyco-protein and its clinical relevance in drug dispositionrdquo Xenobi-otica vol 38 no 7-8 pp 802ndash832 2008

[41] A Kaddoumi S-U Choi L Kinman et al ldquoInhibition ofP-glycoprotein activity at the primate blood-brain barrierincreases the distribution of nelfinavir into the brain but notinto the cerebrospinal fluidrdquo Drug Metabolism and Dispositionvol 35 no 9 pp 1459ndash1462 2007

[42] D Langford A Grigorian R Hurford et al ldquoAltered P-glyco-protein expression in AIDS patients with HIV encephalitisrdquoJournal of Neuropathology and Experimental Neurology vol 63no 10 pp 1038ndash1047 2004

[43] O Janneh A Owen B Chandler et al ldquoModulation of theintracellular accumulation of saquinavir in peripheral bloodmononuclear cells by inhibitors of MRP1 MRP2 P-gp andBCRPrdquo AIDS vol 19 no 18 pp 2097ndash2102 2005

[44] E A Barco and S R Novoa ldquoThe pharmacogenetics of HIVtreatment a practical clinical approachrdquo Journal of Pharmacoge-nomics amp Pharmacoproteomics vol 4 no 1 article 116 2013

[45] E Ngaimisi A Habtewold O Minzi et al ldquoImportance ofethnicity CYP2B6 and ABCB1 genotype for efavirenz pharma-cokinetics and treatment outcomes a parallel-group prospec-tive cohort study in two sub-Saharan Africa populationsrdquo PLoSONE vol 8 no 7 Article ID e67946 2013

[46] M Dhoro S Zvada B Ngara et al ldquoCYP2B6lowast6 CYP2B6lowast18Body weight and sex are predictors of efavirenz pharmacoki-netics and treatment response population pharmacokineticmodeling in an HIVAIDS and TB cohort in Zimbabwerdquo BMCPharmacology and Toxicology vol 16 no 1 article 4 2015

[47] E L Code C L Crespi B W Penman F J Gonzalez T KH Chang and D J Waxman ldquoHuman cytochrome P4502B6interindividual hepatic expression substrate specificity androle in procarcinogen activationrdquo Drug Metabolism and Dispo-sition vol 25 no 8 pp 985ndash993 1997

[48] DWHaasH J Ribaudo R B Kim et al ldquoPharmacogenetics ofefavirenz and central nervous system side effects anAdultAIDSClinical Trials Group studyrdquoAIDS vol 18 no 18 pp 2391ndash24002004

[49] J Li V Menard R L Benish et al ldquoWorldwide variation inhuman drug-metabolism enzyme genes CYP2B6 and UGT2B7implications for HIVAIDS treatmentrdquo Pharmacogenomics vol13 no 5 pp 555ndash570 2012

[50] M Rotger H Tegude S Colombo et al ldquoPredictive value ofknown and novel alleles of CYP2B6 for efavirenz plasma con-centrations inHIV-infected individualsrdquoClinical PharmacologyandTherapeutics vol 81 no 4 pp 557ndash566 2007

[51] M Swart M Skelton Y Ren P Smith S Takuva and CDandara ldquoHigh predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIVAIDSpatientsrdquo Pharmacogenetics and Genomics vol 23 no 8 pp415ndash427 2013

[52] J Wang A Sonnerborg A Rane et al ldquoIdentification of anovel specific CYP2B6 allele in Africans causing impairedmetabolism of the HIV drug efavirenzrdquo Pharmacogenetics andGenomics vol 16 no 3 pp 191ndash198 2006

[53] J K Mukonzo J S Owen J Ogwal-Okeng et al ldquoPharmaco-genetic-based efavirenz dose modification suggestions for anAfrican population and the different CYP2B6 genotypesrdquo PLoSONE vol 9 no 1 Article ID e86919 2014

[54] P Z Sinxadi P D Leger H M McIlleron et al ldquoPhar-macogenetics of plasma efavirenz exposure in HIV-infectedadults and children in South Africardquo British Journal of ClinicalPharmacology vol 80 no 1 pp 146ndash156 2015

[55] M Swart J Evans M Skelton et al ldquoAn expanded analysisof pharmacogenetics determinants of efavirenz response thatincludes 31015840-UTR single nucleotide polymorphisms among blackSouth African HIVAIDS patientsrdquo Frontiers in Genetics vol 6p 356 2015

[56] A Winston and R Puls ldquoCerebrospinal-fluid exposure ofefa-virenz and its major metabolites when dosed at 400 and


600mg once daily a randomized controlled trialrdquo Journal of theInternational AIDS Society vol 17 no 4 supplement 3 ArticleID 19541 2014

[57] M Rotger S Colombo H Furrer et al ldquoInfluence of CYP2B6polymorphism on plasma and intracellular concentrations andtoxicity of efavirenz and nevirapine in HIV-infected patientsrdquoPharmacogenetics and Genomics vol 15 no 1 pp 1ndash5 2005

[58] T W Mahungu C J Smith F Turner et al ldquoCytochromeP450 2B6 516GrarrT is associated with plasma concentrations ofnevirapine at both 200mg twice daily and 400mg once daily inan ethnically diverse populationrdquo HIV Medicine vol 10 no 5pp 310ndash317 2009

[59] L Dickinson M Chaponda D F Carr et al ldquoPopulationpharmacokinetic and pharmacogenetic analysis of nevirapinein hypersensitive and tolerant HIV-infected patients fromMalawirdquo Antimicrobial Agents and Chemotherapy vol 58 no2 pp 706ndash712 2014

[60] K C Brown M C Hosseinipour J M Hoskins et alldquoExploration of CYP450 and drug transporter genotypes andcorrelations with nevirapine exposure in Malawiansrdquo Pharma-cogenomics vol 13 no 1 pp 113ndash121 2012

[61] D W Haas T Gebretsadik G Mayo et al ldquoAssociationsbetween CYP2B6 polymorphisms and pharmacokinetics aftera single dose of nevirapine or efavirenz in African AmericansrdquoThe Journal of Infectious Diseases vol 199 no 6 pp 872ndash8802009

[62] J Fellay C Marzolini E R Meaden et al ldquoResponse to anti-retroviral treatment in HIV-1-infected individuals with allelicvariants of the multidrug resistance transporter 1 a pharmaco-genetics studyrdquoThe Lancet vol 359 no 9300 pp 30ndash36 2002

[63] J K Mukonzo D Roshammar P Waako et al ldquoA novel poly-morphism in ABCB1 gene CYP2B6lowast6 and sex predict single-dose efavirenz population pharmacokinetics in UgandansrdquoBritish Journal of Clinical Pharmacology vol 68 no 5 pp 690ndash699 2009

[64] M Swart Y Ren P Smith and C Dandara ldquoABCB1 4036AgtGand 1236CgtT polymorphisms affect plasma efavirenz levels inSouth African HIVAIDS patientsrdquo Frontiers in Genetics vol 3article 236 2012

[65] D H Johnson D Sutherland E P Acosta H Erdem DRichardson andDWHaas ldquoGenetic andnon-genetic determi-nants of raltegravir penetration into cerebrospinal fluid a singlearmpharmacokinetic studyrdquoPLoSONE vol 8 no 12 Article IDe82672 2013

[66] C Dandara Z Lombard I Du Plooy T McLellan S A NorrisandM Ramsay ldquoGenetic variants in CYP (minus11198602 minus21198629 minus211986219minus31198604 and minus31198605) VKORC1 and ABCB1 genes in a black SouthAfrican population a window into diversityrdquo Pharmacoge-nomics vol 12 no 12 pp 1663ndash1670 2011

[67] I O Abah M Akanbi M E Abah et al ldquoIncidence andpredictors of adverse drug events in an African cohort of HIV-infected adults treated with efavirenzrdquo Germs vol 5 no 3 pp83ndash91 2015

[68] Q Ma F Vaida J Wong et al ldquoLong-term efavirenz useis associated with worse neurocognitive functioning in HIV-infected patientsrdquo Journal of Neurovirology vol 22 no 2 pp170ndash178 2016

[69] J K Mukonzo A Okwera N Nakasujja et al ldquoInfluenceof efavirenz pharmacokinetics and pharmacogenetics on neu-ropsychological disorders in Ugandan HIV-positive patientswith or without tuberculosis a prospective cohort studyrdquo BMCInfectious Diseases vol 13 no 1 article 261 2013

[70] T Hawkins C Geist B Young et al ldquoComparison of neuropsy-chiatric side effects in an observational cohort of efavirenz- andprotease inhibitor-treated patientsrdquo HIV Clinical Trials vol 6no 4 pp 187ndash196 2005

[71] C R Fumaz A Tuldra M J Ferrer et al ldquoQuality of life emo-tional status and adherence of HIV-1-infected patients treatedwith efavirenz versus protease inhibitor-containing regimensrdquoJournal of Acquired Immune Deficiency Syndromes vol 29 no3 pp 244ndash253 2002

[72] P Lochet H Peyriere A Lotthe J M Mauboussin B Delmasand J Reynes ldquoLong-term assessment of neuropsychiatricadverse reactions associated with efavirenzrdquoHIVMedicine vol4 no 1 pp 62ndash66 2003

[73] B Spire P Carrieri M-A Garzot M LrsquoHenaff and Y ObadialdquoFactors associated with Efavirenz discontinuation in a largecommunity-based sample of patientsrdquo AIDS CaremdashPsycho-logical and Socio-Medical Aspects of AIDSHIV vol 16 no 5pp 558ndash564 2004

[74] O O Agbaji P A Agaba P N Ekeh et al ldquoEfavirenz-inducedgynaecomastia in HIV-infected Nigerian men a report of sixcasesrdquo Journal of Medicine and Medical Sciences vol 2 no 11pp 1221ndash1224 2011

[75] C Wyen H Hendra M Vogel et al ldquoImpact of CYP2B6983TgtC polymorphism on non-nucleoside reverse transcrip-tase inhibitor plasma concentrations in HIV-infected patientsrdquoThe Journal of Antimicrobial Chemotherapy vol 61 no 4 pp914ndash918 2008

[76] C Nyakutira D Roshammar E Chigutsa et al ldquoHigh preva-lence of theCYP2B6 516GrarrT(lowast6) variant and effect on the pop-ulation pharmacokinetics of efavirenz inHIVAIDS outpatientsin Zimbabwerdquo European Journal of Clinical Pharmacology vol64 no 4 pp 357ndash365 2008

[77] M Maimbo K Kiyotani T Mushiroda C Masimirembwaand Y Nakamura ldquoCYP2B6 genotype is a strong predictor ofsystemic exposure to efavirenz in HIV-infected ZimbabweansrdquoEuropean Journal of Clinical Pharmacology vol 68 no 3 pp267ndash271 2012

[78] F S Sarfo Y Zhang D Egan et al ldquoPharmacogenetic asso-ciations with plasma efavirenz concentrations and clinicalcorrelates in a retrospective cohort of ghanaian HIV-infectedpatientsrdquo The Journal of Antimicrobial Chemotherapy vol 69no 2 Article ID dkt372 pp 491ndash499 2014

[79] J Di Iulio A FayetM Arab-Alameddine et al ldquoIn vivo analysisof efavirenz metabolism in individuals with impaired CYP2A6functionrdquo Pharmacogenetics and Genomics vol 19 no 4 pp300ndash309 2009

[80] L Dickinson J Amin L Else et al ldquoPharmacokinetic and phar-macodynamic comparison of once-daily Efavirenz (400mg vs600mg) in Treatment-Naıve HIV-infected patients results ofthe ENCORE1 studyrdquo Clinical Pharmacology and Therapeuticsvol 98 no 4 pp 406ndash416 2015

[81] R Nau F Sorgel and HW Prange ldquoLipophilicity at pH 74 andmolecular size govern the entry of the free serum fraction ofdrugs into the cerebrospinal fluid in humans with uninflamedmeningesrdquo Journal of the Neurological Sciences vol 122 no 1pp 61ndash65 1994

[82] S F L Van Lelyveld M Nijhuis F Baatz et al ldquoTherapyfailure following selection of enfuvirtide-resistant HIV-1 incerebrospinal fluidrdquo Clinical Infectious Diseases vol 50 no 3pp 387ndash390 2010

[83] S H Cheeseman S E Hattox M M McLaughlin et al ldquoPhar-macokinetics of nevirapine initial single-rising-dose study in


humansrdquo Antimicrobial Agents and Chemotherapy vol 37 no2 pp 178ndash182 1993

[84] B M Best S L Letendre P Koopmans et al ldquoLow cere-brospinal fluid concentrations of the nucleotide HIV reversetranscriptase inhibitor Tenofovirrdquo Journal of Acquired ImmuneDeficiency Syndromes vol 59 no 4 pp 376ndash381 2012

[85] P L Anderson R C Brundage L Bushman T N Kakuda R PRemmel and C V Fletcher ldquoIndinavir plasma protein bindingin HIV-1-infected adultsrdquo Aids vol 14 no 15 pp 2293ndash22972000

[86] M Boffito D J Back T F Blaschke et al ldquoProtein bindingin antiretroviral therapiesrdquo AIDS Research and Human Retro-viruses vol 19 no 9 pp 825ndash835 2003

[87] A Yilmaz A Izadkhashti R W Price et al ldquoDarunavirconcentrations in cerebrospinal fluid and blood in HIV-1-infected individualsrdquo AIDS Research and Human Retrovirusesvol 25 no 4 pp 457ndash461 2009

[88] E V Capparelli D Holland C Okamoto et al ldquoLopinavirconcentrations in cerebrospinal fluid exceed the 50 inhibitoryconcentration for HIVrdquo Aids vol 19 no 9 pp 949ndash952 2005

[89] L B Avery N Sacktor J C McArthur and C W HendrixldquoProtein-free efavirenz concentrations in cerebrospinal fluidand blood plasma are equivalent applying the law of massaction to predict protein-free drug concentrationrdquo Antimicro-bial Agents andChemotherapy vol 57 no 3 pp 1409ndash1414 2013

[90] W Manosuthi A Chaovavanich S Tansuphaswadikul et alldquoIncidence and risk factors of major opportunistic infectionsafter initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited settingrdquo The Journal ofInfection vol 55 no 5 pp 464ndash469 2007

[91] D P Kisangau H V M Lyaruu K M Hosea and C C JosephldquoUse of traditional medicines in the management of HIVAIDSopportunistic infections in Tanzania a case in the Bukoba ruraldistrictrdquo Journal of Ethnobiology and Ethnomedicine vol 3article 29 2007

[92] Y Khaliq K Gallicano S Venance S Kravcik and D WCameron ldquoEffect of ketoconazole on ritonavir and saquinavirconcentrations in plasma and cerebrospinal fluid from patientsinfected with human immunodeficiency virusrdquo Clinical Phar-macology andTherapeutics vol 68 no 6 pp 637ndash646 2000

[93] C K Kwan and J D Ernst ldquoHIV and tuberculosis a deadlyhuman syndemicrdquo Clinical Microbiology Reviews vol 24 no 2pp 351ndash376 2011

[94] R S Autar F W Wit J Sankote et al ldquoNevirapine plasmaconcentrations and concomitant use of rifampin in patientscoinfected with HIV-1 and tuberculosisrdquo Antiviral Therapy vol10 no 8 pp 937ndash943 2005

[95] E Ribera L Pou R M Lopez et al ldquoPharmacokineticinteraction between nevirapine and rifampicin in HIV-infectedpatients with tuberculosisrdquo Journal of Acquired Immune Defi-ciency Syndromes vol 28 no 5 pp 450ndash453 2001

[96] J Mallolas M Sarasa M Nomdedeu et al ldquoPharmacoki-netic interaction between rifampicin and ritonavir-boostedatazanavir in HIV-infected patientsrdquo HIV Medicine vol 8 no2 pp 131ndash134 2007

[97] E Ribera C Azuaje R M Lopez et al ldquoPharmacokineticinteraction between rifampicin and the once-daily combinationof saquinavir and low-dose ritonavir in HIV-infected patientswith tuberculosisrdquo Journal of Antimicrobial Chemotherapy vol59 no 4 pp 690ndash697 2007

[98] R F A LrsquoHommeHM JNij LGras et al ldquoClinical experiencewith the combined use of lopinavirritonavir and rifampicinrdquoAids vol 23 no 7 pp 863ndash865 2009

[99] G Maartens E Decloedt and K Cohen ldquoEffectiveness andsafety of antiretrovirals with rifampicin crucial issues for high-burden countriesrdquo Antiviral Therapy vol 14 no 8 pp 1039ndash1043 2009

[100] H McIlleron Y Ren J Nuttall et al ldquoLopinavir exposure isinsufficient in children given double doses of lopinavirritonavirduring rifampicin-based treatment for tuberculosisrdquo AntiviralTherapy vol 16 no 3 pp 417ndash421 2011

[101] D Elsherbiny Y Ren H McIlleron G Maartens and U SH Simonsson ldquoPopulation pharmacokinetics of lopinavir incombination with rifampicin-based antitubercular treatmentin HIV-infected South African childrenrdquo European Journal ofClinical Pharmacology vol 66 no 10 pp 1017ndash1023 2010

[102] R A Murphy V C Marconi R T Gandhi D R Kuritzkesand H Sunpath ldquoCoadministration of lopinavirritonavir andrifampicin in HIV and tuberculosis co-infected adults in SouthAfricardquo PLoS ONE vol 7 no 9 Article ID e44793 2012

[103] U S Justesen A B Andersen N A Klitgaard K BroslashsenJ Gerstoft and C Pedersen ldquoPharmacokinetic interactionbetween rifampin and the combination of indinavir and low-dose ritonavir in HIV-infected patientsrdquo Clinical InfectiousDiseases vol 38 no 3 pp 426ndash429 2004

[104] Z Desta N V Soukhova and D A Flockhart ldquoInhibitionof cytochrome P450 (CYP450) isoforms by isoniazid potentinhibition of CYP2C19 and CYP3Ardquo Antimicrobial Agents andChemotherapy vol 45 no 2 pp 382ndash392 2001

[105] P Vernazza S Daneel V Schiffer et al ldquoThe role of compart-ment penetration in PI-Monotherapy the Atazanavir-RitonavirMonomaintenance (ATARITMO) Trialrdquo AIDS vol 21 no 10pp 1309ndash1315 2007

[106] V K Manda R K Mittapalli K A Bohn C E Adkins andP R Lockman ldquoNicotine and cotinine increases the brainpenetration of saquinavir in ratrdquo Journal of Neurochemistry vol115 no 6 pp 1495ndash1507 2010

[107] World Health Organization WHO Traditional Medicine Strat-egy 2002ndash2005 2002 httpwwwwprowhointhealth techno-logybook who traditional medicine strategy 2002 2005pdf

[108] G A Koffuor R Dickson S Y Gbedema E Ekuadzi GDapaah and L F Otoo ldquoThe immunostimulatory and antimi-crobial property of two herbal decoctions used in the manage-ment of HIVAIDS in Ghanardquo African Journal of TraditionalComplementary andAlternativeMedicines vol 11 no 3 pp 166ndash172 2014

[109] K C Chinsembu and M Hedimbi ldquoEthnomedicinal plantsand other natural products with anti-HIV active compoundsand their putative modes of actionrdquo International Journal forBiotechnology and Molecular Biology Research vol 1 no 6 pp74ndash91 2010

[110] D Langlois-Klassen W Kipp G S Jhangri and T RubaaleldquoUse of traditional herbal medicine by AIDS patients in Kaba-role District western Ugandardquo American Journal of TropicalMedicine and Hygiene vol 77 no 4 pp 757ndash763 2007

[111] R M Gyasi E Tagoe-Darko and C M Mensah ldquoUse of tradi-tional medicine by HIVAIDS patients in Kumasi MetropolisGhana a cross-sectional surveyrdquo American International Jour-nal of Contemporary Research vol 3 no 4 pp 117ndash129 2013

[112] N E Thomford K Dzobo D Chopera et al ldquoPharma-cogenomics implications of using herbal medicinal plants on


African populations in health transitionrdquo Pharmaceuticals vol8 no 3 pp 637ndash663 2015

[113] E Mills B C Foster R Van Heeswijk et al ldquoImpact of Africanherbal medicines on antiretroviral metabolismrdquo AIDS vol 19no 1 pp 95ndash97 2005

[114] A C Muller and I Kanfer ldquoPotential pharmacokinetic inter-actions between antiretrovirals and medicinal plants used ascomplementary and African traditional medicinesrdquo Biophar-maceutics andDrugDisposition vol 32 no 8 pp 458ndash470 2011

[115] A Calcagno M C Alberione A Romito et al ldquoPrevalence andpredictors of blood-brain barrier damage in the HAART erardquoJournal of NeuroVirology vol 20 no 5 pp 521ndash525 2014

[116] S Abdulle L Hagberg andMGisslen ldquoEffects of antiretroviraltreatment on blood-brain barrier integrity and intrathecalimmunoglobulin production in neuroasymptomatic HIV-1-infected patientsrdquoHIVMedicine vol 6 no 3 pp 164ndash169 2005

[117] A Calcagno C Atzori A Romito et al ldquoBlood brain barrierimpairment is associated with cerebrospinal fluid markers ofneuronal damage in HIV-positive patientsrdquo Journal of NeuroVi-rology vol 22 no 1 pp 88ndash92 2016

[118] S Nakagawa V Castro and M Toborek ldquoInfection of humanpericytes by HIV-1 disrupts the integrity of the blood-brainbarrierrdquo Journal of Cellular and Molecular Medicine vol 16 no12 pp 2950ndash2957 2012

[119] Y Persidsky J Hill M Zhang et al ldquoDysfunction of brainpericytes in chronic neuroinflammationrdquo Journal of CerebralBlood Flow and Metabolism vol 36 no 4 pp 794ndash807 2016

[120] A Armulik G Genove M Mae et al ldquoPericytes regulate theblood-brain barrierrdquo Nature vol 468 no 7323 pp 557ndash5612010

[121] B Bauer A M S Hartz and D S Miller ldquoTumor necrosisfactor 120572 and endothelin-1 increase p-glycoprotein expressionand transport activity at the blood-brain barrierrdquo MolecularPharmacology vol 71 no 3 pp 667ndash675 2007

[122] M J Cipolla ldquoIntegrated systems physiology frommolecule tofunctionrdquo inThe Cerebral Circulation Morgan amp Claypool LifeSciences San Rafael Calif USA 2009

[123] L Sokoloff ldquoThe action of drugs on the cerebral circulationrdquoPharmacological Reviews vol 11 no 1 pp 1ndash85 1959

[124] L L Brunton B Chabner and B C Knollmann Goodman ampGilmanrsquos the Pharmacological Basis of Therapeutics McGraw-Hill Medical New York NY USA 2011

[125] B M Ances D Sisti F Vaida et al ldquoResting cerebral bloodflow a potential biomarker of the effects of HIV in the brainrdquoNeurology vol 73 no 9 pp 702ndash708 2009

[126] M J Van Der Werf B H B Van Benthem and E J C VanAmeijden ldquoPrevalence incidence and risk factors of anaemiain HIV-positive and HIV-negative drug usersrdquo Addiction vol95 no 3 pp 383ndash392 2000

[127] J O Mugisha L A Shafer L V Der Paal et al ldquoAnaemiain a rural Ugandan HIV cohort prevalence at enrolmentincidence diagnosis and associated factorsrdquo Tropical Medicineand International Health vol 13 no 6 pp 788ndash794 2008

[128] R Omoregie E U Omokaro O Palmer et al ldquoPrevalence ofanaemia among HIV-infected patients in Benin City NigeriardquoTanzania Journal of Health Research vol 11 no 1 pp 1ndash4 2009

[129] F Boccara ldquoCardiovascular complications and atheroscleroticmanifestations in the HIV-infected population type incidenceand associated risk factorsrdquo AIDS vol 22 supplement 3 ppS19ndashS26 2008

[130] M Acevedo D L Sprecher L Calabrese et al ldquoPilot studyof coronary atherosclerotic risk and plaque burden in HIVpatients lsquoa call for cardiovascular preventionrsquordquo Atherosclerosisvol 163 no 2 pp 349ndash354 2002

[131] M Depairon S Chessex P Sudre et al ldquoPremature atheroscle-rosis in HIV-infected individualsmdashfocus on protease inhibitortherapyrdquo AIDS vol 15 no 3 pp 329ndash334 2001

[132] A Hakeem S Bhatti and M Cilingiroglu ldquoThe spectrumof atherosclerotic coronary artery disease in HIV patientsrdquoCurrent Atherosclerosis Reports vol 12 no 2 pp 119ndash124 2010

[133] D M Burger C L Kraaijeveld P L Meenhorstt et al ldquoPen-etration of zidovudine into the cerebrospinal fluid of patientsinfected with HIVrdquo AIDS vol 7 no 12 pp 1581ndash1587 1993

[134] A Antinori C F Perno M L Giancola et al ldquoEfficacy of cere-brospinal fluid (CSF)-penetrating antiretroviral drugs againstHIV in the neurological compartment different patterns ofphenotypic resistance in CSF and plasmardquo Clinical InfectiousDiseases vol 41 no 12 pp 1787ndash1793 2005

[135] D M Burger C L Kraayeveld P L Meenhorst et al ldquoStudy ondidanosine concentrations in cerebrospinal fluidmdashimplicationsfor the treatment and prevention of AIDS dementia complexrdquoPharmacy World amp Science vol 17 no 6 pp 218ndash221 1995

[136] E V Capparelli S L Letendre R J Ellis P Patel D Hollandand J AMcCutchan ldquoPopulation pharmacokinetics of abacavirin plasma and cerebrospinal fluidrdquo Antimicrobial Agents andChemotherapy vol 49 no 6 pp 2504ndash2506 2005

[137] J A McDowell G E Chittick J R Ravitch R E Polk T MKerkering and D S Stein ldquoPharmacokinetics of [(14)C]aba-cavir a human immunodeficiency virus type 1 (HIV-1) reversetranscriptase inhibitor administered in a single oral dose toHIV-1-infected adults a mass balance studyrdquo AntimicrobialAgents and Chemotherapy vol 43 no 12 pp 2855ndash2861 1999

[138] B M Best P P Koopmans S L Letendre et al ldquoEfavirenzconcentrations in CSF exceed IC50 for wild-type HIVrdquo Journalof Antimicrobial Chemotherapy vol 66 no 2 pp 354ndash357 2011

[139] A Winston J Amin A Clarke et al ldquoCerebrospinal fluidexposure of efavirenz and its major metabolites when dosed at400mg and 600mg once daily a randomized controlled trialrdquoClinical Infectious Diseases vol 60 no 7 pp 1026ndash1032 2015

[140] A Calcagno M Simiele M C Alberione et al ldquoCerebrospinalfluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral con-trolrdquo Clinical Infectious Diseases vol 60 no 2 pp 311ndash317 2015

[141] X-J Zhou D V Havlir D D Richman et al ldquoPlasma popula-tion pharmacokinetics and penetration into cerebrospinal fluidof indinavir in combination with zidovudine and lamivudine inHIV-1-infected patientsrdquo AIDS vol 14 no 18 pp 2869ndash28762000

[142] S L Letendre E V Capparelli R J Ellis J A McCutchan andThe HIV Neurobehavioral Research Center Group ldquoIndinavirpopulation pharmacokinetics in plasma and cerebrospinalfluidrdquo Antimicrobial Agents and Chemotherapy vol 44 no 8pp 2173ndash2175 2000

[143] L Garvey M Nelson N Latch et al ldquoCNS effects of a CCR5inhibitor inHIV-infected subjects a pharmacokinetic and cere-bral metabolite studyrdquo Journal of Antimicrobial Chemotherapyvol 67 no 1 pp 206ndash212 2012

[144] F Aweeka A Jayewardene S Staprans et al ldquoFailure to detectnelfinavir in the cerebrospinal fluid of HIV-1- infected patientswith and without AIDS dementia complexrdquo Journal of AcquiredImmune Deficiency Syndromes and Human Retrovirology vol20 no 1 pp 39ndash43 1999


[145] C A Delille S T Pruett V C Marconi et al ldquoEffect of proteinbinding on unbound atazanavir and darunavir cerebrospinalfluid concentrationsrdquo Journal of Clinical Pharmacology vol 54no 9 pp 1063ndash1071 2014

[146] B M Best S L Letendre E Brigid et al ldquoLow atazanavirconcentrations in cerebrospinal fluidrdquo AIDS vol 23 no 1 pp83ndash87 2009

[147] A Yilmaz M Gisslen S Spudich et al ldquoRaltegravir cere-brospinal fluid concentrations in HIV-1 infectionrdquo PLoS ONEvol 4 no 9 article e6877 2009

[148] A Calcagno J Cusato M Simiele et al ldquoHigh interpatientvariability of raltegravir CSF concentrations in HIV-positivepatients a pharmacogenetic analysisrdquoThe Journal of Antimicro-bial Chemotherapy vol 69 no 1 pp 241ndash245 2014

[149] S L Letendre A M Mills K T Tashima et al ldquoING116070 astudy of the pharmacokinetics and antiviral activity of dolute-gravir in cerebrospinal fluid in HIV-1-infected antiretroviraltherapy-naive subjectsrdquo Clinical Infectious Diseases vol 59 no7 pp 1032ndash1037 2014

[150] A Yilmaz V Watson L Else and M Gisslen ldquoCerebrospinalfluid maraviroc concentrations in HIV-1 infected patientsrdquoAIDS vol 23 no 18 pp 2537ndash2540 2009

[151] J M Tiraboschi J Niubo J Curto and D Podzamczer ldquoMar-aviroc concentrations in cerebrospinal fluid in HIV-infectedpatientsrdquo Journal of Acquired Immune Deficiency Syndromesvol 55 no 5 pp 606ndash609 2010

[152] R K Mehlotra M N Ziats M J Bockarie and P A Zim-merman ldquoPrevalence of CYP2B6 alleles in malaria-endemicpopulations of West Africa and Papua New Guineardquo EuropeanJournal of Clinical Pharmacology vol 62 no 4 pp 267ndash2752006

[153] K J Marwa T Schmidt M Sjogren O M S Minzi EKamugisha and G Swedberg ldquoCytochrome P450 single nuc-leotide polymorphisms in an indigenous Tanzanian populationa concern about themetabolism of artemisinin-based combina-tionsrdquoMalaria Journal vol 13 article 420 2014

[154] V Gounden C van Niekerk T Snyman and J A GeorgeldquoPresence of the CYP2B6 516GgtT polymorphism increasedplasma Efavirenz concentrations and early neuropsychiatricside effects in South African HIV-infected patientsrdquo AIDSResearch andTherapy vol 7 article 32 2010

[155] O Ikediobi B Aouizerat Y Xiao M Gandhi S Gebhardt andL Warnich ldquoAnalysis of pharmacogenetic traits in two distinctSouth African populationsrdquoHuman Genomics vol 5 no 4 pp265ndash282 2011

[156] R Gross R Aplenc T TenHave et al ldquoSlow efavirenz meta-bolism genotype is common in Botswanardquo Journal of AcquiredImmune Deficiency Syndromes vol 49 no 3 pp 336ndash337 2008

[157] R Gammal M Court C Haidar et al ldquoClinical Pharma-cogenetics Implementation Consortium (CPIC) guideline forUGT1A1 and atazanavir prescribingrdquo Clinical Pharmacology ampTherapeutics vol 99 no 4 pp 363ndash369 2016

[158] D H Johnson C Venuto M D Ritchie et al ldquoGenomewideassociation study of atazanavir pharmacokinetics and hyper-bilirubinemia in AIDS Clinical Trials Group protocol A5202rdquoPharmacogenetics and Genomics vol 24 no 4 pp 195ndash2032014

[159] S Vardhanabhuti H J Ribaudo R J Landovitz et al ldquoScreen-ing for UGT1A1 genotype in study A5257 would have markedlyreduced premature discontinuation of atazanavir for hyper-bilirubinemiardquoOxford Journals Medicine ampHealth Open ForumInfectious Diseases vol 2 no 3 2015

[160] J Sugatani K Yamakawa K Yoshinari et al ldquoIdentificationof a defect in the UGT1A1 gene promoter and its associationwith hyperbilirubinemiardquo Biochemical and Biophysical ResearchCommunications vol 292 no 2 pp 492ndash497 2002

[161] H Izzedine J-S Hulot E Villard et al ldquoAssociation betweenABCC2 gene haplotypes and tenofovir-induced proximal tubu-lopathyrdquo Journal of Infectious Diseases vol 194 no 11 pp 1481ndash1491 2006

[162] S Rodrıguez-Novoa P Labarga V Soriano et al ldquoPredictorsof kidney tubular dysfunction in HIV-infected patients treatedwith tenofovir A Harmacogenetic Studyrdquo Clinical InfectiousDiseases vol 48 no 11 pp e108ndashe116 2009

[163] S Likanonsakul B Suntisuklappon R Nitiyanontakij et al ldquoAsingle-nucleotide polymorphism in ABCC4 is associated withtenofovir-related beta2-microglobulinuria inThai patients withHIV-1 infectionrdquo PLoS ONE vol 11 no 1 Article ID e01477242016

[164] N Berka J M Gill A Liacini T OrsquoBryan and F MKhan ldquoHuman leukocyte antigen (HLA) and pharmacogenet-ics Screening for HLA-B5701 among human immunodefi-ciency virus-positive patients from southern Albertardquo HumanImmunology vol 73 no 2 pp 164ndash167 2012

[165] A R Hughes M Mosteller A T Bansal et al ldquoAssociationof genetic variations in HLA-B region with hypersensitivity toabacavir in some but not all populationsrdquo Pharmacogenomicsvol 5 no 2 pp 203ndash211 2004

[166] S Rodrıguez-Novoa P Garcıa-Gasco F Blanco et al ldquoValueof the HLA-B5701 allele to predict abacavir hypersensitivity inSpaniardsrdquo AIDS Research and Human Retroviruses vol 23 no11 pp 1374ndash1376 2007

[167] S Mallal E Phillips G Carosi et al ldquoHLA-Blowast5701 screeningfor hypersensitivity to abacavirrdquo The New England Journal ofMedicine vol 358 no 6 pp 568ndash579 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


specific factors that are driven by pharmacokinetics andpharmacogenetics Other factors include physicochemicalproperties of the antiretroviral drug local cerebral bloodflowand chronic inflammation We also summarize associationsbetween antiretroviral drug penetrations CNS efficacy andneurotoxicity

2 Data Collection Methods

We conducted a comprehensive query of PubMed andGoogle Scholar Search terms used included pharmacoge-netics Africa antiretrovirals zidovudine efavirenz teno-fovir saquinavir raltegravir enfuvirtide bevirimat nevi-rapine ritonavir maraviroc zalcitabine delavirdine ampre-navir indinavir didanosine nelfinavir lopinavir stavudineatazanavir fosamprenavir abacavir tipranavir emtricitabinedarunavir lamivudine Central Nervous System blood flowpenetratlowast HIV blood brain barrier CSF CSF concentrationtransporters P-gp ABCB1 protein binding plasma con-centration and drug interaction Additional references wereobtained from the reference lists in the articles identifiedusing this search method Only articles published in Englishlanguage were reviewed

3 Commonly Used Antiretroviral Drugs inSub-Saharan Africa

The World Health Organization (WHO) recommends thatthe first-line ART should consist of a nonnucleoside reversetranscriptase inhibitor (NNRTI) and two nucleos(t)idereverse transcriptase inhibitors (NRTIs) one of which shouldbe zidovudine (ZDV) or tenofovir disoproxil fumarate(TDF) Efavirenz (EFV) is the preferred NNRTI in ARTregimens in sub-Saharan Africa [11 12] although somepatients are treated with nevirapine- (NVP-) based ART [13ndash15] Other NRTIs commonly used as first-line treatment arelamivudine (3TC) and emtricitabine (FTC) Both didanosine(ddI) and stavudine (d4T) are rarely used these days becauseof their toxicities [16 17] The WHO recommendation forsecond-line ART consists of a ritonavir-boosted proteaseinhibitor (PI) plus two or three NRTIs one of which shouldbe ZDV or TDF depending on what was used in first-linetherapy Atazanavir with ritonavir (ATVr) and lopinavirritonavir (LPVr) are the preferred PIs Saquinavir (SQV)has fallen out of favor partly because it has a high pill-burden while indinavir (IDV) has a high risk of toxicity andfosamprenavir (FPV) is relatively expensive Although theintegrase strand transfer inhibitor raltegravir is an optionfor second-line therapy when combined with a boosted PIintegrase inhibitors are typically reserved for third-line regi-mens Other components of third-line therapy include drugslikely to have anti-HIV activity such as the second-generationNNRTI etravirine and the boosted PI darunavirritonavir(DRVr) both of which are rarely available due to relativelyhigh costs [18] Dolutegravir (DTG) a newer integrase strandtransfer inhibitor is not yet available in sub-Saharan Africabut has the potential to gain attention in this region in the nextfew years due to its attractive safety efficacy and resistance

profile DTG was demonstrated to be superior in first-lineART to EFV [19 20] and DRVr [21] in large randomizedtrials

4 CNS Penetration of DifferentAntiretroviral Drugs

Penetration of antiretrovirals into the CNS is critical tooptimize suppression of the CSF HIV viral load and overallreplication in the CNS It has been suggested that the useof antiretroviral compounds with poor penetration into theCNS may be associated with an increased risk of cognitivedecline This is however controversial as shown by the pro-posed CNS Penetration-Effectiveness (CPE) ranking systemwhich categorizes antiretrovirals into three groups (lowintermediate and high CNS penetration) [10] or four groups[22] based on their chemical properties concentration in theCSF and effectiveness in reducing the CSF viral load Studiesevaluating associations between CPE score and neurocog-nitive outcomes have produced inconsistent results [23ndash25]although lower CPE ranking correlatedwith higherHIV viralloads in CSF [10] Studies on CNS penetration of commonlyused antiretrovirals and their CPE rankings are shown inTable 1 Of note the same antiretroviral drug displays vari-ations in CSF concentration (varying penetrating abilities)in different patients within the same study and in differentstudies This likely reflects the multifactorial determinants ofCNS drug penetration

5 Factors Affecting CNS Penetration ofAntiretroviral Drugs

51 General Factors

511 Blood-Brain Barrier and Blood-CSF Barrier The blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) arenormal anatomical structures that evolved to protect the CNSfrom toxic substances In HIV-infected individuals howeverthese barriers also limit penetration and potentially efficacyof some antiretrovirals in the brain The BBB is formedby brain capillary endothelial cells fused together by tightjunctions hence characterized by lack of fenestration and thepaucity of pinocytosis [26 27] On the other hand BCSFBwhich separates CSF and blood consists of the choroid plexusand the arachnoidmembraneThe choroid plexus epitheliumis involved in numerous exchange processes that increase theCSF concentrations of nutrients and hormones and decreasethe CSF concentrations of potentially deleterious compoundsand metabolites [28] These characteristics restrict the pen-etration of large or hydrophilic molecules through the BBBand BCSFB selectively permitting penetration of small andlipophilic moleculesThus antiretrovirals such as NVP ZDVEFV and FTC with physicochemical properties that supportpenetration have an advantage in penetrating the BBB bysimple diffusion Any condition which compromises the BBBandor BCSFBwill likely increase the rate of entrance of drugsinto the brain [29]






418 2 (0ndash674) [134]5 96 (8) [135]

Abacavir 54 36 [136] 33a 35 (31ndash44) [137]




Efavirenz

69 05 (026ndash076)b [138]


26 071 (037)c in600mg [139]


Indinavir

19 17 (886)c [141]

32216 (04ndash228) or 6

usingAUC ratio

[142]



CSF [144]1


Ritonavir 8 000 (000ndash52) [134] 1



28 14 (06ndash34)b [140]13 3d [145]


324 3 (1ndash61) [147]35 206 (05ndash133) [148]

Dolutegravir 12 0546 (0480) [149] NA


312 22 (04ndash17) [151]

12 101 (029) 420(122)e [143]














































54 Other Factors





6 Conclusion


Disclosure


Competing Interests



Acknowledgments


References





















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















418 2 (0ndash674) [134]5 96 (8) [135]

Abacavir 54 36 [136] 33a 35 (31ndash44) [137]




Efavirenz

69 05 (026ndash076)b [138]


26 071 (037)c in600mg [139]


Indinavir

19 17 (886)c [141]

32216 (04ndash228) or 6

usingAUC ratio

[142]



CSF [144]1


Ritonavir 8 000 (000ndash52) [134] 1



28 14 (06ndash34)b [140]13 3d [145]


324 3 (1ndash61) [147]35 206 (05ndash133) [148]

Dolutegravir 12 0546 (0480) [149] NA


312 22 (04ndash17) [151]

12 101 (029) 420(122)e [143]














































54 Other Factors





6 Conclusion


Disclosure


Competing Interests



Acknowledgments


References





















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































54 Other Factors





6 Conclusion


Disclosure


Competing Interests



Acknowledgments


References





















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Acknowledgments


References





















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article pharmacokinetic, pharmacogenetic, and other

Documents