Lantz Alyssa M, Kiweewa Matovu Flavia, Johnson Reilly, Isingel Esther, Nakalega Rita, Kabwigu Samuel, Beksinska Mags E, Nicol Melanie R
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis.
Makerere University-John Hopkins University Research Collaboration, Kampala Uganda.
J Infect Dis. 2024 Dec 16;230(6):1434-1443. doi: 10.1093/infdis/jiae372.
We previously reported the effect of contraception on cervical tenofovir concentrations in Ugandan women with human immunodeficiency virus (HIV). Here we explored the role of cervicovaginal cytokines and drug metabolizing enzymes and transporters (DMETs) to elucidate female genital tract (FGT) drug disposition in a Ugandan cohort.
Cervicovaginal fluid and cervical biopsies were collected from Ugandan women with HIV receiving tenofovir/lamivudine-based therapy and intramuscular depot medroxyprogesterone acetate (n = 25), copper intrauterine device (cuIUD; n = 12), or condoms (n = 13) as contraception. Cytokines were measured in cervicovaginal fluid (CVF). Ectocervical tenofovir diphosphate (TFVdp), lamivudine triphosphate (3TCtp), and deoxyadenosine triphosphate (dATP)/deoxycytidine triphosphate (dCTP) concentrations and immune marker/DMET gene expression were measured in cervical biopsies.
Cervical 3TCtp was not correlated with any CVF cytokines. Cervical TFVdp was correlated with IL-10, IL-7, and IL-17 in CVF. CCR5 mRNA expression in cervical biopsies was higher in cuIUD users versus condom users. Using multivariable linear regression, CVF IL-17, tissue dATP, plasma estradiol, and plasma tenofovir were all significant predictors of cervical TFVdp. Tissue dCTP and plasma lamivudine were significant predictors of cervical 3TCtp.
TFVdp concentrations in cervix appear to be influenced by local inflammation. In contrast, 3TCtp FGT exposure was not affected by genital inflammation or DMETs. CuIUD users have more immune cells present, which may in turn influence local TFVdp disposition.
We investigated changes in tenofovir diphosphate and lamivudine triphosphate due to the microbiome and inflammation. While lamivudine triphosphate was not affected by either, tenofovir diphosphate appeared to be affected by local inflammation. Specifically, Th17 cells may influence tenofovir disposition.
我们之前报道了避孕措施对乌干达感染人类免疫缺陷病毒（HIV）女性宫颈中替诺福韦浓度的影响。在此，我们探讨了宫颈阴道细胞因子以及药物代谢酶和转运体（DMETs）在乌干达队列中对女性生殖道（FGT）药物处置的作用。
从接受基于替诺福韦/拉米夫定治疗且采用醋酸甲羟孕酮长效注射剂避孕（n = 25）、铜宫内节育器（cuIUD；n = 12）或避孕套避孕（n = 13）的乌干达HIV感染女性中收集宫颈阴道液和宫颈活检组织。检测宫颈阴道液（CVF）中的细胞因子。检测宫颈活检组织中宫颈替诺福韦二磷酸酯（TFVdp）、拉米夫定三磷酸酯（3TCtp）以及脱氧腺苷三磷酸（dATP）/脱氧胞苷三磷酸（dCTP）的浓度，并检测免疫标志物/DMET基因表达。
宫颈3TCtp与任何CVF细胞因子均无相关性。宫颈TFVdp与CVF中的白细胞介素 - 10（IL - 10）、白细胞介素 - 7（IL - 7）和白细胞介素 - 17（IL - 17）相关。使用cuIUD的女性宫颈活检组织中CCR5 mRNA表达高于使用避孕套的女性。通过多变量线性回归分析，CVF中的IL - 17、组织dATP、血浆雌二醇和血浆替诺福韦均为宫颈TFVdp的显著预测因子。组织dCTP和血浆拉米夫定是宫颈3TCtp的显著预测因子。
宫颈中TFVdp浓度似乎受局部炎症影响。相比之下，3TCtp在FGT中的暴露不受生殖器炎症或DMETs的影响。使用cuIUD的女性存在更多免疫细胞，这可能反过来影响局部TFVdp的处置。
我们研究了由于微生物群和炎症导致的替诺福韦二磷酸酯和拉米夫定三磷酸酯的变化。虽然拉米夫定三磷酸酯两者均不受影响，但替诺福韦二磷酸酯似乎受局部炎症影响。具体而言，辅助性T细胞17（Th17）细胞可能影响替诺福韦的处置。
