CROI 2015 Program and Abstracts
Abstract Listing
Poster Abstracts
533 Pharmacogenetics of Pregnancy-Induced Changes in Efavirenz Pharmacokinetics Adeniyi Olagunju 1 ; Oluseye Bolaji 2 ; Alieu Amara 1 ; Laura Else 1 ; Ogechi Okafor 3 ; Ebunoluwa Adejuyigbe 2 ; Oyigboja Johnson 4 ; David Back 1 ; Saye Khoo 1 ; Andrew Owen 1
1 University of Liverpool, Liverpool, United Kingdom; 2 Obafemi Awolowo University, Ile-Ife, Nigeria; 3 Bishop Murray Medical Centre, Makurdi, Nigeria; 4 Catholic Caritas Foundation of Nigeria, Makurdi, Nigeria Background: Physiological changes during pregnancy coupled with single nucleotide polymorphisms (SNPs) in drug disposition genes are known to alter the pharmacokinetics (PK) of many drugs. In the present study the magnitude of pregnancy-induced changes in efavirenz (EFV) PK in genetically-defined subgroups was investigated. Methods: This was an observational study with an enrichment design conducted in two phases. In the preliminary phase, we explored associations between selected CYP2B6 , NR1I3 , CYP2A6 , and ABCB1 SNPs and mid-dose EFV concentrations in an unselected cohort of HIV positive women during pregnancy and postpartum. In the second phase, patients were stratified according to CYP2B6 516G>T (rs3745274). Accordingly, randomly selected patients in each genotype group were invited for the intensive PK phase; samples were collected at 0.5, 1, 2, 4, 8, 12 and 24 hours after an observed evening dose of EFV. Results: A total of 211 HIV positive women taking EFV-based regimens for prevention of mother-to-child transmission (PMTCT) of HIV during pregnancy (n = 77) or postpartum (n = 134) were recruited. Of the nine SNPs investigated, only CYP2B6 516G>T was independently associated with EFV plasma concentrations during both pregnancy and postpartum and was used to pre-select patients for the intensive PK phase. A global comparison showed a 42.6% increase in CL/F (p = 0.02), 29.8% reduction in AUC 0-24 ( p = 0.02) and 50.7% reduction in C min ( p = 0.01) during pregnancy compared with postpartum. The median (range) C min was 1000 ng/ml (429-5190) and the change in C max was not statistically significant ( p = 0.07). However, when stratified for CYP2B6 516G>T status, EFV CL/F increased by 100% during pregnancy compared with postpartum ( p = 0.001) in patients with the CYP2B6 516GG genotype. The AUC 0-24 , C max and C min were reduced by 50.6% ( p = 0.001), 17.2% ( p = 0.14) and 61.6% ( p = 0.003) during pregnancy, with values of 25,900 ng.hr/ ml (21,700-32,600), 2640 ng/ml (1260-3490) and 592 ng/ml (429-917), respectively (Table 1). Table 1. EFV pharmacokinetic parameters* during pregnancy and postpartum based on CYP2B6 516G>T genotypes.
Poster Abstracts
*Values are presented as median (range) and p values are for Mann-Whitney U test. Conclusions: The clinical relevance of these findings is uncertain, since dose-reduction of EFV in non-pregnant adults was previously not associated with increased risk of virological failure. Nevertheless, the impact of pharmacogenetic variability on mother-to-child transmission of HIV should be further studied. 534 Antiretroviral Drug Transporters and Metabolic Enzymes in Human Testicular Tissue Billy Huang 1 ; Md.Tozammel Hoque 1 ; Mohammad-Ali Jenabian 3 ; KishandaVyboh 2 ; Nancy Sheehan 2 ; Pierre Brassard 4 ; Maud Bélanger 4 ; Nicolas Chomont 5 ; Jean-Pierre Routy 2 ; Reina Bendayan 1 1 University of Toronto, Toronto, Canada; 2 McGill University, Montréal, Canada; 3 Université du Québec à Montréal, Montréal, Canada; 4 Metropolitan Centre of Plastic Surgery, Montréal, Canada; 5 Vaccine and Gene Therapy Institute of Florida, Port St Lucie, FL, US Background: Previous studies have reported that HIV-1 is capable of both acute and persistent infection in the testes. The naturally restrictive environment in the testes due in part to the blood-testes-barrier (BTB), suggests that this barrier could restrict antiretroviral (ARV) penetration into this tissue and contribute to the formation of a viral sanctuary. This study aims to characterize drug transporters and metabolic enzymes expression and localization in the testes of uninfected and HIV-1-infected men receiving antiretroviral therapy (ART) in order to gain further insight on the factors regulating ARV disposition in this organ. Methods: Testicular tissues were collected from uninfected men (N=8) and HIV-1 infected men on ART (plasma viral load <50 copies/mL for at least 6 months prior to surgery, N=5) who underwent elective orchiectomy for gender reassignment surgery at the Metropolitan Centre of Plastic Surgery in Montreal. We selected four ATP-binding cassette (ABC) transporters, six solute-carrier (SLC) transporters and two cytochrome P450 (CYP450) drug metabolic enzymes to study based on their relevance to ARV disposition, and assessed their gene and protein expression as well as tissue localization.
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CROI 2015
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