16 research outputs found
Pharmacogenomics and pharmacokinetics of dolutegravir and tenofovir in Southern Africans living with HIV
No full textBackground The World Health Organization (WHO) recommends dolutegravir in combination with a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people living with HIV (PLWHIV) initiating antiretroviral therapy (ART). Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are both prodrugs of tenofovir. However, plasma tenofovir exposure is higher when given as TDF, and TAF yields lower plasma but higher intracellular tenofovir concentrations. Although generally well tolerated, excessive weight gain has been associated with dolutegravir and (TAF) in PLWHIV initiating ART or those switching from efavirenz- or TDF-containing ART. Interindividual variability in dolutegravir and tenofovir pharmacokinetics or the interindividual differences in host response may, in part, be explained by host genetics. We characterized associations between genetic polymorphisms and dolutegravir exposure, tenofovir clearance and magnitude of weight gain in Southern Africans initiating ART. Methods We collected clinical and laboratory data in adults randomized to initiate TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262). We measured dolutegravir and tenofovir concentrations and developed population pharmacokinetic models for dolutegravir and tenofovir using non-linear mixed-effects modelling. Genome-wide genotyping followed by imputation was performed. Linear regression models examined associations between genetic polymorphisms and unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), unexplained variability in tenofovir clearance, and percentage weight gain from baseline to week 48. Results Considering genetic associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 x 10-4 ), which was also associated with log10 bilirubin (P = 8.6 x 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 x 10-8 ). In the population pharmacokinetic model, compared to C/C, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively. There were no significant genome-wide associations. Considering genetic associations with unexplained variability in tenofovir clearance, we found no significant associations with tenofovir clearance for either TAF or TDF among 5 polymorphisms previously associated with tenofovir pharmacokinetics (lowest P-value > 0.3 for each drug). Among 11 polymorphisms selected based on both prior strong association with any drug phenotype in PharmGKB and any genome-wide association with any trait in the GWAS catalog, IFNL4 rs12979860 T>C was significantly associated with increased tenofovir clearance (TAF: P = 0.003; TDF: P = 0.003). In genome-wide analyses, the lowest P-values for tenofovir clearance in the TAF and TDF arms were with LINC01684 rs9305223 (P = 3.0 x 10-8 ) and intergenic rs142693425 (P = 1.4 x 10-8 ), respectively. Four additional polymorphisms were genome-wide significant. In genome-wide multivariate linear regression analyses adjusting for baseline age, sex, concomitant NRTI, and population stratification, there were no significant associations between 59 polymorphisms relevant to dolutegravir and tenofovir disposition and the percentage weight gain. We found a genome-wide significant association between TMEM163 rs7590091 and percentage weight gain from baseline to week 48 (P = 3.7 x 10-8 ). Conclusion Among Southern African people living with HIV randomized to TAF or TDF, we identified several potential genetic associations with dolutegravir exposure, tenofovir clearance and weight gain. The novel associations between dolutegravir AUCVAR and rs28899168, tenofovir clearance and IFNL4 rs12979860, and weight gain and TMEM163 rs7590091 require independent replication. These findings enhance our understanding of dolutegravir and tenofovir pharmacogenetics among Southern Africans living with HIV
Associations of genetic variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SLCO1B1 with statin-associated muscle symptom (SAMS) in South African populations
No full textBackground: Dyslipidaemia, particularly elevated plasma LDL-cholesterol levels, is a key modifiable risk factor for cardiovascular disease (CVD). Statins recognized as LDL-c lowering drugs, have traditionally been the cornerstone in dyslipidaemia treatment and are reported to reduce CVD mortality by 20-30%. However, over the years, the efficacy of statins has been compromised by the emergence of adverse effects, especially statinassociated muscle symptoms (SAMS). Strong evidence links SAMS susceptibility to pharmacogenetic variability of ABCB1, ABCG2, CYP3A4, CYP3A5, and SLCO1B1, particularly in Asian and European populations. However, limited knowledge exists regarding the impact of pharmacogenetics on statin tolerance among South African patients. This study aimed to examine the relationships between genetic variants in the five pharmacogenes mentioned and SAMS in a cohort of dyslipidaemia patients from South Africa undergoing statin treatment. Methods: Employing a retrospective matched case-control (1:2) study design, we assessed a cohort of 332 dyslipidaemia patients from Groote Schuur Hospital, South Africa. Most patients were of Mixed Ancestry. A lipid expert determined SAMS status through adjudication. Genetic variants in five key genes—ABCB1 (rs1045642), ABCG2 (rs2231142, rs2199939), CYP3A4 (rs2740574), CYP3A5 (rs776746, rs10264272, and rs41303343), and SLCO1B1 (rs4149056, rs2306283, and rs4363657)—were chosen for genotyping, using PCR-RFLP, TaqMan genotyping assays, and validated through Sanger sequencing. Statistical analysis, encompassing Chi-Square, Mann-Whitney U (Wilcoxon rank sum), and logistic regression tests, was conducted using STATA v15 and R, while linkage disequilibrium and haplotype analysis were performed using SHEsis online software. Non-genetic and genetic variables were correlated with SAMS status. Results: The median age of patients was 58 years, with 50% being female. Univariate analysis revealed significant associations of SAMS with BMI (p=0.026), waist circumference (p=0.03), and triglyceride levels (p=0.01). The ABCB1 rs1045642 C/T genotype (56.36%, OR=1.86, 95%CI=1.10-3.14, p=0.02) was more prevalent among patients with SAMS compared to those without. Conversely, ABCG2 rs2231142 A/A (6.31%, OR=0.13, 95%CI=0-0.81, p=0.02) and SLCO1B1 rs4149056 C/C (6.76%, OR=0.14, 95%CI=0-0.84, p= 0.03) genotypes were significantly less prevalent in cases than controls. The ABCG2 rs2231142A variant allele occurred more frequently in controls (p=0.03). Multivariate analysis, incorporating genetic and clinical variables through stepwise logistic regression, identified ABCB1 rs1045642 C/T as the sole significant predictor for SAMS in this cohort. Moreover, the SLCO1B1 rs4149056T>C and SLCO1B1 rs4363657T>C polymorphisms exhibited strong linkage disequilibrium—further analysis identified six inferred haplotypes for SLCO1B1. Haplotype 6 (G-T-T) was significantly more prevalent in cases (38.9%, OR=1.44, 95%CI=1.03-2.03, p=0.03) than in controls. Conversely, haplotype 2 (G-C-C) exhibited a significantly higher occurrence in controls (6.8%, OR=0.23, 95%CI=0.08-0.69, p=0.04) than in cases. Conclusion: This study underscores the role of genetic variations in ABCB1, ABCG2, and SLCO1B1 in predisposing South African Mixed Ancestry patients to SAMS. Specifically, ABCB1 rs1045642 C/T genotype emerged as a significant predictor for SAMS in this cohort, indicating its potential role in statin toxicity. Significant differences were observed in the distribution of variant alleles for most SNPs in our cohort compared to global populations, suggesting that universal guidelines may not be universally applicable. This observation was further supported by disparities in inferred haplotypes, underscoring the necessity for comprehensive pharmacogenetic studies within the South African population. These findings expand our knowledge of SAMS in a population with limited pharmacogenomic data, potentially informing personalized statin therapy. Key Words: dyslipidaemia, SAMS, pharmacogenetics, ABCB1, ABCG2, SLCO1B1, South Africa
Efavirenz pharmacogenetics and metabolic toxicity in black South Africans
No full textBackground: Efavirenz is associated with hepatotoxicity, dyslipidaemia and dysglycaemia. We aimed to determine if CYP2B6 composite metaboliser genotypes influence lipids, glucose and ALT concentrations. Methods: Data and DNA from South African antiretroviral therapy (ART)-naïve participants initiating efavirenz with emtricitabine plus tenofovir disoproxil fumarate (TDF) were used to characterise associations between CYP2B6 metaboliser genotypes and the percentage difference in metabolic parameters from baseline to week 48 using univariate and multivariate linear regression models. Results: A total of 171 participants were successfully genotyped. Median baseline age was 32 years, CD4 count was 292 cells/mm3 and log10 viral load was 4.42 copies/ml. Univariate analyses showed significant associations between CYP2B6 slow metaboliser genotype and total cholesterol (β = 13.78, p = 0.003), LDL cholesterol (β = 15.89, p = 0.008) and HDL cholesterol (β = 24.78, p = 0.002). These associations remained significant in multivariate analyses adjusting for age, sex, weight, baseline CD4 cell count and viral load [total cholesterol (β = 14.93, p< 0.001), LDL cholesterol (β = 15.57, p = 0.014), and HDL cholesterol (β = 24.22, p< 0.001)]. No associations were found between CYP2B6 metaboliser genotype and triglycerides, glucose or ALT. Conclusion: Among Black South African participants on efavirenz-based ART, CYP2B6 slow metaboliser genotype was associated with high cholesterol concentrations. In an African population with high prevalence of CYP2B6 slow metabolisers, close monitoring of lipids is needed
Pharmacogenetics of Tenofovir (Alafenamide or Disoproxil Fumarate Prodrug) Renal Toxicity in HIV positive Black Southern Africans
No full textBackground: Among individuals treated for HIV-1 infection, renal toxicity is more likely with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide (TAF). Limited previous studies suggest potential genetic associations with TDF-associated renal toxicity. We hypothesized that polymorphisms in genes of potential relevance to tenofovir, TDF and TAF disposition are associated with renal toxicity in people living with HIV in Southern Africa. Material and Methods: Adult participants randomized to initiate TAF or TDF (each given with emtricitabine) in the dolutegravir arms of the ADVANCE trial had the option to co-enrol in a pharmacogenetic sub-study. We assessed changes from week 4 (to minimize impact of early dolutegravir-induced increases in creatinine) to week 48 in estimated glomerular filtration rate (eGFRCKD-EPI), and log-transformed changes from baseline to week 48 in urine retinol binding protein and urine β2-microglobulin, each adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr, respectively). Genotyping was done using Illumina MEGAEX, followed by imputation with TOPMed. Genetic associations with each renal outcome (eGFR, uRBP/Cr and uB2M/Cr) were assessed using multivariable linear regression models adjusting for age, sex, treatment group, and screening body mass index, CD4 count, and log10 HIV-1 RNA. Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal tubular dysfunction, and all polymorphisms (+/- 50 kB) in selected genes of interest: ABCB1, ABCC2, ABCC4, ABCC10, ABCG2, AK2, AK3, CES1, CYP3A4, NME1, SLC22A2, SLC22A6, SLC22A8 and SLC22A11. We also explored associations genome-wide. Results: In ADVANCE, 336 participants randomized to either TAF or TDF consented to genetic testing. All were Black-African, 63% were female, median age was 32 years, CD4 count 292 cells/μL, and log10 HIV-1 RNA 4.4 copies/mL. Among the 14 polymorphisms of primary interest, the lowest Pvalues for change in eGFR, uRBP/Cr and uB2M/Cr were ABCC4 rs899494 (P = 0.021), ABCC10 rs2125739 (P = 0.07), and ABCC4 rs1059751 (P = 0.0087), respectively. Among genes of interest, the lowest P-values for change in eGFR, uRBP/Cr and uB2M/Cr were ABCC4 rs4148481 (P = 1.5x10-4 ), rs691857 (P = 3.2x10-4 ), and PKD2 rs72659631 (P = 8.6x10-4 ), respectively. In genome-wide analyses, the lowest P-values for change in eGFR, uRBP/Cr, and uB2M/Cr were COL27A1 rs1687402 (P = 3.2x10-9 ), CDH4 rs66494466 (P = 3.4 x 10-8 ), and ITGA4 rs3770126 (P = 4.5 x10-7 ), respectively. Conclusions: Among Southern African participants in a randomized trial of dolutegravir plus either TAF/emtricitabine or TDF/emtricitabine, two polymorphisms previously associated with TDF renal toxicity, ABCC4 rs899494 and ABCC4 rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, but did not withstand correction for multiple testing (nor did associations in genes of interest). A polymorphism in COL27A1, which encodes collagen type XXVII alpha 1 chain, was genome-wide associated with change in eGFR. These findings enhance our understanding of the impact of human genetics on tenofovir-associated renal toxicity
Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV
No full textBackground: Dolutegravir, a component of the preferred first-line antiretroviral therapy (ART) regimen has been associated with increased weight gain, which is markedly higher when combined with tenofovir alafenamide (TAF), the newer tenofovir prodrug instead of tenofovir disoproxil fumarate (TDF). South Africa has a high prevalence of obesity, especially among women. Understanding dolutegravir exposure in the patients with obesity is important for dose optimisation. Aims: We compared the pharmacokinetic parameters of dolutegravir in Southern African adults living with HIV with and without obesity. Methods: Blood samples were collected at various time points over a 24 hour-period for dolutegravir assays. Non-compartmental analysis was conducted and geometric mean ratios (GMRs), with 90% confidence intervals (CIs), were generated to compare dolutegravir pharmacokinetic parameters between the groups. Regression analyses to assess predictors of dolutegravir exposure were done. Results: 40 participants were enrolled, 26 were women and 10 had obesity. Dolutegravir area under the concentration-time curve to 24-hours (AUC0-24hr) and the maximum concentrations (Cmax) were marginally lower in participants with obesity: GMR 0.91 (90% CI, 0.71-1.16) and GMR 0.86 (90% CI, 0.68-1.07), respectively. In a multivariate linear regression analysis adjusting for age, sex, body mass index (BMI), creatinine clearance and randomisation arm (TAF or TDF), a unit increase in BMI was associated with 1.2% lower dolutegravir AUC0-24h, (P = 0.035). Conclusion: Dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant. Our findings suggest that there is no need to dose adjust dolutegravir in people with obesity
Treatment of HIV associated neurocognitive disorders
No full textBackground
Human immunodeficiency virus (HIV) invades the central nervous system (CNS) as early as 8 days after HIV infection, causing a wide spectrum of neuropathological changes including HIV associated neurocognitive disorders (HAND). HAND is a spectrum of cognitive impairment, which in its most severe form cause marked interference with day-to-day functioning (HIV-associated dementia). Antiretroviral therapy (ART) has substantially reduced the incidence of HIV-associated dementia, but has not had an impact on the overall prevalence of HAND. The prevalence of milder stages of HAND in ART experienced individuals varies from 15 - 50%. Transporters expressed in the blood brain barrier and blood cerebrospinal fluid (CSF) barrier affect influx and efflux of drugs including antiretrovirals. Antiretrovirals that have better penetration into the CNS may result in improved cognitive function in patients with HAND, however this has not yet been conclusively shown. On the other hand, prolonged CNS exposure to high antiretroviral concentrations has been proposed as a cause of secondary decline in cognitive function as several antiretrovirals are neurotoxic. Efavirenz in particular, but also tenofovir and emtricitabine, have been shown to have direct neurotoxicity in preclinical models. Polymorphisms in genes that encode these enzymes or transporters may therefore affect antiretroviral CSF concentrations. Africans are the most genetically diverse population worldwide and South Africa has the world’s largest ART programme, with most of patients currently receiving efavirenz-tenofovir-emtricitabine. The impact of pharmacogenetic polymorphisms on the pharmacokinetics of efavirenz-tenofovir-emtricitabine CNS penetration are lacking. A number of adjunctive pharmacotherapies for HAND have been studied, including lithium. Multiple mechanisms have been suggested for the potential beneficial cognitive effect of lithium, including the inhibition of glycogen synthase kinase-3- beta, which mediates inflammation signaling pathways and neuronal apoptosis. Lithium has been used in mood disorders and other neuropsychiatric conditions for more than 40 years. In addition, lithium is a low-cost drug and widely available in public service settings in low and middle-income countries. There is a need for controlled data to evaluate the efficacy of lithium as adjunctive therapy for HAND. Finally, it is unknown whether lithium causes additive nephrotoxicity in combination with tenofovir.
Methods
We conducted a 24-week randomised placebo-controlled trial of lithium as adjunctive pharmacotherapy in participants with moderate to severe HAND established on ART for at least 6 months, with suppressed viral loads. We randomised 66 participants to lithium (n=32) or placebo (n= 34). Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, while our secondary endpoint was the change in proton magnetic resonance spectroscopy (1 H-MRS) brain metabolite concentrations. We collected paired plasma-CSF samples in 47 adult participants with and without HAND treated with efavirenz-tenofovir-emtricitabine. We considered 2049 single-nucleotide polymorphisms (SNPs), including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. We investigated genetic polymorphisms associated with CSF exposure of efavirenz and its metabolites, tenofovir and emtricitabine. The secondary objective was to explore the pharmacokineticpharmacodynamic relationships with neurocognitive performance. Finally, we investigated the change in estimated glomerular filtration rate (eGFR) in participants who received concomitant tenofovir and lithium.
Results
The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); p = 0.716. The improvement remained similar when analysed according to age, severity of impairment, CD4+ count, time on ART and ART regimen. Standard 1 H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. There was no statistically significant difference in the reduction in eGFR or in potassium between the two arms during the 24 weeks. A model that included the composite CYP2B6 15582/516/983 genotype in univariate analyses best predicted the log10-transformed concentrations of plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 8-hydroxyefavirenz-to-efavirenz ratio and CSF efavirenz. Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742, ABCB1 rs115780656 and CYP2A6 -48A→C. The CYP2A6 -48A→C polymorphism was independently associated with higher CSF 8-hydroxy-efavirenz-to-efavirenz ratio. The CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenzto-efavirenz ratio in univariate on multivariate analyses adjusting for CYP2B6 516G→T and 983T→C. No polymorphisms were associated with CSF-to-plasma ratios of all 3 drugs, plasma or CSF 8-hydroxy-efavirenz, tenofovir or emtricitabine concentrations, or neurocognitive performance.
Conclusion
Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment. We found that 24-week treatment of HIV-infected patients with lithium and tenofovir did not result in increased nephrotoxicity. We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz-to-efavirenz ratio, plasma 8-hydroxy-efavirenz-to-efavirenz ratio, CSF 8-hydroxy-efavirenz-to-efavirenz ratio and CSF efavirenz
Objectively measured medication adherence using assays for carvedilol and enalaprilat in patients with heart failure in Mozambique and Nigeria
No full textBackground: Poor medication adherence leads to poor health outcomes and increased healthcare costs among patients with heart failure (HF). This study aimed to objectively assess medication adherence by measuring carvedilol and enalaprilat plasma concentrations among patients with HF. Methods: The present sub-study of the Safety, Tolerability, and Efficacy of Rapid Optimization, helped by NT-proBNP testing, of Heart Failure therapies (STRONG-HF) study involved adult patients with acute HF admitted in two Mozambican and two Nigerian hospitals who were not optimally treated with oral enalapril and carvedilol. Patients in the high-intensity arm of the STRONG-HF study, and those not meeting the biomarker criteria for persistent congestion, were included in the “frequent visit” (FV) arm. In the FV arm, blood for bioanalysis of plasma enalaprilat or/and carvedilol was drawn at the 2,6,12th week post-discharge. Patients in the usual care arm of STRONG-HF were included in the “standard visit” (SV) arm, which followed the usual local practice with blood sampling in week 12. Results: The study involved 113 (79 FV and 34 SV) participants with a mean age of 48.6 years and a mean left ventricular (LV) ejection fraction of 33.1%. Theenalaprilat below the lower level of quantification (LLOQ) was documented in 7.7%, 11.9%, and 15.6% of participants in FV during the 2,6 and 12th weeks. Carvedilol concentration below LLOQ was documented in 37%, 30%, and 44.4% of participants in the FV arm during the 2,6 and 12th weeks, respectively. For the SV arm, enalaprilat and carvedilol concentrations below LLOQ in the twelfth week were documented in 37.3% and 42.9% of patients, respectively. Conclusion: Up to a third of patients using enalapril and carvedilol did not take any medication during the 12 weeks of follow-up. Non adherence was more common in patients who had less follow up, emphasizing the importance of close follow up to adherence. No adherence was also more common in medications know to have more side effects such as carvedilol
Genetic Variation in ABCB1, ADRB1, CYP3A4, CYP3A5, NEDD4L and NR3C2 Confers Differential Susceptibility to Resistant Hypertension among South Africans
No full textResistant hypertension (RHTN) prevalence ranges from 4 to 19% in Africa. There is a paucity of data on the role of genetic variation on RHTN among Africans. We set out to investigate the role of polymorphisms in ABCB1, ADRB1, CYP3A4, CYP3A5, NEDD4L, and NR3C2, on RHTN susceptibility among South Africans. Using a retrospective matched case–control study, 190 RHTN patients (cases: blood pressure (BP) ≥ 140/90 mmHg on ≥3 anti-hypertensives or BP < 140/90 mmHg on >3 anti-hypertensives) and 189 non-RHTN patients (controls: <3 anti-hypertensives, BP < 140/90 or ≥140/90 mmHg), 12 single nucleotide polymorphisms were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), quantitative PCR and Sanger sequencing. Genetic association analyses were conducted using the additive model and multivariable logistic regression. Homozygosity for CYP3A5 rs776746C/C genotype (p = 0.02; OR: 0.44; CI: 0.22–0.89) was associated with reduced risk for RHTN. Homozygous ADRB1 rs1801252G/G (p = 0.02; OR: 3.30; CI: 1.17–10.03) and NEDD4L rs4149601A/A genotypes (p = 0.001; OR: 3.82; CI: 1.67–9.07) were associated with increased risk for RHTN. Carriers of the of ADRB1 rs1801252—rs1801253 G–C haplotype had 2.83-fold odds of presenting with RHTN (p = 0.04; OR: 2.83; CI: 1.05–8.20). These variants that are associated with RHTN may have clinical utility in the selection of antihypertensive drugs in our population
Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV
No full textPharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites.
No full textBackground:There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. Objectives:We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. Methods:We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. Results:We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (β = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (β = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (β = -0.31, P = 1.8 × 10-04) and CSF efavirenz (β = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (β = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (β = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (β = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (β = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. Conclusions:We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio
