Interaction of Depot Medroxyprogesterone Acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood Mononuclear Cells and Cervical Tissue Susceptibility to HIV Infection and Pharmacokinetics

Abstract

Background: Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is highly effective in reducing HIV acquisition in women. We sought to determine the impact of DMPA on F/TDF pharmacokinetics and pharmacodynamics.Methods: Twelve healthy premenopausal cisgender women were enrolled and each completed 4 sequential conditions: (1) baseline, (2) steady-state F/TDF alone, (3) steady-state F/TDF + DMPA, and (4) DMPA alone. Assessments included clinical, pharmacokinetic, viral infectivity (ex vivo challenge of peripheral blood mononuclear cells by X4-and R5-tropic green fluorescent protein pseudoviruses and cervical tissue by HIV BaL ), endocrine, immune cell phenotyping, and renal function.Results: Compared with baseline, F/TDF (6 DMPA) significantly decreased both %R5-and X4-infected CD4 T cells and F/ TDF + DMPA decreased cervical explant p24 (all P , 0.05). The %R5-and X4-infected CD4 T cells were higher during DMPA alone than during F/TDF periods and lower than baseline (not statistically significant). Cervical explant p24 fell between baseline and F/TDF values (not statistically significant). There were neither statistically significant differences in F/TDF pharmacokinetics, including total or renal clearance of either antiviral drug, nor changes in glomerular filtration rate with the addition of DMPA. There were few immune cell phenotypic differences across conditions.Conclusions: F/TDF decreased HIV infection in both challenge assays, whereas DMPA alone did not enhance HIV infection in either challenge assay. DMPA did not alter F/TDF pharmacokinetics or renal function.

Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis

“…Comparing the participant’s urine data to a recent study of people with normal renal function taking FTC/TDF [ 37 ], the TFV A 0 − 24 was 38 mg, which made up 28% of the 136 mg TFV provided by 300 mg TDF, while the clearance was 289 mL/min, which is 20-fold higher than the clearance in the participant. This supports that TFV is not getting sufficiently cleared in the participant by his kidneys nor by his PD, causing the accumulation.…”

Clinical trial simulation to evaluate tenofovir disoproxil fumarate/emtricitabine HIV pre-exposure prophylaxis dosing during pregnancy

“…We included data from two studies in the popPK modeling: the Partners Demonstration Project and data from the TDF/FTC arm of a phase I, prospective, open-label study conducted in Baltimore, Maryland by Coleman and colleagues ( 31 , 32 ). The Partners Demonstration Project was a multi-site, randomized, double-blind, placebo-controlled clinical trial conducted in Kenya and Uganda, which included PK data from 116 female participants, including 33 pregnant and postpartum participants who became pregnant while taking TDF/FTC and elected to continue on TDF/FTC.…”