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.

A Systematic Review on Cardiometabolic Risks and Perinatal Outcomes among Pregnant Women Living with HIV in the Era of Antiretroviral Therapy

“…Therefore, 201 full texts were retrieved and subjected to screening, from which nine were excluded as they were research protocols, one was retracted from a journal, 45 did not include pregnant HIV women, seven were not on HIV, 34 were not on ART, and 74 did not report any outcome of interest, such as any outcome of perinatal or marker of CMR. Only 31 clinical studies [ 12 , 26 , 33 , 36 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ] conducted on 20,904 HIV women on ART before or during pregnancy were found relevant based on our eligibility criteria ( Figure 1 ). These clinical studies were published in peer-reviewed journals between 1999 and 2023.…”

“…These clinical studies were published in peer-reviewed journals between 1999 and 2023. The publications were from Southern Africa (South Africa [ 45 , 52 , 69 ] and Botswana [ 66 ], Eastern Africa (Ethiopia [ 36 ], Tanzania [ 69 ], Kenya [ 64 ], Uganda [ 60 , 62 , 69 ], Mozambique [ 33 , 61 ], Malawi [ 69 ], Zambia [ 52 , 69 ], and Zimbabwe [ 69 ]), Southern Europe (Spain [ 46 , 47 ]), Northern Europe (United Kingdom [ 55 ]) and Western Europe (Netherlands [ 12 , 57 ]), Eastern Asia (China [ 26 , 67 ]), Southern Asia (India [ 69 ] and Thailand [ 49 ]), Southern America (Brazil [ 43 , 50 , 51 , 56 ]) and Northern America (Canada [ 60 ] and USA [ 44 , 48 , 53 , 54 , 58 , 59 , 60 , 63 , 65 , 68 ]). The characteristics of included studies are presented in Table 1 .…”

Pregnancy Outcomes in Pregnant Women with HIV on Tenofovir Disoproxil Fumarate (TDF) Compared to Tenofovir Alafenamide (TAF)

“…While TDF and TAF have been studied extensively in nonpregnant populations from a pharmaco-epidemiologic perspective [10][11][12][13][14][15][16][17] there are limited studies of TAF use during pregnancy [18,19] despite the increasing use of TAF fixed dose combination ARVs during pregnancy for treatment of maternal HIV infection and for prevention of perinatal transmission. To date, TDF data in pregnancy has been reassuring, as the Promoting Maternal Infant Survival Everywhere (PROMISE) randomized clinical trial did not identify associations between high TDF exposure, as measured by maternal tenofovir diphosphate (TFV-DP) concentrations in dried blood swabs, and adverse maternal, fetal, and neonatal outcomes [20]. Although TAF use in non-pregnant adults has been associated with weight gain and metabolic syndrome [21,22], only one study has evaluated the maternal and fetal outcomes in pregnant and postpartum women living with HIV on TAF compared to TDF [23].…”