Effect of Pregnancy on Intracellular Tenofovir Diphosphate Exposure and Thresholds following Oral Emtricitabine-Tenofovir Disoproxil fumarate Pre-Exposure Prophylaxis: A Directly Observed Dosing Study.

INTRODUCTION: Intraerythrocytic tenofovir diphosphate (TFV-DP) concentrations from emtricitabine/tenofovir disoproxil fumarate (F/TDF) pre-exposure prophylaxis (PrEP) measured in dried blood spots (DBS) are ∼30-40% lower during pregnancy, but data on TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) are limited. We evaluated the effect of pregnancy on intracellular TFV-DP concentrations in PBMCs. METHODS: Directly observed dosing (DOD) of daily oral F/TDF was administered to 18 healthy non-pregnant and 18 pregnant Kenyan women without HIV for eight weeks. Blood for DBS and PBMC was collected weekly for non-pregnant and bi-weekly for pregnant women. TFV-DP concentrations in DBS and PBMCs were quantified using validated liquid chromatography-tandem mass spectrometry. Steady-state fitted TFV-DP concentrations in PBMC and DBS were compared between pregnant and non-pregnant women. RESULTS: Median (IQR) age was 23 (20-27) years and gestational age was 16 (14-20) weeks for pregnant women at enrollment. Median (IQR) Cockroft Gault-estimated creatinine clearance was 131 (113-146) mL/Min for non-pregnant versus 176 (154-196) mL/Min for pregnant women. 1922 of 1925 (99.8%) expected doses were directly observed. Fitted steady-state median (IQR) TFV-DP concentrations in DBS were 1545 (1203, 1887) fmol/punch in non-pregnant versus 919 (835, 1003) fmol/punch in pregnant women [percent change: 40.5%, 95%CI (29.5%, 51.5%); p<0.001]. Modeled steady-state geometric mean (95%CI) PBMC TFV-DP concentrations were 56.2 (48.0, 65.8) fmol/106 cells in non-pregnant versus 47.8 (40.4, 56.5) fmol/106 cells in pregnant women [geometric mean ratio (GMR, 95%CI): 0.85 (0.68, 1.06); p=0.15]. CONCLUSION: Steady-state TFV-DP concentrations in PBMCs were reassuringly not meaningfully different between pregnant and non-pregnant women.