Eniayewu, Oluwasegun, Azuka, Uche, Ogah, Jonah, Adejuyigbe, Ebunoluwa, Bolaji, Oluseye and Olagunju, Adeniyi 
ORCID: 0000-0002-6588-5749
(2023)
Pharmacogenetics of efavirenz exposure in cervicovaginal fluid during pregnancy and postpartum.
[Preprint]
Abstract
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>Adequate antiretroviral drug distribution into the female genital tract (FGT) could play an important role in reducing the risk of heterosexual and mother-to-child transmission of HIV. In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A total of 159 women (147 pregnant and 12 postpartum) living with HIV and receiving efavirenz-containing antiretroviral therapy were recruited across two sites in Nigeria (Federal Medical Centre, and Bishop Murray Medical Centre, Makurdi) between 2017-2020. In stage 1, sparse CVF and dried blood spot (DBS) samples were obtained from each participant during pregnancy to assess possible association between drug concentration and<jats:italic>CYP2B6</jats:italic>polymorphisms (516G>T and 983 T>C). In the second stage, participants were stratified into three genotype groups (extensive, intermediate and low metabolisers) and re-enrolled for intensive pharmacokinetic sampling.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In stage 1 (88 CVF, 81 plasma and 73 paired samples),<jats:italic>CYP2B6 516G>T</jats:italic>was independently associated with both CVF (β = 997 ng/mL (90% CI: 598, 1357),<jats:italic>p =</jats:italic>5.7 x 10<jats:sup>-5</jats:sup>) and plasma (β = 1400 ng/mL (90% CI: 1051, 1748),<jats:italic>p =</jats:italic>5.7 x 10<jats:sup>-9</jats:sup>) efavirenz concentration during pregnancy. In the second stage (12 pregnant, 12 postpartum), median (IQR) efavirenz C<jats:sub>min</jats:sub>in CVF during pregnancy versus postpartum was 243 ng/ml (168-402) vs 447 ng/ml (159-974), C<jats:sub>max</jats:sub>was 1031 ng/ml (595-1771) vs 1618 ng/ml (675-2695), and AUC<jats:sub>0-24</jats:sub>was 16465 ng.h/ml (9356-30417) vs 30715 ng.h/ml (10980-43714). Overall, median CVF-to-plasma AUC ratio was 0.34 during pregnancy and 0.46 postpartum. When patients were stratified using<jats:italic>CYP2B6 516G>T</jats:italic>, efavirenz median clearance increased by 57.9% during pregnancy compared with postpartum control (<jats:italic>p</jats:italic>= 0.232) in patients with the<jats:italic>CYP2B6</jats:italic>516GT genotype. The AUC<jats:sub>0-24h</jats:sub>, C<jats:sub>max</jats:sub>and C<jats:sub>min</jats:sub>reduced by 33.8% ((p=0.182), 8.6% (0.175) and 59.5% (0.171) during pregnancy, with values of 20671 ng.h/ml (15993-28712), 1550 ng/ml (1090-2090) and 330 ng/ml (250-440), respectively, compared with 31229 ng.h/ml (27660-41873), 1695 ng/ml (1540-3003) and 814 ng/ml (486-981) during postpartum in this genotype.</jats:p><jats:p>Median efavirenz C<jats:sub>min</jats:sub>in CVF was 1.93 and 3.55 times higher than the PBIC<jats:sub>90</jats:sub>of 126 ng/ml in the pregnant and postpartum cohorts, respectively.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Efavirenz is well distributed into the CVF, and both pregnancy and polymorphisms in its disposition genes affect CVF exposure.</jats:p></jats:sec>
| Item Type: | Preprint |
|---|---|
| Uncontrolled Keywords: | Genetics, Clinical Research, HIV/AIDS, 6.1 Pharmaceuticals, 6 Evaluation of treatments and therapeutic interventions, Reproductive health and childbirth, Infection, 3 Good Health and Well Being |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 17 Oct 2023 07:26 |
| Last Modified: | 14 Mar 2024 17:54 |
| DOI: | 10.1101/2023.10.15.23297046 |
| Open Access URL: | https://www.medrxiv.org/content/10.1101/2023.10.15... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173779 |
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