Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study)

Abstract

BackgroundThe global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3).Methods and findingsIn DolPHIN-1, HIV-infected treatment-naïve pregnant women (28–36 weeks of gestation, age 26 (19–42), weight 67kg (45–119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma.No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3–8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum.ConclusionDespite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy.Trial registrationclinicaltrials.gov NCT02245022

An observational study of initial HIV RNA decay following initiation of combination antiretroviral treatment during pregnancy

“…Less convincing reductions in pVL at day 14, regardless of third agent in the cART regime, should be a cause for concern. Current BHIVA guidelines recommending all women should have started demonstrated in our study and other published data (27), the latest gestational age before which women on INSTI-based cART should have commenced cART will need to be explored in future studies.…”

An observational study of initial HIV RNA decay following initiation of combination antiretroviral treatment during pregnancy

“…However, it is important to note that cART regimens in this study only included PIs, NNR-TIs and ABC/3TC/AZT and did not include INSTIbased cART. Given the faster rate of HIV RNA declines in women on INSTIs as demonstrated in our study and other published data [26], the latest gestational age before which women on INSTI-based cART should have commenced cART will need to be explored in future studies. Excluding ABC/3TC/AZT due to small subject numbers, only 66-77% of women on PIs, NNRTIs and INSTIs had undetectable pVL at 36 weeks' gestation, when obstetric delivery plans are usually finalised.…”

“…However, it is important to note that cART regimens in this study only included PIs, NNRTIs and ABC/3TC/AZT and did not include INSTI-based cART. Given the faster rate of HIV RNA declines in women on INSTIs as demonstrated in our study and other published data [ 26 ], the latest gestational age before which women on INSTI-based cART should have commenced cART will need to be explored in future studies.…”

“…Overall, women in this cohort experienced a median 1.8 log 10 copies/mL decline in pVL 14 days after initiating cART, with the shortest T/2 and thus, largest HIV RNA decline seen in women on INSTIs (despite small numbers of women on INSTIs), in keeping with the DolPHIN-1 ( Dol utegravir in p regnant HI V mothers and their n eonates) [ 26 ] study results demonstrating superior virological responses with dolutegravir-based cART compared to efavirenz-based cART when initiated in late pregnancy in low and middle-income settings. This strengthens the recommendation for assessing response to cART at this early stage and emphasises that clinicians and patients should expect around a 99% reduction in maternal pVL after 2 weeks of cART.…”

Drug–Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV: Are They Different from Non-Pregnant Individuals?

“…The degree of interaction does not seem to change. indicates a positive effect, \ indicates a negative effect, ---indicates likely negligible effect, *, ** and *** show interrelated effects decreased plasma proteins have been suggested as causes [111,120,121]. It is still uncertain if UGT1A1 is induced during pregnancy [14], as some studies suggested UGT1A1 induction during pregnancy [122,123], but an increased metabolic ratio of DTG-glucuronide/DTG could not be demonstrated in a small pharmacokinetic study with pregnant women using DTG [120].…”