AIDS Research and Treatment
Volume 2016 (2016), Article ID 2587094, 13 pages
http://dx.doi.org/10.1155/2016/2587094

Review Article

Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

Jacinta Nwamaka Nwogu,1,2 Qing Ma,3,4,5 Chinedum Peace Babalola,1,2 Waheed Adeola Adedeji,⁶ Gene D. Morse,3,4,5 and Babafemi Taiwo⁷

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
²Centre for Drug Discovery Development and Production, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
³School of Pharmacy and Pharmaceutical Sciences and New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, 701 Ellicott Street, Buffalo, NY 14203, USA
⁴Pharmacy Practice (Medicine and Pediatrics), School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 285 Kapoor Hall, Buffalo, NY 14214, USA
⁵Center for Integrated Global Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
⁶Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria
⁷Division of Infectious Diseases, Center for Global Health, Feinberg School of Medicine, Northwestern University, 645 N. Michigan Avenue, Suite 900, Chicago, IL, USA

Received 22 April 2016; Accepted 21 August 2016

Academic Editor: Soraya Seedat

Copyright © 2016 Jacinta Nwamaka Nwogu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Neurological complications associated with the human immunodeficiency virus (HIV) are a matter of great concern. While antiretroviral (ARV) drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity.

1. Introduction

Human immunodeficiency virus (HIV) remains a leading cause of morbidity and mortality, especially in sub-Saharan Africa where 70% of the people living with HIV globally live. HIV penetrates the central nervous system (CNS) within a few days of infection [1–4], establishing residence in macrophages and microglia cells and producing CNS inflammation that may lead to neuronal injury and neurological complications. Combination antiretroviral therapy (ART) for HIV effectively suppresses plasma HIV viremia [5–7] and as a result considerably increases life expectancy [8]. ART also confers neurological benefit in most individuals by suppressing CNS viral replication and inflammation. However, up to 40% of individuals exhibit neurocognitive impairment despite successful suppression of plasma viremia [9]. Potential explanations for this include poor penetration of ARV drugs into the CNS, which may allow continued HIV replication and inflammation in that compartment [10]. In addition, some antiretroviral drugs may be neurotoxic. In this review article, we provide an overview of the various factors influencing the CNS penetration of antiretroviral drugs. These include general factors such as drug transporters, the blood-brain barrier, and blood-cerebrospinal fluid barrier and host specific factors that are driven by pharmacokinetics and pharmacogenetics. Other factors include physicochemical properties of the antiretroviral drug, local cerebral blood flow, and chronic inflammation. We also summarize associations between antiretroviral drug penetrations, CNS efficacy, and neurotoxicity.

2. Data Collection Methods

We conducted a comprehensive query of PubMed and Google Scholar. Search terms used included pharmacogenetics, Africa, antiretrovirals, zidovudine, efavirenz, tenofovir, saquinavir, raltegravir, enfuvirtide, bevirimat, nevirapine, ritonavir, maraviroc, zalcitabine, delavirdine, amprenavir, indinavir, didanosine, nelfinavir, lopinavir, stavudine, atazanavir, fosamprenavir, abacavir, tipranavir, emtricitabine, darunavir, lamivudine, Central Nervous System, blood flow, penetrat, HIV, blood brain barrier, CSF, CSF concentration, transporters, P-gp, ABCB1, protein binding, plasma concentration, and drug interaction. Additional references were obtained from the reference lists in the articles identified using this search method. Only articles published in English language were reviewed.

3. Commonly Used Antiretroviral Drugs in Sub-Saharan Africa

The World Health Organization (WHO) recommends that the first-line ART should consist of a nonnucleoside reverse transcriptase inhibitor (NNRTI) and two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), one of which should be zidovudine (ZDV) or tenofovir disoproxil fumarate (TDF). Efavirenz (EFV) is the preferred NNRTI in ART regimens in sub-Saharan Africa [11, 12], although some patients are treated with nevirapine- (NVP-) based ART [13–15]. Other NRTIs commonly used as first-line treatment are lamivudine (3TC) and emtricitabine (FTC). Both didanosine (ddI) and stavudine (d4T) are rarely used these days because of their toxicities [16, 17]. The WHO recommendation for second-line ART consists of a ritonavir-boosted protease inhibitor (PI) plus two or three NRTIs, one of which should be ZDV or TDF, depending on what was used in first-line therapy. Atazanavir with ritonavir (ATV/r) and lopinavir/ritonavir (LPV/r) 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, and fosamprenavir (FPV) is relatively expensive. Although the integrase strand transfer inhibitor, raltegravir, is an option for second-line therapy when combined with a boosted PI, integrase inhibitors are typically reserved for third-line regimens. Other components of third-line therapy include drugs likely to have anti-HIV activity such as the second-generation NNRTI etravirine and the boosted PI darunavir/ritonavir (DRV/r), both of which are rarely available due to relatively high costs [18]. Dolutegravir (DTG), a newer integrase strand transfer inhibitor, is not yet available in sub-Saharan Africa but has the potential to gain attention in this region in the next few years due to its attractive safety, efficacy, and resistance profile. DTG was demonstrated to be superior in first-line ART to EFV [19, 20] and DRV/r [21] in large randomized trials.

4. CNS Penetration of Different Antiretroviral Drugs

Penetration of antiretrovirals into the CNS is critical to optimize suppression of the CSF HIV viral load and overall replication in the CNS. It has been suggested that the use of antiretroviral compounds with poor penetration into the CNS may be associated with an increased risk of cognitive decline. This is however controversial as shown by the proposed CNS Penetration-Effectiveness (CPE) ranking system, which categorizes antiretrovirals into three groups (low, intermediate, and high CNS penetration) [10] or four groups [22] based on their chemical properties, concentration in the CSF, and effectiveness in reducing the CSF viral load. Studies evaluating associations between CPE score and neurocognitive outcomes have produced inconsistent results [23–25], although lower CPE ranking correlated with higher HIV viral loads in CSF [10]. Studies on CNS penetration of commonly used antiretrovirals and their CPE rankings are shown in Table 1. Of note, the same antiretroviral drug displays variations in CSF concentration (varying penetrating abilities) in different patients within the same study and in different studies. This likely reflects the multifactorial determinants of CNS drug penetration.

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

Antiretroviral drug
Sample size
CSF concentration as a percentage of plasma concentration (%)
References
Revised CPE rank [22]

Median (range)
Mean (SD)

Zidovudine
50
60 (4–262)

[133]
4

18
2 (0–674)

[134]

5

96 (8)
[135]

Abacavir
54
36

[136]
3

3
35 (31–44)

[137]

Lamivudine
55
23 (0–490)

[134]
2

Stavudine
31
20 (0–20.4)

[134]
2

Didanosine
4

27 (14)
[135]
2

5
Undetected

[134]

Tenofovir
38
5.7 (3–10)

[84]
1

Efavirenz
69
0.5 (0.26–0.76)

[138]
3

11
Undetected

[134]

26

0.71 (0.37) in 600 mg
[139]

11
1.3 (0.8–1.6)

[140]

Nevirapine
16
63 (41–77)

[134]
4

Indinavir
19

1.7 (88.6)
[141]
3

22
16 (0.4–228) or 6 using
AUC ratio

[142]

Lopinavir/r
26
0.23% (0.12–0.75)

[88]
3

12

0.85 (0.47)
[143]

Nelfinavir
6
Not detected in CSF

[144]
1

9
Not detected in CSF

[134]

Ritonavir
8
0.00 (0.00–52)

[134]
1

Darunavir/r
14

0.5
[145]
3

14
0.9 (0.3–1.8)

[87]

Atazanavir
9
1.12 (0.5–13.9)

[146]
2

8
1.4 (0.6–3.4)

[140]

13

3
[145]

Raltegravir
41
17 (1.8–33.8)

[140]
3

24
3 (1–61)

[147]

35
20.6 (0.5–133)

[148]

Dolutegravir
12

0.546 (0.480)
[149]
N/A

Maraviroc
7
3.0 (1–10)

[150]
3

12
2.2 (0.4–17)

[151]

12

1.01 (0.29), 4.20 (1.22)
[143]

Subjects with multiple plasma and CSF samples, median (IQR), mean (coefficient of variation), geometric mean, % Maraviroc CSF/unbound plasma ratio, and N/A = not available. The ranks assigned to the antiretrovirals in Table 1 are based on revised ranking system proposed by Letendre et al. and not CSF/plasma ratio from the authors findings in the table. Higher CPE score means higher CNS penetration.

5. Factors Affecting CNS Penetration of Antiretroviral Drugs

5.1. General Factors

5.1.1. Blood-Brain Barrier and Blood-CSF Barrier

The blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) are normal anatomical structures that evolved to protect the CNS from toxic substances. In HIV-infected individuals, however, these barriers also limit penetration and, potentially, efficacy of some antiretrovirals in the brain. The BBB is formed by brain capillary endothelial cells fused together by tight junctions, hence characterized by lack of fenestration and the paucity of pinocytosis [26, 27]. On the other hand, BCSFB, which separates CSF and blood, consists of the choroid plexus and the arachnoid membrane. The choroid plexus epithelium is involved in numerous exchange processes that increase the CSF concentrations of nutrients and hormones and decrease the CSF concentrations of potentially deleterious compounds and metabolites [28]. These characteristics restrict the penetration of large or hydrophilic molecules through the BBB and BCSFB, selectively permitting penetration of small and lipophilic molecules. Thus, antiretrovirals such as NVP, ZDV, EFV, and FTC, with physicochemical properties that support penetration, have an advantage in penetrating the BBB by simple diffusion. Any condition which compromises the BBB and/or BCSFB will likely increase the rate of entrance of drugs into the brain [29].

5.1.2. Drug Transporters

Transporters are membrane proteins that facilitate the movement of molecules into or out of cells. They can be categorized in different ways including efflux and influx transporters or the adenosine triphosphate binding cassette (ABC) and solute carrier (SLC) transporters. The CNS penetration of antiretroviral drugs that are substrates of drug transporters is partly dependent on the level of expression of the transporters. Due to the substrate specificity of these transporters, drugs that possess significant similarities to them are transported into or out of cells. Efflux and influx transporters can play a critical role in determining drug concentrations in the systemic circulation and in cells. However, the overall rate constant for efflux of drug from the brain is approximately 75-fold higher and from CSF is 8-fold higher than the respective rate constants for influx [30]. This implies that efflux of drugs out of cells occurs more frequently when compared to drug influx into the cells, due to ubiquitous expression of efflux transporters. The emphasis is on the ABC transporters, for example, permeability-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs), because of their effect on the CNS penetration of some antiretrovirals.

The brain penetration of antiretrovirals that are substrates of transport proteins is partly affected by these transporters. The efflux pumps (P-gp, MRPs, and breast cancer resistance protein (BCRP)) are present at the BBB and have been shown to extrude substrate drugs from this site. Thus, they limit PIs from penetrating the CNS [31–36] due to their affinity for these transporters. The most important efflux transporter influencing the brain penetration of antiretrovirals is P-gp, because of its multiple binding sites for substrates and inhibitors [37, 38]. Apart from PIs, P-gp limits brain penetration of the NRTIs, abacavir, and ZDV [32, 39] and can also efflux some structurally unrelated hydrophobic molecules.

The expression and functionality of P-gp can be modulated by inhibition and induction, which can affect the pharmacokinetics, efficacy, safety, or tissue levels of P-gp substrates [40]. For example, PIs (substrates of P-gp) generally have poor brain penetration, but their penetrability may be enhanced by coadministration with specific P-gp inhibitor such as ritonavir [36]. Consistent with this, a study in nonhuman primates reported that P-gp inhibition at the BBB significantly enhanced the distribution of nelfinavir into the brain [41]. A previous study showed that patients with HIV encephalitis have higher brain P-gp levels compared to patients without HIV encephalitis [42], suggesting that patients with HIV encephalitis may be predisposed to lower CNS penetration of substrate drugs. In addition, MRP has been reported to contribute to the poor brain penetrations of PIs [43].

5.2. Host Specific Factors

5.2.1. Pharmacogenetics

Pharmacogenetics is the discipline that analyses the genetic basis for the interindividual variation in the body disposition of drugs [44]. Pharmacogenetics has found application in the treatment of numerous diseases including HIV infection. Since pharmacogenetics can predict drug exposure, hence response to therapy or risk of toxicity, it is of particular importance for the drugs that have a narrow therapeutic index and/or metabolic pathways affected by polymorphisms in the drug metabolizing enzymes.

Cytochrome P450 2B6 has received much attention in HIV therapy due to its ubiquitous role in the metabolism of antiretroviral drugs. CYP2B6 is highly polymorphic [45, 46] and is characterized by wide interindividual variability in expression and activity [47]. Both EFV and NVP are mainly metabolized by CYP2B6 with African populations having higher poor metabolizer frequency [48, 49], hence potentially prone to development of adverse reactions with these agents. Indeed, previous studies have reported significant associations of some CYP2B6 variants with elevated plasma EFV [50–55], which is relevant to CNS EFV levels/effects since higher plasma concentration may result in higher CNS penetration. In line with this, Winston and Puls in their study, though with a small sample size, reported an association of CSF EFV concentration with CYP2B6 genotype [56]. Further, CYP2B6 polymorphism also affects NVP plasma levels [57–59]. NVP concentrations increased by 92% with the presence of CYP2B6 516T allele and decreased by 31% with the presence of in Malawians [60]. However, another study reported that CYP2B6 516/983 genotypes had no effect on NVP concentrations [61]. Table 2 shows the wide variability in poor metabolizer frequencies in different African populations as reported in different studies. This observation suggests that results from one African population should not be extrapolated to other African populations, since Africans are very heterogenic with respect to drug disposition and pharmacogenetics. This is in line with recommended multinational clinical trial across sub-Saharan Africa in order to validate the EFV dose recommendation [53].

Table 2: Some reported frequencies of CYP2B6 polymorphism in different African populations.

Population
Frequency (%)
Number of subjects
Reference

African American
20
50
[48]

African American
36
85
[49]

African American
34
93
[152]

Tanzanians
36
95
[153]

Malawians
31 (15)
26
[60]

Ghanaians
46
42
[152]

Ghanaians
25
800
[78]

Ethiopians
45.5 (8.7)
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
41 (23)
80
[154]

Xhosa (South Africa)
17
109
[155]

CMA (South Africa)
9
67
[155]

Botswana
36.6
101
[156]

Zimbabwe
49
71
[76]

Uganda
35.6
121
[63]

Uganda
29
7 males
[13]

Mozambique
7
78
[14]

GT (TT) and loss of function CYP2B6 18.

In addition, polymorphisms in drug transporter genes can influence penetration of substrate drugs into the CNS. Illustratively, polymorphism in ABCB1 was shown to influence plasma concentrations of NFV [62] and of EFV [63, 64]. It was also reported that ABCB1 c.3435C>T contributed to NVP-induced hepatotoxicity risk [14]. On the contrary, CSF RAL concentrations did not differ by ABCB1 3435C>T genotype in healthy volunteers [65]. Significant variability in ABCB1 genes has been reported in black South Africans [66]. Hence, antiretroviral CNS penetration may vary in such population.

The evidences to date suggest that genetic profile could be put into consideration prior to initiation of a given antiretroviral agent, especially those for which their primary metabolism is by enzyme(s) with genetic polymorphism. The most relevant drug in this respect in sub-Saharan Africa is EFV. However, much work still needs to be done to translate the potential of EFV pharmacogenetics into clinical practice. Other common antiretroviral drugs used in sub-Saharan Africa which are also affected by pharmacogenetics have been highlighted in Table 3.

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

Antiretroviral drug
Enzyme involved
Effect

Efavirenz
CYP2B6
Increase in efavirenz concentrations and increased risk of discontinuation [50–56]

Nevirapine
CYP2B6
Increase in nevirapine plasma concentrations and increase hypersensitivity adverse effect associated with nevirapine [57–60]

Atazanavir
UGT1A1
Hyperbilirubinemia (indirect plasma bilirubin increase) and jaundice [157–160]

Tenofovir
ABCC2, ABCC4
Renal function decline [161–163]

Abacavir
HLA-B5701
Hypersensitivity associated with abacavir [164–167]

Pharmacogenetics and Efavirenz. Despite the efficacy of EFV in viral suppression, neuropsychiatric side effects are common [57, 67–72], and some patients on EFV-based therapy discontinue treatment as a result of neurotoxicity and other adverse effects [67, 73, 74]. Some of these cases are possibly associated with CYP2B6 polymorphisms that predispose to higher drug concentrations [75]. Accordingly, it has been suggested that a lower dose of EFV should be given to patients with poor metabolizer genotype compared to fast metabolizers with functional CYP2B6 alleles [53, 76]. Of note, patients carrying showed extremely high plasma EFV concentrations compared to those carrying either or , and patients also had higher plasma EFV concentrations than patients with genotype [77]. In another study was again associated with increased plasma EFV concentration [52]. These results showed that efavirenz plasma concentration may partly depend on CYP2B6 genotype.

CYP2A6 polymorphism (CYP2A6 248T>G) has also been reported to be associated with high EFV plasma level in a Ghanaian cohort study [78]. Cytochrome P450 2A6 has minor contribution to the metabolism of EFV [79]. However, this pathway may become increasingly important for individuals with poor metabolizer CYP2B6 genes. Dual CYP2B6 and CYP2A6 slow metabolism may lead to extremely high EFV exposure [79].

While it has been proposed that pharmacogenetic testing to identify patients carrying poor metabolizer genotypes may help optimize EFV dosing and minimize potential neurotoxicity from high EFV concentration, routine pharmacogenetic testing is not currently recommended. However, the finding that EFV 400 mg once daily dose is virologically noninferior and better tolerated than current 600 mg dosing [80] should motivate consideration of the lower dose for routine use.

5.3. Pharmacokinetics and Drug Specific Factors

5.3.1. Drug Characteristics

(a) Molecular Weight and Lipophilicity. The physicochemical properties of antiretroviral drugs influence their entry into the CNS. Many drugs cross cellular membranes by simple diffusion, in which drug molecules diffuse freely across membrane from the area where the concentration is high to the area of lower concentration. The rate of penetration of a drug into the brain by simple diffusion depends on its lipid solubility and size [81]. Antiretrovirals with very high molecular weight tend to have relatively poor CNS penetration. For example, enfuvirtide, a fusion inhibitor with molecular mass above 4,000 Da, penetrates poorly into the CNS [82]. On the other hand, abacavir and ZDV with molecular weights of 286.332 g/mol and 267.242 g/mol, respectively, are better positioned to penetrate the CNS.

The lipophilic nature of the BBB preferentially allows penetration of low molecular weight molecules with optimal lipophilicity. Oil/water partition coefficient is a useful tool in predicting the lipid solubility of neutral molecules. The higher the partition coefficient, the greater the lipophilicity and the better the brain penetration of the drug. That means drugs with lower partition coefficient will not easily penetrate the BBB by simple diffusion. However, the optimal partition coefficient 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 difficult for highly lipophilic drugs (lipid soluble) to diffuse from the lipid layer of the BBB into the brain extracellular fluid [26]. For acidic and basic drugs, the degree of ionization, which is pH dependent, determines lipid solubility. For example, weakly acidic drugs will exist in more unionized form at lower pH and the more a given drug exists in unionized form, the better the membrane permeability is. In contrast, weakly basic drugs will exist in more ionized form at lower pH. To illustrate the impact of this using Henderson-Hasselbalch equation, NVP which is a weakly basic drug with pKa of 2.8 [83] will exist largely in unionized form in plasma (pH of about 7.4) and this may be a contributing factor to good CNS penetration of NVP.

(b) Protein Binding. Drugs, especially lipophilic ones, bind to circulating proteins, which are usually albumin, acid glycoproteins, globulins, and lipoproteins. Different antiretroviral drugs vary in the extent to which they bind to protein. Only the unbound antiretroviral drugs are available to cross membrane. Nucleoside analogues like ZDV, 3TC, ddI, d4T, and abacavir have molecular weights less than 500 Da and low protein binding, allowing better CNS penetration. However, having a low molecular weight and low protein binding is not enough to ensure high CNS penetration. For example, tenofovir has low molecular weight (287.213 g/mol) and low protein binding and was reported to have low CNS penetration [84]. Contrary to most nucleoside analogues, PIs have high molecular weights (>500 Da) and protein binding (greater than 90%) with the exception of IDV [26, 85, 86] and are also substrates of efflux transporters. Molecular weight > 500 Da and protein binding > 90% generally impede membrane penetration of drugs [26], the characteristics that may contribute to the low brain penetration of PIs. Of note, many antiretrovirals exert substantial antiviral activity in the CNS even when the CSF concentration is low compared to plasma levels, provided the CSF levels exceed efficacy thresholds. This is the case with some boosted PIs such as DRV/r [87] and LPV/r [88]. Similarly, EFV is over 99% bound to protein [89] and has sufficient concentration in the CSF for viral suppression and induction of adverse events in that compartment. Generally, several factors combine to determine the CNS penetration and effects of different antiretroviral drugs. These factors have been summarized in Table 4.

Table 4: Summary of the factors affecting antiretroviral drug CNS penetrations.

General factors
Pharmacokinetics/pharmacogenetics
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 inhibition/induction
(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

5.3.2. Drug Interaction

HIV infection is associated with several opportunistic infections [90, 91] as well as other coinfections and comorbidities. As a result, many HIV patients receiving ART also use concomitant medications for other conditions, thus predisposing to drug-drug interactions. Pharmacokinetic interactions occur when the precipitant drug (the drug causing the interaction) alters the concentrations of the object drug (affected drug). Many drug interactions occur as a result of enzyme induction or inhibition, which may lead to decrease or increase in the plasma concentration (and presumably CNS levels) of the object drug. The interactions are sometimes more complex with some drugs simultaneously inhibiting and inducing multiple enzymatic pathways or with two drugs exhibiting bidirectional interactions. Some drugs can also increase the brain uptake of other drugs from the blood through enzyme inhibition. For example, ketoconazole increased CSF concentration of ritonavir by 178% [92].

Tuberculosis is the most common opportunistic infection during HIV infection [93]. Several drug-drug interactions between antiretrovirals and antituberculosis agents have been reported, with the most dramatic ones occurring with rifampin, a potent CYP 450 inducer. Illustratively, the plasma concentration of NVP was reduced by 37.3% [94] and the median AUC was reduced from 56.2 to 32.8 microg/mL per hour (−41.6%) when coadministered with rifampin [95]. This is mainly because rifampin induces the enzyme CYP2B6, which is responsible for the biotransformation of NVP. The interactions between rifampin and EFV are also substantial and may necessitate an increase in EFV dose when coadministered, while interactions between rifampin and boosted PIs are so consequential that coadministration is generally contraindicated [96–103]. Interactions may occur with other antituberculosis drugs; for example, isoniazid is a potent inhibitor of both CYP2C19 and CYP3A4 [104]. Therefore, concomitant administration of drugs that are substrate to both CYP2C19 and CYP3A4 like NFV, may lead to clinically important drug-drug interaction.

Importantly, several drug interactions that may facilitate CNS penetration of antiretrovirals occur via inhibition of the efflux transporters that are involved in limiting brain penetration of drugs. As such, CNS penetration of some antiretrovirals may be enhanced by coadministering suitable efflux inhibitor such as ritonavir [87], an inhibitor of efflux transporter and CYP 450 enzymes [105]. Nicotine significantly increased SQV blood-to-brain transfer in rats through inhibition of efflux transporters [106]. Most clinically important drug-drug interactions can be explained in part by modulation of important transporters’ activity.

Use of traditional medicine is a common practice, especially in Africa where patients often simultaneously seek treatment from both conventional and traditional health providers. The WHO estimated that up to 80% of the African population uses traditional medicine [107]. Some medicinal plants have been identified as having antiretroviral properties [91, 108, 109]. While the antiretroviral efficacy of such herbal products has not been demonstrated in well conducted randomized clinical trials, patients may resort to their use due to limited access to recommended antiretroviral drugs, intolerance to the conventional medicine, or cultural factors. Hence, herbal use is common among people on ART [110, 111]. Unfortunately, many HIV patients do not disclose this to their antiretroviral prescribers.

Many traditional medicines have complex metabolic pathways including CYP 450 enzymes [112] and may perpetrate clinically important drug interactions. For example, an in vitro study identified the potential for clinically significant drug interactions for both H. hemerocallidea and Sutherlandia (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 antiretrovirals, this may lead to increased plasma concentration and CNS penetration of the substrate antiretroviral drugs. This may particularly enhance CNS penetration of PIs because they are substrates of both CYP3A4 and P-gp. There is a paucity of data on the metabolism of medicinal plants in general. However, clinical studies and case reports involving many antiretroviral-herb pharmacokinetic interactions have been reviewed [114].

5.4. Other Factors

5.4.1. Chronic Inflammation

The presence of chronic inflammation in HIV patients may compromise the BBB and affect the pattern of antiretroviral penetration into the CNS. In one study, 24.6% of patients treated with ART and 38.6% of untreated patients were found to have BBB alteration [115]. The percentage difference between treated and untreated individuals was not significant, suggesting that BBB impairment persists in some HIV patients even during ART. Consistent with this, other studies found persistent BBB impairment in some patients despite CSF viral load reduction after antiretroviral therapy [116, 117].

Alteration in the cells (e.g., pericytes, astrocytes, and endothelial cells) that provide support to the BBB can also affect CNS penetration of antiretrovirals, and this is common in HIV infection. Brain pericytes, for example, are positioned within the neurovascular unit to support BBB maintenance [118]. Brain pericyte coverage was found to be diminished in HIV-infected patients and this was associated with pericyte dysfunction in chronic neuroinflammation. These changes were accompanied by shrinking of tight junction protein and presence of phosphorylated occludin, indicative of BBB compromise [119]. Using a set of adult viable pericyte deficient mouse mutants, it was shown that pericyte deficiency increases the permeability of the BBB to water and a range of low molecular mass and high-molecular-mass tracers [120]. These data suggest enhanced CNS penetration of antiretrovirals in HIV positive individuals with persistent CNS inflammation compared to HIV negative individuals. On the contrary, in vitro experiments showed that chronic inflammation can upregulate P-gp expression and activity and so tighten the BBB to CNS-acting drugs that are P-gp substrates [121]. Therefore, the presence of chronic inflammation with subsequent disruption of BBB and the supporting cells in the brain may be an important determinant of CNS penetration of antiretroviral drugs.

5.4.2. Local Cerebral Blood Flow

The brain receives 15–20% of the cardiac output, making it one of the most perfused organs in the body [122]. Factors that regulate the cerebral blood flow (CBF) include the net pressure gradient across the cerebral vascular beds (the most important of which is the mean arterial blood pressure) and the cerebral vascular resistance. These, together with the autoregulation process, allow the brain to control the cerebral blood perfusion [123]. The antiretroviral drug distribution to the brain follows the pattern of other drugs’ distribution to the brain [124] such that the initial rapid phase in drug distribution reflects the cardiac output and regional blood flow, and the brain, being one of the highly perfused organs in the body, receives most of the drug few minutes after absorption. Subsequent phases of drug distribution are affected by several variables, such as the local cerebral perfusion, lipid solubility of the drug, integrity of tight junctions in the brain, arrangement of the perivascular glial cells, drug binding to plasma protein, and the diffusion gradient [124].

A reduction in resting cerebral blood flow has been demonstrated in HIV patients and linked to development of HAND [125]. Additionally, anaemia is a common haematological disorder among patients with HIV/AIDS [126–128], and when severe, it may compromise cerebral perfusion. Premature atherosclerosis among patients with HIV/AIDS may also adversely affect cerebral perfusion and CNS penetration of antiretroviral drugs [129–132]. On the other hand, inflammation of the brain and the meninges that may complicate HIV infection increases the cerebral blood flow and, potentially, drug access to the CNS.

6. Conclusion

Antiretroviral drug concentrations in the CNS reflect interplay of several factors that promote drug entry and others that limit entry. The balance achieved varies between individuals and for each drug. Since manifestations of HAND remain apparent in many patients despite suppression of plasma viremia, optimizing CNS permeability of antiretrovirals should be an integral part of antiretroviral drug development. The ideal agents would have optimal CNS efficacy while being free of neurotoxicity. Research is needed to further understand the effect of antiretroviral CNS penetration on HAND and to discover appropriate interventions.

Disclosure

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Competing Interests

The authors declare that there is no conflict of interests regarding publication of this paper.

Acknowledgments

Research training for this publication was supported by the Fogarty International Center and National Institute of Mental Health of the National Institutes of Health under Award no. D43TW009608. It was also supported by the National Institutes of Health under the following award numbers: Dr. Gene D. Morse was supported by 1UL1TR001412 and D43TW010313; Dr. Qing Ma was supported by K08MH098794.

References

P. W. Wright, F. F. Vaida, R. J. Fernández et al., “Cerebral white matter integrity during primary HIV infection,” AIDS, vol. 29, no. 4, pp. 433–442, 2015.

G. Schnell, R. W. Price, R. Swanstrom, and S. Spudich, “Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection,” Journal of Virology, vol. 84, no. 5, pp. 2395–2407, 2010.

G. Tambussi, A. Gori, B. Capiluppi et al., “Neurological symptoms during primary Human Immunodeficiency Virus (HIV) infection correlate with high levels of HIV RNA in cerebrospinal fluid,” Clinical Infectious Diseases, vol. 30, no. 6, pp. 962–965, 2000.

L. E. Davis, B. L. Hjelle, V. E. Miller et al., “Early viral brain invasion in iatrogenic human immunodeficiency virus infection,” Neurology, vol. 42, no. 9, pp. 1736–1739, 1992.

A. D'Arminio Monforte, P. Cinque, A. Mocroft et al., “Changing incidence of central nervous system diseases in the EuroSIDA cohort,” Annals of Neurology, vol. 55, no. 3, pp. 320–328, 2004.

A. Mocroft, C. Katlama, A. M. Johnson et al., “AIDS across Europe, 1994–98: the EuroSIDA study,” The Lancet, vol. 356, no. 9226, pp. 291–296, 2000.

M. Egger, B. Hirschel, P. Francioli et al., “Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study,” The British Medical Journal, vol. 315, no. 7117, pp. 1194–1199, 1997.

A. Mocroft, B. Ledergerber, C. Katlama et al., “Decline in the AIDS and death rates in the EuroSIDA study: an observational study,” The Lancet, vol. 362, no. 9377, pp. 22–29, 2003.

L. Nabha, L. Duong, and J. Timpone, “HIV-associated neurocognitive disorders: perspective on management strategies,” Drugs, vol. 73, no. 9, pp. 893–905, 2013.

S. Letendre, J. Marquie-Beck, E. Capparelli et al., “Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system,” Archives of Neurology, vol. 65, no. 1, pp. 65–70, 2008.

World Health Organization, “Consolidated guidelines on general HIV care and the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach,” 2013, http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf

G. Meintjes, J. Black, F. Conradie et al., “Adult antiretroviral therapy guidelines 2014,” Southern African Journal of HIV Medicine, vol. 15, no. 4, pp. 121–143, 2014.

S. R. Penzak, G. Kabuye, P. Mugyenyi et al., “Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda,” HIV Medicine, vol. 8, no. 2, pp. 86–91, 2007.

C. Ciccacci, P. Borgiani, S. Ceffa et al., “Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique,” Pharmacogenomics, vol. 11, no. 1, pp. 23–31, 2010.

D. F. Carr, M. Chaponda, E. M. Cornejo Castro et al., “CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations,” The Journal of Antimicrobial Chemotherapy, vol. 69, no. 12, pp. 3329–3334, 2014.

V. Phan, S. Thai, K. Choun, L. Lynen, and J. van Griensven, “Incidence of treatment-limiting toxicity with stavudine-based antiretroviral therapy in Cambodia: a retrospective cohort study,” PLoS ONE, vol. 7, no. 1, Article ID e30647, 2012.

R. Subbaraman, S. K. Chaguturu, K. H. Mayer, T. P. Flanigan, and N. Kumarasamy, “Adverse effects of highly active antiretroviral therapy in developing countries,” Clinical Infectious Diseases, vol. 45, no. 8, pp. 1093–1101, 2007.

B. Simmons, A. Hill, N. Ford, K. Ruxrungtham, and J. Ananworanich, “Prices of second-line antiretroviral treatment for middle-income countries inside versus outside sub-Saharan Africa,” Journal of the International AIDS Society, vol. 17, no. 4, supplement 3, Article ID 19604, 2014.

S. Walmsley, A. Baumgarten, J. Berenguer et al., “Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the single randomized clinical trial,” Journal of Acquired Immune Deficiency Syndromes, vol. 70, no. 5, pp. 515–519, 2015.

S. L. Walmsley, A. Antela, N. Clumeck et al., “Dolutegravir plus Abacavir-Lamivudine for the treatment of HIV-1 infection,” The New England Journal of Medicine, vol. 369, no. 19, pp. 1807–1818, 2013.

B. Clotet, J. Feinberg, J. Van Lunzen et al., “Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study,” The Lancet, vol. 383, no. 9936, pp. 2222–2231, 2014.

S. L. Letendre, R. J. Ellis, B. M. Ances, and J. A. McCutchan, “Neurologic complications of HIV disease and their treatment,” Topics in HIV Medicine, vol. 18, no. 2, pp. 45–55, 2010.

K. Robertson, H. Jiang, J. Kumwenda et al., “Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: aids clinical trials group study A5199, the international neurological study,” Clinical Infectious Diseases, vol. 55, no. 6, pp. 868–876, 2012.

C. M. Marra, Y. Zhao, D. B. Clifford et al., “Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance,” AIDS, vol. 23, no. 11, pp. 1359–1366, 2009.

N. Ciccarelli, M. Fabbiani, M. Colafigli et al., “Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected patients with controlled plasma viraemia,” Antiviral Therapy, vol. 18, no. 2, pp. 153–160, 2013.

R. H. Enting, R. M. W. Hoetelmans, J. M. A. Lange, D. M. Burger, J. H. Beijnen, and P. Portegies, “Antiretroviral drugs and the central nervous system,” AIDS, vol. 12, no. 15, pp. 1941–1955, 1998.

P. Ballabh, A. Braun, and M. Nedergaard, “The blood-brain barrier: an overview: structure, regulation, and clinical implications,” Neurobiology of Disease, vol. 16, no. 1, pp. 1–13, 2004.

E. C. M. de Lange, “Potential role of ABC transporters as a detoxification system at the blood-CSF barrier,” Advanced Drug Delivery Reviews, vol. 56, no. 12, pp. 1793–1809, 2004.

W. M. Scheld, R. G. Dacey, H. R. Winn, J. E. Welsh, J. A. Jane, and M. A. Sande, “Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone,” The Journal of Clinical Investigation, vol. 66, no. 2, pp. 243–253, 1980.

R. E. Galinsky, B. L. Hoesterey, and B. D. Anderson, “Brain and cerebrospinal fluid uptake of zidovudine (AZT) in rats after intravenous injection,” Life Sciences, vol. 47, no. 9, pp. 781–788, 1990.

L. Bousquet, C. Roucairol, A. Hembury et al., “Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood-brain barrier,” AIDS Research and Human Retroviruses, vol. 24, no. 9, pp. 1147–1154, 2008.

M. Eilers, U. Roy, and D. Mondal, “MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells,” Experimental Biology and Medicine, vol. 233, no. 9, pp. 1149–1160, 2008.

O. Janneh, R. C. Hartkoorn, E. Jones et al., “Cultured CD4T cells and primary human lymphocytes express hOATPs: intracellular accumulation of saquinavir and lopinavir,” British Journal of Pharmacology, vol. 155, no. 6, pp. 875–883, 2008.

C. J. Bachmeier, T. J. Spitzenberger, W. F. Elmquist, and D. W. Miller, “Quantitative assessment of HIV-1 protease inhibitor interactions with drug efflux transporters in the blood-brain barrier,” Pharmaceutical Research, vol. 22, no. 8, pp. 1259–1268, 2005.

S. Park and P. J. Sinko, “P-glycoprotein and mutlidrug resistance-associated proteins limit the brain uptake of saquinavir in mice,” The Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 3, pp. 1249–1256, 2005.

J. W. Polli, J. L. Jarrett, S. D. Studenberg et al., “Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor,” Pharmaceutical Research, vol. 16, no. 8, pp. 1206–1212, 1999.

I. Carrier, M. Julien, and P. Gros, “Analysis of catalytic carboxylate mutants E552Q and E1197Q suggests asymmetric ATP hydrolysis by the two nucleotide-binding domains of P-glycoprotein,” Biochemistry, vol. 42, no. 44, pp. 12875–12885, 2003.

Y. Zhou, M. M. Gottesman, and I. Pastan, “Studies of human MDR1-MDR2 chimeras demonstrate the functional exchangeability of a major transmembrane segment of the multidrug transporter and phosphatidylcholine flippase,” Molecular and Cellular Biology, vol. 19, no. 2, pp. 1450–1459, 1999.

N. Giri, N. Shaik, G. Pan et al., “Investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) on pharmacokinetics and central nervous system penetration of abacavir and zidovudine in the mouse,” Drug Metabolism and Disposition, vol. 36, no. 8, pp. 1476–1484, 2008.

S.-F. Zhou, “Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition,” Xenobiotica, vol. 38, no. 7-8, pp. 802–832, 2008.

A. Kaddoumi, S.-U. Choi, L. Kinman et al., “Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid,” Drug Metabolism and Disposition, vol. 35, no. 9, pp. 1459–1462, 2007.

D. Langford, A. Grigorian, R. Hurford et al., “Altered P-glycoprotein expression in AIDS patients with HIV encephalitis,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 10, pp. 1038–1047, 2004.

O. Janneh, A. Owen, B. Chandler et al., “Modulation of the intracellular accumulation of saquinavir in peripheral blood mononuclear cells by inhibitors of MRP1, MRP2, P-gp and BCRP,” AIDS, vol. 19, no. 18, pp. 2097–2102, 2005.

E. Á. Barco and S. R. Nóvoa, “The pharmacogenetics of HIV treatment: a practical clinical approach,” Journal of Pharmacogenomics & Pharmacoproteomics, vol. 4, no. 1, article 116, 2013.

E. Ngaimisi, A. Habtewold, O. Minzi et al., “Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes: a parallel-group prospective cohort study in two sub-Saharan Africa populations,” PLoS ONE, vol. 8, no. 7, Article ID e67946, 2013.

M. Dhoro, S. Zvada, B. Ngara et al., “CYP2B6∗6, CYP2B6∗18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe,” BMC Pharmacology and Toxicology, vol. 16, no. 1, article 4, 2015.

E. L. Code, C. L. Crespi, B. W. Penman, F. J. Gonzalez, T. K. H. Chang, and D. J. Waxman, “Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation,” Drug Metabolism and Disposition, vol. 25, no. 8, pp. 985–993, 1997.

D. W. Haas, H. J. Ribaudo, R. B. Kim et al., “Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study,” AIDS, vol. 18, no. 18, pp. 2391–2400, 2004.

J. Li, V. Menard, R. L. Benish et al., “Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: implications for HIV/AIDS treatment,” Pharmacogenomics, vol. 13, no. 5, pp. 555–570, 2012.

M. Rotger, H. Tegude, S. Colombo et al., “Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals,” Clinical Pharmacology and Therapeutics, vol. 81, no. 4, pp. 557–566, 2007.

M. Swart, M. Skelton, Y. Ren, P. Smith, S. Takuva, and C. Dandara, “High predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIV/AIDS patients,” Pharmacogenetics and Genomics, vol. 23, no. 8, pp. 415–427, 2013.

J. Wang, A. Sönnerborg, A. Rane et al., “Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz,” Pharmacogenetics and Genomics, vol. 16, no. 3, pp. 191–198, 2006.

J. K. Mukonzo, J. S. Owen, J. Ogwal-Okeng et al., “Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes,” PLoS ONE, vol. 9, no. 1, Article ID e86919, 2014.

P. Z. Sinxadi, P. D. Leger, H. M. McIlleron et al., “Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa,” British Journal of Clinical Pharmacology, vol. 80, no. 1, pp. 146–156, 2015.

M. Swart, J. Evans, M. Skelton et al., “An expanded analysis of pharmacogenetics determinants of efavirenz response that includes 3′-UTR single nucleotide polymorphisms among black South African HIV/AIDS patients,” Frontiers in Genetics, vol. 6, p. 356, 2015.

A. Winston and R. Puls, “Cerebrospinal-fluid exposure of efavirenz and its major metabolites when dosed at 400 and 600 mg once daily; a randomized controlled trial,” Journal of the International AIDS Society, vol. 17, no. 4, supplement 3, Article ID 19541, 2014.

M. Rotger, S. Colombo, H. Furrer et al., “Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients,” Pharmacogenetics and Genomics, vol. 15, no. 1, pp. 1–5, 2005.

T. W. Mahungu, C. J. Smith, F. Turner et al., “Cytochrome P450 2B6 516G→T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population,” HIV Medicine, vol. 10, no. 5, pp. 310–317, 2009.

L. Dickinson, M. Chaponda, D. F. Carr et al., “Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypersensitive and tolerant HIV-infected patients from Malawi,” Antimicrobial Agents and Chemotherapy, vol. 58, no. 2, pp. 706–712, 2014.

K. C. Brown, M. C. Hosseinipour, J. M. Hoskins et al., “Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians,” Pharmacogenomics, vol. 13, no. 1, pp. 113–121, 2012.

D. W. Haas, T. Gebretsadik, G. Mayo et al., “Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African Americans,” The Journal of Infectious Diseases, vol. 199, no. 6, pp. 872–880, 2009.

J. Fellay, C. Marzolini, E. R. Meaden et al., “Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study,” The Lancet, vol. 359, no. 9300, pp. 30–36, 2002.

J. K. Mukonzo, D. Röshammar, P. Waako et al., “A novel polymorphism in ABCB1 gene, CYP2B6∗6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans,” British Journal of Clinical Pharmacology, vol. 68, no. 5, pp. 690–699, 2009.

M. Swart, Y. Ren, P. Smith, and C. Dandara, “ABCB1 4036A>G and 1236C>T polymorphisms affect plasma efavirenz levels in South African HIV/AIDS patients,” Frontiers in Genetics, vol. 3, article 236, 2012.

D. H. Johnson, D. Sutherland, E. P. Acosta, H. Erdem, D. Richardson, and D. W. Haas, “Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study,” PLoS ONE, vol. 8, no. 12, Article ID e82672, 2013.

C. Dandara, Z. Lombard, I. Du Plooy, T. McLellan, S. A. Norris, and M. Ramsay, “Genetic variants in CYP ( and ), VKORC1 and ABCB1 genes in a black South African population: a window into diversity,” Pharmacogenomics, vol. 12, no. 12, pp. 1663–1670, 2011.

I. O. Abah, M. Akanbi, M. E. Abah et al., “Incidence and predictors of adverse drug events in an African cohort of HIV-infected adults treated with efavirenz,” Germs, vol. 5, no. 3, pp. 83–91, 2015.

Q. Ma, F. Vaida, J. Wong et al., “Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients,” Journal of Neurovirology, vol. 22, no. 2, pp. 170–178, 2016.

J. K. Mukonzo, A. Okwera, N. Nakasujja et al., “Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study,” BMC Infectious Diseases, vol. 13, no. 1, article 261, 2013.

T. Hawkins, C. Geist, B. Young et al., “Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients,” HIV Clinical Trials, vol. 6, no. 4, pp. 187–196, 2005.

C. R. Fumaz, A. Tuldrà, M. J. Ferrer et al., “Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens,” Journal of Acquired Immune Deficiency Syndromes, vol. 29, no. 3, pp. 244–253, 2002.

P. Lochet, H. Peyrière, A. Lotthé, J. M. Mauboussin, B. Delmas, and J. Reynes, “Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz,” HIV Medicine, vol. 4, no. 1, pp. 62–66, 2003.

B. Spire, P. Carrieri, M.-A. Garzot, M. L'Henaff, and Y. Obadia, “Factors associated with Efavirenz discontinuation in a large community-based sample of patients,” AIDS Care—Psychological and Socio-Medical Aspects of AIDS/HIV, vol. 16, no. 5, pp. 558–564, 2004.

O. O. Agbaji, P. A. Agaba, P. N. Ekeh et al., “Efavirenz-induced gynaecomastia in HIV-infected Nigerian men: a report of six cases,” Journal of Medicine and Medical Sciences, vol. 2, no. 11, pp. 1221–1224, 2011.

C. Wyen, H. Hendra, M. Vogel et al., “Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients,” The Journal of Antimicrobial Chemotherapy, vol. 61, no. 4, pp. 914–918, 2008.

C. Nyakutira, D. Röshammar, E. Chigutsa et al., “High prevalence of the CYP2B6 516G→T(∗6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe,” European Journal of Clinical Pharmacology, vol. 64, no. 4, pp. 357–365, 2008.

M. Maimbo, K. Kiyotani, T. Mushiroda, C. Masimirembwa, and Y. Nakamura, “CYP2B6 genotype is a strong predictor of systemic exposure to efavirenz in HIV-infected Zimbabweans,” European Journal of Clinical Pharmacology, vol. 68, no. 3, pp. 267–271, 2012.

F. S. Sarfo, Y. Zhang, D. Egan et al., “Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of ghanaian HIV-infected patients,” The Journal of Antimicrobial Chemotherapy, vol. 69, no. 2, Article ID dkt372, pp. 491–499, 2014.

J. Di Iulio, A. Fayet, M. Arab-Alameddine et al., “In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function,” Pharmacogenetics and Genomics, vol. 19, no. 4, pp. 300–309, 2009.

L. Dickinson, J. Amin, L. Else et al., “Pharmacokinetic and pharmacodynamic comparison of once-daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-infected patients: results of the ENCORE1 study,” Clinical Pharmacology and Therapeutics, vol. 98, no. 4, pp. 406–416, 2015.

R. Nau, F. Sörgel, and H. W. Prange, “Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges,” Journal of the Neurological Sciences, vol. 122, no. 1, pp. 61–65, 1994.

S. F. L. Van Lelyveld, M. Nijhuis, F. Baatz et al., “Therapy failure following selection of enfuvirtide-resistant HIV-1 in cerebrospinal fluid,” Clinical Infectious Diseases, vol. 50, no. 3, pp. 387–390, 2010.

S. H. Cheeseman, S. E. Hattox, M. M. McLaughlin et al., “Pharmacokinetics of nevirapine: initial single-rising-dose study in humans,” Antimicrobial Agents and Chemotherapy, vol. 37, no. 2, pp. 178–182, 1993.

B. M. Best, S. L. Letendre, P. Koopmans et al., “Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, Tenofovir,” Journal of Acquired Immune Deficiency Syndromes, vol. 59, no. 4, pp. 376–381, 2012.

P. L. Anderson, R. C. Brundage, L. Bushman, T. N. Kakuda, R. P. Remmel, and C. V. Fletcher, “Indinavir plasma protein binding in HIV-1-infected adults,” Aids, vol. 14, no. 15, pp. 2293–2297, 2000.

M. Boffito, D. J. Back, T. F. Blaschke et al., “Protein binding in antiretroviral therapies,” AIDS Research and Human Retroviruses, vol. 19, no. 9, pp. 825–835, 2003.

A. Yilmaz, A. Izadkhashti, R. W. Price et al., “Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals,” AIDS Research and Human Retroviruses, vol. 25, no. 4, pp. 457–461, 2009.

E. V. Capparelli, D. Holland, C. Okamoto et al., “Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV,” Aids, vol. 19, no. 9, pp. 949–952, 2005.

L. B. Avery, N. Sacktor, J. C. McArthur, and C. W. Hendrix, “Protein-free efavirenz concentrations in cerebrospinal fluid and blood plasma are equivalent: applying the law of mass action to predict protein-free drug concentration,” Antimicrobial Agents and Chemotherapy, vol. 57, no. 3, pp. 1409–1414, 2013.

W. Manosuthi, A. Chaovavanich, S. Tansuphaswadikul et al., “Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting,” The Journal of Infection, vol. 55, no. 5, pp. 464–469, 2007.

D. P. Kisangau, H. V. M. Lyaruu, K. M. Hosea, and C. C. Joseph, “Use of traditional medicines in the management of HIV/AIDS opportunistic infections in Tanzania: a case in the Bukoba rural district,” Journal of Ethnobiology and Ethnomedicine, vol. 3, article 29, 2007.

Y. Khaliq, K. Gallicano, S. Venance, S. Kravcik, and D. W. Cameron, “Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus,” Clinical Pharmacology and Therapeutics, vol. 68, no. 6, pp. 637–646, 2000.

C. K. Kwan and J. D. Ernst, “HIV and tuberculosis: a deadly human syndemic,” Clinical Microbiology Reviews, vol. 24, no. 2, pp. 351–376, 2011.

R. S. Autar, F. W. Wit, J. Sankote et al., “Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis,” Antiviral Therapy, vol. 10, no. 8, pp. 937–943, 2005.

E. Ribera, L. Pou, R. M. Lopez et al., “Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis,” Journal of Acquired Immune Deficiency Syndromes, vol. 28, no. 5, pp. 450–453, 2001.

J. Mallolas, M. Sarasa, M. Nomdedeu et al., “Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients,” HIV Medicine, vol. 8, no. 2, pp. 131–134, 2007.

E. Ribera, C. Azuaje, R. M. Lopez et al., “Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis,” Journal of Antimicrobial Chemotherapy, vol. 59, no. 4, pp. 690–697, 2007.

R. F. A. L'Homme, H. M. J. Nij, L. Gras et al., “Clinical experience with the combined use of lopinavir/ritonavir and rifampicin,” Aids, vol. 23, no. 7, pp. 863–865, 2009.

G. Maartens, E. Decloedt, and K. Cohen, “Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries,” Antiviral Therapy, vol. 14, no. 8, pp. 1039–1043, 2009.

H. McIlleron, Y. Ren, J. Nuttall et al., “Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis,” Antiviral Therapy, vol. 16, no. 3, pp. 417–421, 2011.

D. Elsherbiny, Y. Ren, H. McIlleron, G. Maartens, and U. S. H. Simonsson, “Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children,” European Journal of Clinical Pharmacology, vol. 66, no. 10, pp. 1017–1023, 2010.

R. A. Murphy, V. C. Marconi, R. T. Gandhi, D. R. Kuritzkes, and H. Sunpath, “Coadministration of lopinavir/ritonavir and rifampicin in HIV and tuberculosis co-infected adults in South Africa,” PLoS ONE, vol. 7, no. 9, Article ID e44793, 2012.

U. S. Justesen, Å. B. Andersen, N. A. Klitgaard, K. Brøsen, J. Gerstoft, and C. Pedersen, “Pharmacokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir in HIV-infected patients,” Clinical Infectious Diseases, vol. 38, no. 3, pp. 426–429, 2004.

Z. Desta, N. V. Soukhova, and D. A. Flockhart, “Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A,” Antimicrobial Agents and Chemotherapy, vol. 45, no. 2, pp. 382–392, 2001.

P. Vernazza, S. Daneel, V. Schiffer et al., “The role of compartment penetration in PI-Monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial,” AIDS, vol. 21, no. 10, pp. 1309–1315, 2007.

V. K. Manda, R. K. Mittapalli, K. A. Bohn, C. E. Adkins, and P. R. Lockman, “Nicotine and cotinine increases the brain penetration of saquinavir in rat,” Journal of Neurochemistry, vol. 115, no. 6, pp. 1495–1507, 2010.

World Health Organization, WHO Traditional Medicine Strategy 2002–2005, 2002, http://www.wpro.who.int/health_technology/book_who_traditional_medicine_strategy_2002_2005.pdf.

G. A. Koffuor, R. Dickson, S. Y. Gbedema, E. Ekuadzi, G. Dapaah, and L. F. Otoo, “The immunostimulatory and antimicrobial property of two herbal decoctions used in the management of HIV/AIDS in Ghana,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 11, no. 3, pp. 166–172, 2014.

K. C. Chinsembu and M. Hedimbi, “Ethnomedicinal plants and other natural products with anti-HIV active compounds and their putative modes of action,” International Journal for Biotechnology and Molecular Biology Research, vol. 1, no. 6, pp. 74–91, 2010.

D. Langlois-Klassen, W. Kipp, G. S. Jhangri, and T. Rubaale, “Use of traditional herbal medicine by AIDS patients in Kabarole District, western Uganda,” American Journal of Tropical Medicine and Hygiene, vol. 77, no. 4, pp. 757–763, 2007.

R. M. Gyasi, E. Tagoe-Darko, and C. M. Mensah, “Use of traditional medicine by HIV/AIDS patients in Kumasi Metropolis, Ghana: a cross-sectional survey,” American International Journal of Contemporary Research, vol. 3, no. 4, pp. 117–129, 2013.

N. E. Thomford, K. Dzobo, D. Chopera et al., “Pharmacogenomics implications of using herbal medicinal plants on African populations in health transition,” Pharmaceuticals, vol. 8, no. 3, pp. 637–663, 2015.

E. Mills, B. C. Foster, R. Van Heeswijk et al., “Impact of African herbal medicines on antiretroviral metabolism,” AIDS, vol. 19, no. 1, pp. 95–97, 2005.

A. C. Müller and I. Kanfer, “Potential pharmacokinetic interactions between antiretrovirals and medicinal plants used as complementary and African traditional medicines,” Biopharmaceutics and Drug Disposition, vol. 32, no. 8, pp. 458–470, 2011.

A. Calcagno, M. C. Alberione, A. Romito et al., “Prevalence and predictors of blood-brain barrier damage in the HAART era,” Journal of NeuroVirology, vol. 20, no. 5, pp. 521–525, 2014.

S. Abdulle, L. Hagberg, and M. Gisslén, “Effects of antiretroviral treatment on blood-brain barrier integrity and intrathecal immunoglobulin production in neuroasymptomatic HIV-1-infected patients,” HIV Medicine, vol. 6, no. 3, pp. 164–169, 2005.

A. Calcagno, C. Atzori, A. Romito et al., “Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients,” Journal of NeuroVirology, vol. 22, no. 1, pp. 88–92, 2016.

S. Nakagawa, V. Castro, and M. Toborek, “Infection of human pericytes by HIV-1 disrupts the integrity of the blood-brain barrier,” Journal of Cellular and Molecular Medicine, vol. 16, no. 12, pp. 2950–2957, 2012.

Y. Persidsky, J. Hill, M. Zhang et al., “Dysfunction of brain pericytes in chronic neuroinflammation,” Journal of Cerebral Blood Flow and Metabolism, vol. 36, no. 4, pp. 794–807, 2016.

A. Armulik, G. Genové, M. Mäe et al., “Pericytes regulate the blood-brain barrier,” Nature, vol. 468, no. 7323, pp. 557–561, 2010.

B. Bauer, A. M. S. Hartz, and D. S. Miller, “Tumor necrosis factor α and endothelin-1 increase p-glycoprotein expression and transport activity at the blood-brain barrier,” Molecular Pharmacology, vol. 71, no. 3, pp. 667–675, 2007.

M. J. Cipolla, “Integrated systems physiology: from molecule to function,” in The Cerebral Circulation, Morgan & Claypool Life Sciences, San Rafael, Calif, USA, 2009.

L. Sokoloff, “The action of drugs on the cerebral circulation,” Pharmacological Reviews, vol. 11, no. 1, pp. 1–85, 1959.

L. L. Brunton, B. Chabner, and B. C. Knollmann, Goodman & Gilman's the Pharmacological Basis of Therapeutics, McGraw-Hill Medical, New York, NY, USA, 2011.

B. M. Ances, D. Sisti, F. Vaida et al., “Resting cerebral blood flow: a potential biomarker of the effects of HIV in the brain,” Neurology, vol. 73, no. 9, pp. 702–708, 2009.

M. J. Van Der Werf, B. H. B. Van Benthem, and E. J. C. Van Ameijden, “Prevalence, incidence and risk factors of anaemia in HIV-positive and HIV-negative drug users,” Addiction, vol. 95, no. 3, pp. 383–392, 2000.

J. O. Mugisha, L. A. Shafer, L. V. Der Paal et al., “Anaemia in a rural Ugandan HIV cohort: prevalence at enrolment, incidence, diagnosis and associated factors,” Tropical Medicine and International Health, vol. 13, no. 6, pp. 788–794, 2008.

R. Omoregie, E. U. Omokaro, O. Palmer et al., “Prevalence of anaemia among HIV-infected patients in Benin City, Nigeria,” Tanzania Journal of Health Research, vol. 11, no. 1, pp. 1–4, 2009.

F. Boccara, “Cardiovascular complications and atherosclerotic manifestations in the HIV-infected population: type, incidence and associated risk factors,” AIDS, vol. 22, supplement 3, pp. S19–S26, 2008.

M. Acevedo, D. L. Sprecher, L. Calabrese et al., “Pilot study of coronary atherosclerotic risk and plaque burden in HIV patients: ‘a call for cardiovascular prevention’,” Atherosclerosis, vol. 163, no. 2, pp. 349–354, 2002.

M. Depairon, S. Chessex, P. Sudre et al., “Premature atherosclerosis in HIV-infected individuals—focus on protease inhibitor therapy,” AIDS, vol. 15, no. 3, pp. 329–334, 2001.

A. Hakeem, S. Bhatti, and M. Cilingiroglu, “The spectrum of atherosclerotic coronary artery disease in HIV patients,” Current Atherosclerosis Reports, vol. 12, no. 2, pp. 119–124, 2010.

D. M. Burger, C. L. Kraaijeveld, P. L. Meenhorstt et al., “Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV,” AIDS, vol. 7, no. 12, pp. 1581–1587, 1993.

A. Antinori, C. F. Perno, M. L. Giancola 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,” Clinical Infectious Diseases, vol. 41, no. 12, pp. 1787–1793, 2005.

D. M. Burger, C. L. Kraayeveld, P. L. Meenhorst et al., “Study on didanosine concentrations in cerebrospinal fluid—implications for the treatment and prevention of AIDS dementia complex,” Pharmacy World & Science, vol. 17, no. 6, pp. 218–221, 1995.

E. V. Capparelli, S. L. Letendre, R. J. Ellis, P. Patel, D. Holland, and J. A. McCutchan, “Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid,” Antimicrobial Agents and Chemotherapy, vol. 49, no. 6, pp. 2504–2506, 2005.

J. A. McDowell, G. E. Chittick, J. R. Ravitch, R. E. Polk, T. M. Kerkering, and D. S. Stein, “Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study,” Antimicrobial Agents and Chemotherapy, vol. 43, no. 12, pp. 2855–2861, 1999.

B. M. Best, P. P. Koopmans, S. L. Letendre et al., “Efavirenz concentrations in CSF exceed IC50 for wild-type HIV,” Journal of Antimicrobial Chemotherapy, vol. 66, no. 2, pp. 354–357, 2011.

A. Winston, J. Amin, A. Clarke 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,” Clinical Infectious Diseases, vol. 60, no. 7, pp. 1026–1032, 2015.

A. Calcagno, M. Simiele, M. C. Alberione et al., “Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control,” Clinical Infectious Diseases, vol. 60, no. 2, pp. 311–317, 2015.

X.-J. Zhou, D. V. Havlir, D. D. Richman et al., “Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients,” AIDS, vol. 14, no. 18, pp. 2869–2876, 2000.

S. L. Letendre, E. V. Capparelli, R. J. Ellis, J. A. McCutchan, and The HIV Neurobehavioral Research Center Group, “Indinavir population pharmacokinetics in plasma and cerebrospinal fluid,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 8, pp. 2173–2175, 2000.

L. Garvey, M. Nelson, N. Latch et al., “CNS effects of a CCR5 inhibitor in HIV-infected subjects: a pharmacokinetic and cerebral metabolite study,” Journal of Antimicrobial Chemotherapy, vol. 67, no. 1, pp. 206–212, 2012.

F. Aweeka, A. Jayewardene, S. Staprans et al., “Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1- infected patients with and without AIDS dementia complex,” Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, vol. 20, no. 1, pp. 39–43, 1999.

C. A. Delille, S. T. Pruett, V. C. Marconi et al., “Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations,” Journal of Clinical Pharmacology, vol. 54, no. 9, pp. 1063–1071, 2014.

B. M. Best, S. L. Letendre, E. Brigid et al., “Low atazanavir concentrations in cerebrospinal fluid,” AIDS, vol. 23, no. 1, pp. 83–87, 2009.

A. Yilmaz, M. Gisslén, S. Spudich et al., “Raltegravir cerebrospinal fluid concentrations in HIV-1 infection,” PLoS ONE, vol. 4, no. 9, article e6877, 2009.

A. Calcagno, J. Cusato, M. Simiele et al., “High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis,” The Journal of Antimicrobial Chemotherapy, vol. 69, no. 1, pp. 241–245, 2014.

S. L. Letendre, A. M. Mills, K. T. Tashima et al., “ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects,” Clinical Infectious Diseases, vol. 59, no. 7, pp. 1032–1037, 2014.

A. Yilmaz, V. Watson, L. Else, and M. Gisslèn, “Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients,” AIDS, vol. 23, no. 18, pp. 2537–2540, 2009.

J. M. Tiraboschi, J. Niubo, J. Curto, and D. Podzamczer, “Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients,” Journal of Acquired Immune Deficiency Syndromes, vol. 55, no. 5, pp. 606–609, 2010.

R. K. Mehlotra, M. N. Ziats, M. J. Bockarie, and P. A. Zimmerman, “Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea,” European Journal of Clinical Pharmacology, vol. 62, no. 4, pp. 267–275, 2006.

K. J. Marwa, T. Schmidt, M. Sjögren, O. M. S. Minzi, E. Kamugisha, and G. Swedberg, “Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations,” Malaria Journal, vol. 13, article 420, 2014.

V. Gounden, C. van Niekerk, T. Snyman, and J. A. George, “Presence of the CYP2B6 516G>T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients,” AIDS Research and Therapy, vol. 7, article 32, 2010.

O. Ikediobi, B. Aouizerat, Y. Xiao, M. Gandhi, S. Gebhardt, and L. Warnich, “Analysis of pharmacogenetic traits in two distinct South African populations,” Human Genomics, vol. 5, no. 4, pp. 265–282, 2011.

R. Gross, R. Aplenc, T. TenHave et al., “Slow efavirenz metabolism genotype is common in Botswana,” Journal of Acquired Immune Deficiency Syndromes, vol. 49, no. 3, pp. 336–337, 2008.

R. Gammal, M. Court, C. Haidar et al., “Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing,” Clinical Pharmacology & Therapeutics, vol. 99, no. 4, pp. 363–369, 2016.

D. H. Johnson, C. Venuto, M. D. Ritchie et al., “Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202,” Pharmacogenetics and Genomics, vol. 24, no. 4, pp. 195–203, 2014.

S. Vardhanabhuti, H. J. Ribaudo, R. J. Landovitz et al., “Screening for UGT1A1 genotype in study A5257 would have markedly reduced premature discontinuation of atazanavir for hyperbilirubinemia,” Oxford Journals Medicine & Health Open Forum Infectious Diseases, vol. 2, no. 3, 2015.

J. Sugatani, K. Yamakawa, K. Yoshinari et al., “Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia,” Biochemical and Biophysical Research Communications, vol. 292, no. 2, pp. 492–497, 2002.

H. Izzedine, J.-S. Hulot, E. Villard et al., “Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy,” Journal of Infectious Diseases, vol. 194, no. 11, pp. 1481–1491, 2006.

S. Rodríguez-Nóvoa, P. Labarga, V. Soriano et al., “Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: A Harmacogenetic Study,” Clinical Infectious Diseases, vol. 48, no. 11, pp. e108–e116, 2009.

S. Likanonsakul, B. Suntisuklappon, R. Nitiyanontakij et al., “A single-nucleotide polymorphism in ABCC4 is associated with tenofovir-related beta2-microglobulinuria in Thai patients with HIV-1 infection,” PLoS ONE, vol. 11, no. 1, Article ID e0147724, 2016.

N. Berka, J. M. Gill, A. Liacini, T. O'Bryan, and F. M. Khan, “Human leukocyte antigen (HLA) and pharmacogenetics: Screening for HLA-B*57:01 among human immunodeficiency virus-positive patients from southern Alberta,” Human Immunology, vol. 73, no. 2, pp. 164–167, 2012.

A. R. Hughes, M. Mosteller, A. T. Bansal et al., “Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations,” Pharmacogenomics, vol. 5, no. 2, pp. 203–211, 2004.

S. Rodríguez-Nóvoa, P. García-Gascó, F. Blanco et al., “Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards,” AIDS Research and Human Retroviruses, vol. 23, no. 11, pp. 1374–1376, 2007.

S. Mallal, E. Phillips, G. Carosi et al., “HLA-B∗5701 screening for hypersensitivity to abacavir,” The New England Journal of Medicine, vol. 358, no. 6, pp. 568–579, 2008.