Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study
(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 >...
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MDPI AG
2021-12-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/11/12/1303 |
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| author | Adugna Chala Birkneh Tilahun Tadesse Tolossa Eticha Chaka Jackson Mukonzo Eliford Ngaimisi Kitabi Sintayehu Tadesse Anton Pohanka Eyasu Makonnen Eleni Aklillu |
| author_facet | Adugna Chala Birkneh Tilahun Tadesse Tolossa Eticha Chaka Jackson Mukonzo Eliford Ngaimisi Kitabi Sintayehu Tadesse Anton Pohanka Eyasu Makonnen Eleni Aklillu |
| author_sort | Adugna Chala |
| collection | DOAJ |
| description | (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 (<i>n</i> = 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 <i>CYP2B6, CYP3A5, UGT2B7, ABCB1,</i> and <i>SLCO1B1</i> 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, <i>CYP2B6*6</i> and <i>ABCB1c.3435 C</i> > <i>T</i> 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 <i>SLCO1B, CYP3A5, UGT2B7,</i> and <i>ABCB</i>1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and <i>CYP2B6*6</i> and <i>ABCB1c.3435 C > T</i> 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. |
| first_indexed | 2024-03-10T03:46:03Z |
| format | Article |
| id | doaj.art-941466009f9f4471bf52d6d27f331791 |
| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-10T03:46:03Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Personalized Medicine |
| spelling | doaj.art-941466009f9f4471bf52d6d27f3317912023-11-23T09:07:40ZengMDPI AGJournal of Personalized Medicine2075-44262021-12-011112130310.3390/jpm11121303Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort StudyAdugna Chala0Birkneh Tilahun Tadesse1Tolossa Eticha Chaka2Jackson Mukonzo3Eliford Ngaimisi Kitabi4Sintayehu Tadesse5Anton Pohanka6Eyasu Makonnen7Eleni Aklillu8Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, EthiopiaDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, SwedenDepartment of Pediatrics and Child Health, Adama Hospital Medical College, Adama P.O. Box 84, EthiopiaDepartment of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala P.O. Box 7072, UgandaDivision of Pharmacometrics, Food and Drugs Administration, Office of Clinical Pharmacology, Silver Spring, MD 20993, USADepartment of Pediatrics, College of Medicine and Health Sciences, Hawassa University, Hawassa 1560, EthiopiaDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, SwedenDepartment of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, EthiopiaDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden(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 (<i>n</i> = 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 <i>CYP2B6, CYP3A5, UGT2B7, ABCB1,</i> and <i>SLCO1B1</i> 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, <i>CYP2B6*6</i> and <i>ABCB1c.3435 C</i> > <i>T</i> 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 <i>SLCO1B, CYP3A5, UGT2B7,</i> and <i>ABCB</i>1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and <i>CYP2B6*6</i> and <i>ABCB1c.3435 C > T</i> 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.https://www.mdpi.com/2075-4426/11/12/1303efavirenzCYP2B6autoinductionpharmacogeneticschildren |
| spellingShingle | Adugna Chala Birkneh Tilahun Tadesse Tolossa Eticha Chaka Jackson Mukonzo Eliford Ngaimisi Kitabi Sintayehu Tadesse Anton Pohanka Eyasu Makonnen Eleni Aklillu Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study Journal of Personalized Medicine efavirenz CYP2B6 autoinduction pharmacogenetics children |
| title | Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study |
| title_full | Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study |
| title_fullStr | Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study |
| title_full_unstemmed | Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study |
| title_short | Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study |
| title_sort | predictors of efavirenz plasma exposure auto induction profile and effect of pharmacogenetic variations among hiv infected children in ethiopia a prospective cohort study |
| topic | efavirenz CYP2B6 autoinduction pharmacogenetics children |
| url | https://www.mdpi.com/2075-4426/11/12/1303 |
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