First reported use of elvitegravir and cobicistat during pregnancy

Data on safety and pharmacokinetics of new antiretroviral agents during pregnancy is usually not available at the time of drug approval [1]. To the best of our knowledge, the use of elvitegravir and cobicistat (both FDA pregnancy category B) in pregnancy has not yet been reported [2]. Here, we present a case of elvitegravir/cobicistat use during pregnancy. A 30-year-old black woman (1.66 m) was first diagnosed with HIV-1 in 2012. She reported to be abstinent of smoking, recreational drugs and alcohol. To facilitate compliance, elvitegravir/cobicistat/emtricitabine/tenofovir (once-daily, 150/150/200/300 mg; Stribild) fixed-dose therapy was initiated about 8 weeks before conception. At 31 weeks of gestation, viral load was undetectable (<50 copies/ml) and CD4+ cell count was 965 cells/μl. During week 34 of gestation a pharmacokinetic, (PK) curve was recorded over the 24-h dosing interval (Fig. 1; PK parameters were derived by noncompartmental analysis and reported in the figure legend). The woman (77 kg) had undetectable viral load and CD4+ cell count was 1180 cells/μl.Fig. 1: Elvitegravir and cobicistat plasma concentration–time curves during and after pregnancy.(a) The AUC 0–24 h, C max, C min and half-life for elvitegravir during pregnancy (open circles) were 15.0 h*mg/l, 1.20 mg/l, 0.06 mg/l and 4.1 h, respectively. During postpartum (closed squares) AUC 0–24 h, C max, C min and half-life were 14.0 h*mg/l, 1.10 mg/l, 0.15 mg/l, 6.7 h, respectively. (b) For cobicistat the AUC 0–24 h and C max during pregnancy (open circles) were 4.43 h*mg/l and 0.75 mg/l. The C min of cobicistat was below the lower limit of quantification (0.03 mg/l). The AUC 0–24 h, C max and C min postpartum were 7.88 h*mg/l, 1.43 mg/l and 0.145 mg/l, respectively.At 39 weeks of gestation, the woman gave birth via planned cesarean section for obstetrical reasons. Maternal viral load was undetectable and CD4+ cell count was 791 cells/μl. Delivery was without complications and observed congenital abnormalities. The Apgar scores were 9/10/10 at 1, 5 and 10 min, respectively. The newborn (2950 g) received zidovudine (Retrovir syrup) for 4 weeks. HIV RNA was negative at birth and after 1 month. Proviral DNA was also negative at birth, and after 1 and 3 months. At 8 months of age, the girl seemed to have developed normally. At delivery, elvitegravir concentrations in the maternal and cord plasma were both 0.30 mg/l. Compared with other antiretrovirals this cord-to-maternal concentration ratio of 1 is high [3]. The concentrations of cobicistat in maternal and cord plasma were below the lower limit of quantification of the validated high-performance-liquid-chromatography method (0.03 mg/l). Six weeks after delivery, a second PK curve was recorded as a postpartum control to assess the effect of pregnancy on elvitegravir and cobicistat pharmacokinetics (Fig. 1). The woman (72 kg) had undetectable viral load and CD4+ cell count was 1183 cells/μl. Overall, exposure to elvitegravir [area under the curve (AUC) (0–24 h)] during pregnancy was similar to postpartum. Postpartum elvitegravir AUC and Cmax were relatively low compared with the previously reported values (mean ± SD) of 23 ± 8 mg*h/l and 1.7 ± 0.4 mg/l, respectively [4]. The Cmin (0.06 mg/l) after observed medication intake in the third trimester was approximately 60% lower than postpartum and was below the suggested target concentration of 0.13 mg/l [5]. However, substantial intra-subject variability was observed during pregnancy for Ctrough after unobserved intake: predose concentration of 0.48 mg/l (∼C22 h; PK curve) and 0.30 mg/l (∼C24h) at delivery. Once-daily elvitegravir requires boosting; for example, by the CYP3A4 inhibitor cobicistat [6]. Exposure (AUC 0–24 h) to cobicistat was 44% lower during pregnancy compared with postpartum. This decrease could hypothetically result in diminished boosting of elvitegravir. This is possibly reflected by the low Cmin of elvitegravir found in the third trimester. Postpartum AUC and Cmax for cobicistat were similar to previously reported values (mean ± SD) of 8.3 ± 3.8 mg*h/l and 1.1 ± 0.4 mg/l, respectively. In this case, the viral load remained undetectable throughout pregnancy despite a Cmin below the suggested target concentration. Placental transfer of elvitegravir was relatively high. Until more data about elvitegravir/cobicistat use during pregnancy become available, we recommend employing therapeutic drug monitoring of elvitegravir. Acknowledgements S.S., A.C. and D.B. are the primary authors who conceived and designed the study. All authors collectively contributed to interpreting results and drafting and editing of the article. The PANNA network is financially supported by ’European AIDS Treatment Network (NEAT)’, European Commission, DG Research, 6th Framework program, contract LSHP-CT-2006-037570, BMS, MSD, Viiv Healthcare, and Janssen Pharmaceuticals N.V. We thank the patients for participating in this study and the laboratory personnel at the Laboratory of the Department of Pharmacy of the Radboud University Nijmegen Medical Center for analyzing the samples. We also thank the staff from all the centers that are participating in the PANNA network. Conflicts of interest There are no conflicts of interest.