Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

Aklillu, Eleni; Zumla, Alimuddin; Habtewold, Abiy; Amogne, Wondwossen; Makonnen, Eyasu; Yimer, Getnet; Burhenne, Jürgen; Diczfalusy, Ulf

doi:10.1111/bph.15309

Cited by 11 publications

(9 citation statements)

References 59 publications

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“…We also showed that cases had significantly elevated HOMA-IR, FSG, FSI, and TG levels than controls, indicating the presence of GMDs. The overall observed genotype and allele frequency proportions were similar to the findings of previous studies from Ethiopia [ 29 , 30 ].…”

Section: Discussionsupporting

confidence: 89%

CYP3A and CYP2B6 Genotype Predicts Glucose Metabolism Disorder among HIV Patients on Long-Term Efavirenz-Based ART: A Case-Control Study

Tadesse

Mlugu

Shibeshi

et al. 2022

JPM

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Long-term antiretroviral treatment (cART) increases the risk of glucose metabolism disorders (GMDs). Genetic variation in drug-metabolizing enzymes and transporters may influence susceptibility to cART-associated GMDs. We conducted a case-control study to investigate the association of pharmacogenetic variations with cART-induced GMDs. A total of 240 HIV patients on long-term efavirenz-based cART (75 GMD cases and 165 controls without GMDs) were genotyped for CYP3A4*1B, CYP3A5 (*3,*6), CYP2B6*6, UGT2B7*2, ABCB1 (c.3435C>T, c.4036A>G), and SLCO1B1 (*1b, *5). GMD cases were defined as the presence of impaired fasting glucose, insulin resistance, or diabetes mellitus (DM). Case-control genotype/haplotype association and logistic regression analysis were performed by adjusting for age, sex, and BMI. The major CYP3A haplotype were CYP3A5*3 (53.8%), CYP3A4*1B (17.3%), combinations of CYP3A4*1B, and CYP3A5*6 (10.9%), and CYP3A wild type (7%). CYP3A5*6 allele (p = 0.005) and CYP3A5*6 genotype (p = 0.01) were significantly associated with GMD cases. Multivariate analysis indicated CYP3A haplotype as a significant predictor of GMD (p = 0.02) and IFG (p = 0.004). CYP2B6*6 significantly predicted DM (p = 0.03). CYP3A haplotype and CYP2B6*6 genotype are independent significant predictors of GMD and DM, respectively, among HIV patients on long-term EFV-based cART.

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Section: Discussionsupporting

confidence: 89%

CYP3A and CYP2B6 Genotype Predicts Glucose Metabolism Disorder among HIV Patients on Long-Term Efavirenz-Based ART: A Case-Control Study

Tadesse

Mlugu

Shibeshi

et al. 2022

JPM

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“…Studies in primary human hepatocytes have indicated that efavirenz autoinduction is non-linear, and timeand concentration-dependent [39,40]. Using an endogenous marker, we previously monitored the time course and extents of CYP3A and CYP2B6 induction among adult HIV patients from Tanzania [41][42][43], Uganda [16], and Ethiopia [31,33,35]. Results from adult HIV-infected patients indicate that efavirenz autoinduction is long-term and significantly reduces its plasma concentration over time, particularly among the CYP2B6*1/*1 genotype.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was extracted from whole blood samples using a QIAamp DNA Blood Midi Kit (Spin Protocol) (Qiagen GmbH, Hilden, Germany). Genotyping for common functional variant alleles in five genes relevant for efavirenz disposition was conducted by real-time PCR using Taqman ® assay reagents for allelic discrimination (Applied Biosystems Genotyping Assay) as described previously [19,35]. Common functional variant alleles were selected for genotyping based on the reported impact on enzyme activity and relevance for the black-African population.…”

Section: Genotyping For Cyp2b6 Cyp3a5 Slco1b1 Abcb1 and Ugt2b7mentioning

confidence: 99%

Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study

Chala

Tadesse

Chaka

et al. 2021

JPM

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(1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3–16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.

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“…However, when normalized to cortisol, the variation is no longer significant within the day (Lee, 1995). Similarly, plasma 4β-hydroxycholesterol, another CYP3A metabolite, is ideally normalized to cholesterol in order to provide more robust data (Mao et al, 2017;Aklillu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Reveals Five Endogenous Biomarkers in Human Urine and Plasma to Predict Cyp2d6 Activity

Magliocco

Matthey

Bararpour

et al. 2021

Preprint

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Background and Purpose: Individualized assessment of the activity of cytochrome P450 2D6 (CYP2D6), a highly variable drug-metabolizing enzyme, is performed through phenotyping during which a probe drug is administered to measure the enzyme’s activity. In order to avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-invasive tools for real-time phenotyping of CYP2D6 could significantly contribute to the expansion of precision medicine in clinical practice. This study focuses on the identification of endogenous markers of the CYP2D6 enzyme in human biofluids using a liquid chromatography (LC)-high-resolution mass spectrometry (HRMS)-based metabolomics approach. Experimental Approach: Data from a control session were compared to data from an inhibition session. Before the latter, healthy volunteers (extensive and ultrarapid metabolizers) received a daily dose of paroxetine 20 mg over seven days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. Key Results: In CYP2D6 extensive and ultrarapid metabolizers (n = 37), mean relative intensities of five features were significantly reduced during the inhibition session compared to the control session (fold changes ≤ 0.67, FDR-adjusted P < 0.0001). Furthermore, mean relative intensities of these candidates were significantly higher in the CYP2D6 extensive-ultrarapid metabolizer group (n = 37) compared to the poor metabolizer group (n = 6) (fold changes ≤ 0.67, P < 0.0001). Conclusion and Implications: The applied untargeted metabolomics strategy was able to identify five CYP2D6 endogenous metabolites, a promising discovery for non-invasive phenotyping and personalised medicine.

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Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

Cited by 11 publications

References 59 publications

CYP3A and CYP2B6 Genotype Predicts Glucose Metabolism Disorder among HIV Patients on Long-Term Efavirenz-Based ART: A Case-Control Study

CYP3A and CYP2B6 Genotype Predicts Glucose Metabolism Disorder among HIV Patients on Long-Term Efavirenz-Based ART: A Case-Control Study

Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study

Metabolomics Reveals Five Endogenous Biomarkers in Human Urine and Plasma to Predict Cyp2d6 Activity

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