Antenatal Intracellular Concentrations of Tenofovir Diphosphate and Emtricitabine Triphosphate and Associations Between Tenofovir Diphosphate and Severe Adverse Pregnancy Outcomes: IMPAACT-PROMISE (1077BF) Trial

Abstract

Background: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration.

Methods: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression.

Results: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively.

Conclusions: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.

Figure 1.. Flow diagram illustrating participant inclusion and exclusion

Key: TDF, tenofovir; FTC, emtricitabine; vPTD, very preterm delivery (birth prior to 34 weeks of gestation); SB, stillbirth (at or after 20 weeks gestation); or EID, early infant death (prior to 14 days old); DBS, Dried Blood Spot; antepartum randomization (first 14 weeks of gestation or later) had 3 arms A, B and C; ‘ ‘antepartum-Arm C’ had a combination of TDF, FTC and LPV/r. Antepartum antiretroviral drug regimens were taken through the postpartum randomization (6–14 days after delivery/birth). A woman randomized to antepartum-Arm C was considered a “case” and to have met the composite safety endpoint if any of the three adverse pregnancy outcomes (vPTD, SB or EID) was observed. Cases were matched with two controls based on clinical research site and gestational age at entry to PROMISE Antepartum Component.

Figure 2:. Boxplot of TFV-DP differences between cases and controls at weeks 4 and 8 post ART initiation

The red line represents the median, the green diamond represents the mean, the box margins represent the 1^st and 3^rd quartiles, and the whiskers at the ends of the box represent 1.5xthe interquartile range (IQR).

Figure 3:. Boxplot of FTC-TP differences between cases and controls at weeks 4 and 8 post ART initiation

The red line represents the median, the green diamond represents the mean, the box margins represent the 1^st and 3^rd quartiles, and the whiskers at the ends of the box represent 1.5x the interquartile range (IQR).