Browsing by Author "Neary, Megan"

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    The Effect of Gene Variants on Levonorgestrel Pharmacokinetics when Combined with Antiretroviral Therapy containing Efavirenz or Nevirapine
    (Clinical Pharmacology & Therapeutics, 2017) Neary, Megan; Lamorde, Mohammed; Olagunju, Adeniyi; Darin, Kristin M.; Merry, Concepta; Byakika-Kibwika, Pauline; Back, David J.; Siccardi, Marco; Owen, Andrew; Scarsi, Kimberly K.
    Reduced levonorgestrel concentrations from the levonorgestrel contraceptive implant was previously seen when given concomitantly with efavirenz. We sought to assess whether single nucleotide polymorphisms (SNPs) in genes involved in efavirenz and nevirapine metabolism were linked to these changes in levonorgestrel concentration. SNPs in CYP2B6, CYP2A6, NR1I2 and NR1I3 were analysed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz- or nevirapine-based ART, in comparison to ART-naïve women using multivariate linear regression. Efavirenz group: CYP2B6 516G>T was associated with lower levonorgestrel log10 Cmax and log10 AUC. CYP2B6 15582C>T was associated with lower log10 AUC. Nevirapine group: CYP2B6 516G>T was associated with higher log10 Cmax and lower log10 Cmin. Pharmacogenetic variations influenced subdermal levonorgestrel pharmacokinetics in HIV-positive women, indicating that the magnitude of the interaction with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is influenced by host genetics.
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    Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics of Efavirenz 400 mg Once Daily During Pregnancy and Post-Partum
    (Clinical Infectious Diseases, 2018) Lamorde, Mohammed; Wang, Xinzhu; Neary, Megan; Bisdomini, Elisa; Nakalema, Shadia; Byakika-Kibwika, Pauline; Mukonzo, Jackson K.; Khan, Waheed; Owen, Andrew; McClure, Myra; Boffito, Marta
    A clinical trial showed that efavirenz 400 mg once daily (EFV400) is as effective as the standard adult dose. World Health Organization recommends EFV400 as an alternative first-line agent, but data are lacking in the third trimester of pregnancy (TT). We investigated the pharmacokinetics, efficacy, and CYP2B6 pharmacogenetics in HIV-infected women (WLWH) on EFV400 during TT and post-partum (PP). Methods. An open-label 2-center study (United Kingdom, Uganda) was conducted in WLWH receiving antiretroviral regimens containing efavirenz 600 mg, who had their efavirenz dose reduced to EFV400. Weekly therapeutic drug monitoring (TDM), steadystate pharmacokinetic profiles (TT and PP), safety, virological efficacy, and CYP2B6 polymorphisms at positions 516 (C > T) and 938 (T > C) were evaluated.
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    Relating CYP2B6 Genotype and EFV Resistance Among Women Living With HIV With High Viremia in Uganda: A Nested Cross-Sectional Study.
    (Research Square, 2021) Buzibye, Allan; Wools-Kaloustian, Kara; Olagunju, Adeniyi; Twinomuhwezi, Ellon; Yiannoutsos, Constantin; Owen, Andrew; Neary, Megan; Matovu, Joshua; Banturaki, Grace; Castelnuovo, Barbara; Lamorde, Mohammed; Khoo, Saye; Waitt, Catriona; Kiragga, Agnes
    We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV started on anti-retroviral therapy during pregnancy and with high viremia during post-partum. Methods This was a cross sectional study. Women between 6-12 weeks post-partum with viral load >1000 copies/ml were eligible. Sanger sequencing to detect resistant mutations and host genotyping were performed. We categorized efavirenz metabolizer genotype according to the AIDS clinical trials group algorithm as slow, intermediate and extensive; and compared efavirenz resistance among the metabolizer genotypes. Results Over a one-year period (July 2017-July 2018), three hundred and thirty two women were screened of whom 112 (34.8%) had viral load ≥1000 copies/ml of whom 62 had whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. We observed a higher frequency of efavirenz resistance among slow metabolizers (47% versus 34% in extensive and 28% in intermediate, metabolizers) but due to low numbers, this was not statistically significant. Conclusions Our findings raise the possibility that CYP2B6 polymorphism may contribute to efavirenz drug resistance in women started on antiretroviral therapy during pregnancy and with high viremia in the post-partum period. If confirmed in a larger study, this would have important implications for all patients in sub- Saharan Africa receiving efavirenz and add further support to the changes in World Health Organization policy to switch away from efavirenz as first line antiretroviral therapy in countries with a high prevalence of CYP2B6 polymorphisms.