CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

neonatal transmission. DolPHIN-1 (NCT02245022) examined the PK and safety of dolutegravir (DTG) in pregnant women and their infants presenting with untreated HIV late in pregnancy (28-36wks gestation). Methods: Women recruited from Uganda and South Africa (SA) were randomised to receive DTG-based therapy (50mg OD) or efavirenz-based standard of care (SoC). DTG PK sampling (0-24h) was undertaken 14days after therapy initiation (third trimester; T3) and within 2wks of delivery (postpartum; PP). Where possible, matched maternal and cord samples were taken at delivery. Breastmilk (BM) was sampled PP, 2-6h and 24h post-dose. After PP sampling, patients switched to SoC and a plasma and BM sample was taken 1-3days post-switch. Nonlinear mixed effects (NONMEM v. 7.3) was used to describe DTG PK in maternal plasma, cord and BM. Covariates included maternal age, weight, pregnancy (T3 vs. PP), gestational age, delivery (vaginal vs. C-section), site (Uganda vs. SA) and wks PP. Model evaluation was performed by visual predictive check (VPC). Results: Twenty-eight women [14 Uganda, 14 SA; median (range) age, weight: 27yr (19-42), 67kg (44-160), respectively] contributed 528 plasma, 7 cord and 80 BM samples to the model; 27 had paired T3/PP visits [gestational age: 39wks (35-43)]. A 2-compartment model described DTG in plasma, which was linked to a fetal compartment of negligible volume and a BM compartment of fixed volume (0.125L) by first-order processes. Apparent oral clearance (CL/F) was higher than previously reported for HIV+, treatment-naïve patients (1.47 vs. 0.90L/h) but not significantly different between T3 and PP. Model VPC and measured DTG are shown (Figure). Median (range) simulated cord AUC 0-24 was 37.7mg.h/L (27.7-6.9; n=7) and was 107% (105-112) that of plasma. BM AUC 0-24 was 1.13mg.h/L (0.64-4.22; n=27) and was consistently 3% (2-7) that of plasma when simulated 48-240h post-switch. BM C av was 0.047mg/L (0.027-0.18) corresponding to a relative infant dose (RID) to that of the mother of 0.26% (0.11-0.97). Conclusion: Rich and sparse data collection allowed estimation of DTG disposition in maternal plasma, cord and BM by population PK modelling. RID of DTG from BM was within the suggested safety threshold of 10%, although accumulation in the infants was observed, potentially due to delayed excretion.

756 LOPINAVIR (AN HIV PROTEASE INHIBITOR) IMPAIRS UTERINE REMODELING DURING PREGNANCY Smriti Kala 1 , Caroline Dunk 2 , Lena Serghides 1

1 University Health Network, Toronto, ON, Canada, 2 Mt Sinai Hospital, Toronto, ON, Canada Background: Exposure to protease inhibitor (PI) based combination antiretroviral therapy (cART) during pregnancy; especially Lopinavir (LPV) based cART during periconception, increases the prevalence of preterm delivery and low birth weight. PIs may contribute to these adverse events by lowering progesterone (P4) levels. P4 plays a central role in uterine preparation for pregnancy, and a critical P4-dependent process in early pregnancy is remodeling of the uterine endometrium to form the decidua. The key events of this process include decidualization of endometrial stroma, and remodeling of decidual spiral arteries into highly dilated vessels to adequately supply maternal blood to the placenta and fetus. As PI-cART causes P4 dysregulation, we hypothesized that decidualization and spiral artery remodeling are likely to be impaired upon exposure to LPV based cART. Hence we investigated the effects of PIs on the decidua. Methods: Human HIV-negative decidua and placenta tissue was collected from elective first trimester terminations. The placenta-decidua co-culture model was used to investigate the effects of PIs on spiral artery remodeling by immunohistochemistry. The placental villous explant culture was used to study extravillous trophoblast (EVT) invasion across matrigel. A primary decidual cell culture systemwas used to assess PI-induced changes in soluble and intracellular protein factors using ELISA and multiplex approaches. Flow cytometry was used to examine the viability of various decidual cell types. Results: Treatment with LPV impaired the EVT outgrowth as well as remodeling of decidual spiral arteries. A dysregulation of decidualization was observed, marked by reduced stromal expression of prolactin and IGFBP1, the key biomarkers of decidualization. The viability of uterine NK (uNK) cells was affected, concomitant with changes in the secretion profile of uNK and stroma cell specific growth-factors and cytokines/chemokines such as VEGF, PlGF, IL-15, MMP-9 and CXCL16. The effects of LPV treatment could be attributed to a decrease in the expression of transcription factor STAT3, known to regulate decidualization. Conclusion: Overall, our data reveal that LPV based cART causes dysregulation of decidualization and impairment of spiral artery remodeling, thereby possibly contributing to inadequate placentation and poor birth outcomes. Our findings suggest a possible mechanism to explain why LPV exposure from conception may be associated with higher rates of adverse birth outcomes. Laura Dickinson 1 , Kenneth Kintu 2 , Julie Anne Coombs 3 , Alieu Amara 1 , Christie Heiberg 3 , Stephen I. Walimbwa 2 , Yashna Singh 3 , Shadia Nakalema 2 , Laura Else 1 , Landon Myer 4 , Catriona Waitt 1 , Mohammed Lamorde 2 , Catherine Orrell 3 , Saye Khoo 1 , for the DolPHIN-1 Study Team 1 University of Liverpool, Liverpool, UK, 2 Infectious Disease Institute, Kampala, Uganda, 3 Desmond Tutu HIV Foundation, Cape Town, South Africa, 4 University of Cape Town, Cape Town, South Africa Background: Women diagnosed with HIV late in pregnancy (≥28wks) require safe and effective treatment to quickly reduce viral load and prevent

Poster Abstracts

758 DOLUTEGRAVIR PHARMACOKINETICS DURING PREGNANCY AND POSTPARTUM

Angela Colbers 1 , Pauline Bollen 1 , Jolien Freriksen 1 , Deborah Konopnicki 2 , Katharina Weizsäcker 3 , Carmen Hidalgo Tenorio 4 , José Moltó 5 , Graham P. Taylor 6 , Irene Alba Alejandre 7 , Reinout van Crevel 1 , David M. Burger 1 , for the PANNA 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 Saint-Pierre University Hospital, Brussels, Belgium, 3 Charité Universitätsmedizin, Berlin, Germany, 4 University Hospital Virgen de las Nieves, Granada, Spain, 5 Hospital Germans Trias i Pujol, Barcelona, Spain, 6 Imperial College Healthcare NHS Trust, London, UK, 7 University of Munich, Munich, Germany Background: Although dolutegravir (DTG) should be avoided around conception and until the first 8 gestational weeks due to potential neural tube defects, a place for DTG remains in the treatment of pregnant women thereafter in several scenarios, such as late presentation or as salvage regimen. Adequate antiretroviral (ARV) exposure is important to prevent the development of resistance and mother-to-child transmission of HIV. However, pregnancy-

757 POPULATION PK OF DOLUTEGRAVIR IN PLASMA, CORD, AND BREASTMILK: RESULTS FROM DOLPHIN-1

CROI 2019 292