Large variability in plasma efavirenz concentration in Papua New Guinea HIV/AIDS patients associated with high frequency of CYP2B6 516T allele

Andriguetti, Natália Bordin; Schalkwyk, Helena Katherina Van; Barratt, Daniel T.; Tucci, Joseph; Pumuye, Paul P.; Somogyi, Andrew A.

doi:10.1111/cts.13120

Cited by 8 publications

(11 citation statements)

References 47 publications

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“…Early discontinuation of EFV in rs28399499 CC homozygotes 29 might account for the absence of this genotype among the participants of our study, as well as other studies in patients under EFV‐containing regimens for several months 30,31 . The CYP2B6 SNPs had no effect on [8‐OH‐EFV], in contrast to recent results from Papua New Guinea HIV/AIDS patients, showing higher [8‐OH‐EFV] in rs3745274 heterozygotes, compared to both wildtype and variant homzygotes 6 . Population diversity, including diferences in frequency of the rs3745274, may account for these discrepancy results.…”

Section: Discussioncontrasting

confidence: 51%

“…Compared to dolutegravir, a major drawback of EFV exposure is the common occurrence of central nervous system side effects, such as dizziness, headache, depression, nightmares, insomnia and suicidal ideation, which may lead to poor adherence and/or discontinuation of treatment. The severity of these adverse effects subsides progressively upon continuous drug exposure 4–6 . Indeed, the HIV‐infected persons recruited for the present study declared to be tolerant and adherent to the prescribed EFV‐containing ART regimens.…”

Section: Introductionmentioning

confidence: 84%

“…The severity of these adverse effects subsides progressively upon continuous drug exposure. [4][5][6] Indeed, the HIV-infected persons recruited for the present study declared to be tolerant and adherent to the prescribed EFV-containing ART regimens. This study investigates the impact of selected CYP2B6 and ABCB1 single nucleotide polymorphisms (SNPs) on the plasma concentrations of EFV (denoted [EFV]), its major metabolite, 8-hydroxy-efavirenz ([8-OH-EFV]) and their ratio ([8-OH-EFV]/[EFV]) in HIV-positive adult Brazilians, receiving EFV-containing ART regimens for >6 months.…”

Section: Introductionmentioning

confidence: 94%

“…Our results extend to an admixed Brazilian cohort the evidence for major impact of CYP2B6 polymorphism on EFV pharmacokinetics, which has been consistently reported for several distinct populations worldwide. 6,7,10,[26][27][28] The 2 CYP2B6 SNPs selected for our study, namely rs3745274 (516G > T) and rs28399499 (983 T > C), encode CYP2B6 isoforms with reduced and null activity, respectively. Accordingly, carriers of the minor allele at each locus showed increased…”

Section: Allele Genotype and Diplotype Frequency Distributionmentioning

confidence: 99%

“…30,31 The CYP2B6 SNPs had no effect on [8-OH-EFV], in contrast to recent results from Papua New Guinea HIV/AIDS patients, showing higher [8-OH-EFV] in rs3745274 heterozygotes, compared to both wildtype and variant homzygotes. 6 Population diversity, including diferences in frequency of the rs3745274, may account for these discrepancy results.…”

Section: Allele Genotype and Diplotype Frequency Distributionmentioning

confidence: 99%

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Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

Ximenez

Elias

Nardotto

et al. 2022

Brit J Clinical Pharma

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Aims To investigate the influence of pharmacogenetic polymorphisms on efavirenz (EFV) exposure and metabolism in HIV‐infected Brazilians under treatment with EFV‐containing antiretroviral (ART) regimens. Methods HIV‐positive adults (n = 82) on stable ART regimens containing 600 mg EFV once daily for at least 6 months were recruited at 2 university hospitals. Blood samples collected at mid‐dose interval were used to quantify the plasma concentrations of EFV (denoted [EFV]), its major metabolite 8‐OH‐EFV ([8‐OH‐EFV]) and [8‐OH‐EFV]/[EFV] metabolic ratio, and to genotype single nucleotide polymorphisms in CYP2B6 (rs3745274, c.516G > T; rs28399499, c.983 T > C) and ABCB1 (rs3842, c.4036G > A). CYP2B6 metabolic phenotypes were inferred from the CYP2B6 diplotypes. Linear regression modelling was applied to identify sociodemographic, clinical and pharmacogenetic predictors of [EFV] and [8‐OH‐EFV]/[EFV] metabolic ratio. Results Wide (50‐fold) interindividual variation in [EFV], [8‐OH‐EFV] and [8‐OH‐EFV]/[EFV] was observed; 69.5% of participants had [EFV] within the nominal therapeutic range (1000–4000 ng/mL), while 19.5 and 11.0% had [EFV] below and above this range, respectively. Multiple regression modelling retained only CYP2B6 metabolic phenotypes or the combined rs3745274 and rs28399499 genotypes, as significant predictors of [EFV] and [8‐OH‐EFV]/[EFV]. Conclusion EFV exposure and disposition varied widely among HIV‐infected Brazilians under stable treatment with EFV‐containing ART regimens. About 1/10 of the participants had [EFV] exceeding nominal supratherapeutic concentration (4000 ng/mL), but reported tolerance to the ARV regimens, while 1/5 of participants had nominal subtherapeutic [EFV] (<1000 ng/mL) but adequate virological response. Genotype for the 2 CYP2B6 single nucleotide polymorphisms studied explained 48% of variation in [EFV] and 35% of variation in [8‐OH‐EFV]/[EFV].

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Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 94%

Section: Allele Genotype and Diplotype Frequency Distributionmentioning

confidence: 99%

Section: Allele Genotype and Diplotype Frequency Distributionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

Ximenez

Elias

Nardotto

et al. 2022

Brit J Clinical Pharma

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Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia

Chala

Kitabi

Ahmed

et al. 2023

CPT Pharmacom & Syst Pharma

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Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter-and intra-individual pharmacokinetic (PK) variability are not well-characterized in children. We investigated the effects of genetic and non-genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population-PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3-16 years (n = 100), were enrolled in Ethiopia and received EFV-based combination ART. EFV concentrations after the first dose and at steady-state collected over a span of 1 year were modeled using population-based methods. A onecompartment model with first-order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12-h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 μg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes.

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Uncoupling of Cytochrome P450 2B6 and stimulation of reactive oxygen species production in pharmacogenomic alleles affected by interethnic variability

Yamoune,

Müller,

Langmia

et al. 2024

Biochimica et Biophysica Acta (BBA) - General Subjects

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Large variability in plasma efavirenz concentration in Papua New Guinea HIV/AIDS patients associated with high frequency of CYP2B6 516T allele

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 8 publications

References 47 publications

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia

Uncoupling of Cytochrome P450 2B6 and stimulation of reactive oxygen species production in pharmacogenomic alleles affected by interethnic variability

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