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-related physiological changes may alter ARV exposure. As limited data are available on PK of DTG during pregnancy, we present data on 3rd trimester DTG exposure in HIV-positive pregnant women.
Multi-centre phase IV study in HIV infected pregnant women recruited in European HIV treatment centers. Patients treated with DTG 50mg QD during pregnancy had 24-hour PK profiling in the 3rd trimester (T3) and 3-7 weeks postpartum (PP). Paired cord (CB) and maternal (MB) blood samples were taken at delivery. Safety and virological data were collected. DTG plasma concentrations were determined with a validated LC-MS/MS method (LLOQ of 0.01mg/L). Geometric mean ratio (GMR) T3 PK versus PP with 90% confidence interval (CI) was calculated for AUC0-24h, Cmax and Ctrough.
14 patients (10 black, 4 white/other), median (range) age 32 (21-42) yrs were included. 5 patients did not attend at postpartum, 1 patient was excluded from PK analysis because of invalid plasma concentrations. Median (range) GA at delivery was 39 wks (34-40); birth weight was 3258 gr (2120-4040). Peri-delivery all patients had HIV VL<50cps/mL. 10 children were HIV un-infected (4 unknown status).One intrauterine fetal death (34 weeks GA) occurred due to cholestasis pregnancy syndrome, 1 infant had hypospadia, 1 had polydactily (as other members of her family). Two maternal hospital admissions occurred to exclude pre-eclampsia. Ratios T3/PP (GMR (90%CI), n=8) were: 0.88 (0.67-1.16) for AUC0-24h; 0.94 (0.75-1.18) for Cmax; 0.74 (0.50-1.09) for Ctrough. One patient had a subtherapeutic Ctrough (<0.3 mg/L) in the T3 of pregnancy. Median (range) CB:MB ratio was 1.4 (1.1-1.8; n=8).
Although variability is high, DTG AUC0-24h seems similar in pregnancy and postpartum. In T3 DTG plasma Ctrough was above the efficacy level of 0.3 mg/L in all but one patient. These findings, coupled with the undetectable viral loads at delivery, support standard dosing of DTG during pregnancy.