Bictegravir is an integrase strand transfer inhibitor available in fixed-dose combination with emtricitabine and tenofovir alafenamide for HIV treatment. The objectives of this study were to develop a population pharmacokinetic model for bictegravir during pregnancy and postpartum, identify main drivers of between-subject variability, and evaluate the role of adherence patterns in maintaining therapeutic exposure. Intensive bictegravir concentration-time data were used from IMPAACT 2026, a pharmacokinetic study of selected antiretroviral drugs during pregnancy and postpartum. Five hundred and eight bictegravir plasma concentrations from 27 participants during the second and third trimesters of pregnancy and postpartum were utilized for model development. A one-compartment structural model best described bictegravir PK. Pregnancy increased bictegravir apparent clearance (CL/F) by 61% compared to postpartum, while Black/African American race was associated with a 32% increase in apparent volume of distribution (Vd/F). Plasma albumin concentrations were associated with a 43% decrease in CL/F and body weight was associated with a 120% increase in Vd/F over the range of observed values. Monte Carlo simulations predicted median (90% prediction interval) pre-dose bictegravir concentrations of 920 ng/mL (265-2081) during the third trimester and 3399 ng/mL (1423-6391) postpartum, exceeding the protein-adjusted 95% effective concentration (162 ng/mL). Adherence simulations predicted a single missed dose at steady-state during the third trimester results in 43.7% of virtual subjects with concentrations below pharmacodynamic target, while two consecutive missed doses result in 90.4% with concentrations below target. These results show that while standard bictegravir dosing is effective during pregnancy, consistent adherence is critical to maintain effective therapeutic exposures.

BACKGROUND:There are no published data on clofazimine pharmacokinetics during pregnancy, and safety data are limited. We present data from pregnant and postpartum women receiving clofazimine for treatment of rifampicin-resistant tuberculosis (RR-TB). METHODS:IMPAACT P1026s was an observational study to assess the pharmacokinetics of tuberculosis and/or antiretroviral drugs during pregnancy. Between 2017 and 2019, pregnant women receiving ≥2 second-line antituberculosis drugs in routine care were enrolled in the second or third trimester and had intensive pharmacokinetic sampling at least once during pregnancy, and 2-8 weeks postpartum. Pharmacokinetic parameters were estimated using noncompartmental methods and compared between the antepartum and postpartum periods using geometric mean ratios (GMR) with 90% confidence intervals (CIs) and the Wilcoxon signed rank test for paired data. RESULTS:Eleven pregnant women from South Africa, 7 (64%) with HIV, were receiving clofazimine (100 mg daily) at enrollment, of which 82% received clofazimine for more than 8 weeks prior to pharmacokinetic evaluation. Nine (82%) women continued treatment postpartum. Peak plasma concentrations and area-under-the-concentration-time-curve over 12 hours were comparable to historical clofazimine pharmacokinetic data in nonpregnant women with RR-TB but were approximately 30% higher in the third trimester of pregnancy compared to the postpartum period. Eight women and 8 infants experienced at least one severe adverse event while on study but direct relatedness to clofazimine was considered unlikely. CONCLUSIONS:Overall, antepartum and postpartum clofazimine exposures were comparable to those reported in nonpregnant women with RR-TB. Exposures were lower than expected in the postpartum period, particularly compared with the third trimester of pregnancy.

Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB. Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20–26 weeks’ and 30–38 weeks’ gestation and at 2–8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4–6 months after birth. A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55

Background: Limited data exist on bictegravir pharmacokinetics in pregnancy among persons with HIV (PWH) and infant washout. Setting: Nonrandomized, open-label, multicenter phase-IV prospective study of bictegravir pharmacokinetics and safety in pregnant PWH and their infants. Methods: Steady-state 24-hour pharmacokinetic sampling of oral bictegravir 50 mg once daily (a component of fixed-dose combination bictegravir/emtricitabine/tenofovir alafenamide) during the second and third trimesters and postpartum was performed. Cord blood and infant washout samples were collected. Total and free bictegravir concentrations were measured by validated liquid chromatography with tandem mass spectrometry methods. Within- participant geometric mean ratios (GMR) with 90% confidence intervals (CI) were calculated to compare pharmacokinetics between second and third trimester versus postpartum. Infant HIV testing results were obtained. Results: Twenty-seven maternal-infant pairs were enrolled. Bictegravir area under the concentration-time curve from time 0 through 24 hours post-dose was 46% lower in the second trimester (n = 12; P = 0.002; GMR 0.54; 90% CI: 0.43 to 0.69) and 52% lower in the third trimester (n = 24; P < 0.0001; GMR 0.48; 90% CI: 0.43 to 0.55), compared with postpartum. C24 concentrations were above the estimated bictegravir protein-adjusted 95% effective concentration of 0.162 mg/mL. The median ratio of cord-to-maternal blood concentration was 1.38 (n = 17; quartiles: 1.17-1.63). Median T1/2 for infant bictegravir washout was 33.2 hours (quartiles: 25.7-45.9) with a Cmax of 2.06 mg/mL (quartiles: 1.37-2.72). Overall, 88%-92% of participants maintained suppression <40 copies/mL throughout pregnancy and postpartum. All available infant HIV testing results were negative. The safety profile for pregnant PWH and infants was acceptable. Conclusions: Bictegravir exposure was lower during pregnancy compared with postpartum, yet C24 concentrations were greater than the bictegravir protein-adjusted 95% effective concentration.

Abstract Objective  We examined mode of delivery among pregnant women with epilepsy (PWWE) versus pregnant controls (PC). We hypothesize that PWWE are more likely to deliver by cesarean. Study Design  The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an observational, prospective, multicenter investigation of pregnancy outcomes funded by the National Institute of Health (NIH). MONEAD enrolled patients from December 2012 through January 2016. PWWE were matched to PC in a case:control ratio of 3:1. This analysis had 80% power to detect a 36% increase in cesarean frequency assuming a baseline rate of 30% among PC at an α  = 0.05. Results  This report analyzed 331 PWWE (76%) and 102 PC (24%) who gave birth while enrolled in the study. PWWE and PC had similar rates of cesarean delivery (34.7 vs. 28.6%; p  = 0.27). Of women with cesarean, rates of cesarean without labor were similar between groups for those delivering in recruitment hospitals (48.2 vs. 50.0%) but in nonrecruitment hospitals, cesarean rates without labor were over two-fold higher among PWWE than those of PC (68.8 vs. 30.8%; p  = 0.023). Receipt of a cesarean after labor did not differ for PWWE compared to PC or by type of antiepileptic drug among the PWWE. Conclusion  These findings suggest that the obstetrical experiences of PWWE and PC are similar. An interesting deviation from this observation was the mode of delivery with higher unlabored cesarean rates occurring among PWWE in nonrecruitment hospitals. As the study recruitment hospitals were tertiary academic centers and nonrecruitment hospitals tended to be community-based institutions, differences in perinatal expertise might contribute to this difference. Key Points Unlabored cesarean rates higher among women with epilepsy. Provider preference may influence delivery mode among women with epilepsy. Type and amount of antiepileptic drug was not associated with mode of delivery.

Background Pregnant people with coronavirus disease 2019 (COVID-19) experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy.Methods IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated.Results Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9-31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI, 1.35-3.03) with each additional infusion in nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected.Conclusions Plasma remdesivir PK parameters were comparable between pregnant and nonpregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.Clinical Trials Registration NCT04582266. The plasma PK of remdesivir and its major metabolites were comparable between hospitalized pregnant and nonpregnant women with COVID-19, suggesting no dose adjustments are needed for intravenous remdesivir in pregnancy.

Though Hispanic youth with perinatally acquired HIV (PHIV) comprise 14% of those living with PHIV, little research has documented their lived experiences. Eighteen Hispanic adolescents and young adults (AYA) with PHIV were recruited from two pediatric infectious disease clinics in California (mean age = 20.8 years, 12 females and 6 males). Interview transcripts were analyzed for emergent themes regarding relationships, childbearing intentions, and future career aspirations. Participants acknowledged HIV as cause for rejection and fear of transmission from partners. Most desired children in the future. Those with children (n = 7) expressed a strong desire to continue their education for the benefit of their children. Many did not view HIV as a barrier to their career aspirations. HIV influenced their daily lives. However, the challenges of poverty, loss, and trauma also significantly shaped their well-being. Health care providers offered emotional and instrumental support which helped AYA make progress towards their goals.

ABSTRACT Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2–8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC 0–24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC 0–24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC 0–24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC 0–24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

During pregnancy in women with epilepsy, lower blood concentrations of antiseizure medications can have adverse clinical consequences.To characterize pregnancy-associated concentration changes for several antiseizure medications among women with epilepsy.Enrollment in this prospective, observational cohort study, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), occurred from December 19, 2012, to February 11, 2016, at 20 US sites. Enrolled cohorts included pregnant women with epilepsy and nonpregnant control participants with epilepsy. Inclusion criteria were women aged 14 to 45 years, an intelligence quotient greater than 70 points, and, for the cohort of pregnant women, a fetal gestational age younger than 20 weeks. A total of 1087 women were assessed for eligibility; 397 were excluded and 230 declined. Data were analyzed from May 1, 2014, to June 30, 2021.Medication plasma concentrations in women taking monotherapy or in combination with noninteracting medications. The cohort of pregnant women was monitored through 9 months post partum, with similar time points for control participants.Dose-normalized concentrations were calculated as total or unbound plasma medication concentrations divided by total daily dose. Phlebotomy was performed during 4 pregnancy study visits and 3 postpartum visits for the pregnant women and 7 visits over 18 months for control participants. The primary hypothesis was to test pregnancy changes of dose-normalized concentrations from nonpregnant postpartum samples compared with those of control participants.Of the 351 pregnant women and 109 control participants enrolled in MONEAD, 326 pregnant women (median [range] age, 29 [19-43] years) and 104 control participants (median [range] age, 29 [16-43] years) met eligibility criteria for this analysis. Compared with postpartum values, dose-normalized concentrations during pregnancy were decreased by up to 56.1% for lamotrigine (15.60 μg/L/mg to 6.85 μg/L/mg; P < .001), 36.8% for levetiracetam (11.33 μg/L/mg to 7.16 μg/L/mg; P < .001), 17.3% for carbamazepine (11.56 μg/L/mg to 7.97 μg/L/mg; P = .03), 32.6% for oxcarbazepine (11.55 μg/L/mg to 7.79 μg/L/mg; P < .001), 30.6% for unbound oxcarbazepine (6.15 μg/L/mg to 4.27 μg/L/mg; P < .001), 39.9% for lacosamide (26.14 μg/L/mg to 15.71 μg/L/mg; P < .001), and 29.8% for zonisamide (40.12 μg/L/mg to 28.15 μg/L/mg; P < .001). No significant changes occurred for unbound carbamazepine, carbamazepine-10,11-epoxide, and topiramate, although a decrease was observed for topiramate (29.83 μg/L/mg to 13.77 μg/L/mg; P = .18). Additionally, compared with dose-normalized concentrations from control participants, pregnancy dose-normalized median (SE) concentrations decreased significantly by week of gestational age: carbamazepine, -0.14 (0.06) μg/L/mg (P = .02); carbamazepine unbound, -0.04 (0.01) μg/L/mg (P = .01); lacosamide, -0.23 (0.07) μg/L/mg (P < .001); lamotrigine, -0.20 (0.02) μg/L/mg (P < .001); levetiracetam, -0.06 (0.03) μg/L/mg (P = .01); oxcarbazepine, -0.14 (0.04) μg/L/mg (P < .001); oxcarbazepine unbound, -0.11 (0.03) μg/L/mg (P < .001); and zonisamide, -0.53 (0.14) μg/L/mg (P < .001) except for topiramate (-0.35 [0.20] μg/L/mg per week) and carbamazepine-10,11-epoxide (0.02 [0.01] μg/L/mg).Study results suggest that therapeutic drug monitoring should begin early in pregnancy and that increasing doses of these anticonvulsants may be needed throughout the course of pregnancy.

Background: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV. Methods: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6–12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5–9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant. Results: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF. Conclusion: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.

Background: Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs. Setting: NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. Methods: Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal–Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs. Results: Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m2/wk versus 0.11 kg/m2/wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) (P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs. Conclusions: A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.

Objectives: Long-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics. Study Design: We enrolled postpartum women using etonogestrel implants and receiving ritonavirboosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrel concentrations between antiretroviral regimens. We considered a minimum serum etonogestrel concentration of 90 pg/mL adequate for ovulation suppression. Results: We collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boostedatazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (C (min)) of ritonavir-boosted-atazanavir and ritonavirboosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion. Conclusions: Unlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations. (C) 2021PublishedbyElsevierInc.

Purpose The purpose of this study is to assess the efficacy of magnesium oxide (MgO) alone and, secondarily, MgO plus riboflavin as preventive treatment of migraines in pregnancy. We hypothesize that MgO alone will be effective for the majority of patients and, when clinically indicated, the addition of riboflavin will result in further benefit. Methods This was a retrospective cohort study of pregnant patients treated for migraines between 2015 and 2020. We evaluated pre-/post-differences in the following primary outcomes: migraine frequency, severity, and duration. Secondary outcomes included associated migraine symptoms. Results Of 203 total patients, 117 received MgO alone and 86 received MgO plus riboflavin. There were no significant differences in baseline demographics between the two groups. There was a statistically significant decrease in migraine frequency, severity, and duration in the groups receiving MgO alone and MgO plus riboflavin (p < 0.01 for all). In total, 154 patients reported migraine-associated symptoms, of which 119 (77%) improved after treatment, 18 (12%) did not improve, and 17 (11%) patients' data were missing. The MgO plus riboflavin group had a lower gestational age at treatment initiation and was more likely to receive treatment prior to pregnancy (p < 0.01). Significant differences were observed for several baseline migraine symptoms, including photophobia, phonophobia, nausea, and vomiting, which were more common in the group receiving MgO plus riboflavin (p < 0.05 for all). Conclusion Migraine frequency, severity, and duration all decreased with MgO alone and MgO plus riboflavin in this pregnancy cohort. Associated symptoms also significantly decreased for both groups.

OBJECTIVE To evaluate the pharmacokinetics of tenofovir alafenamide (TAF) 10 mg with cobicistat and 25 mg without boosting in pregnant and postpartum women with HIV and to characterize TAF placental transfer and infant washout pharmacokinetics. DESIGN Open-label, multicenter phase IV prospective study of TAF pharmacokinetics during pregnancy, postpartum, delivery and infant washout. METHODS Pregnant women receiving TAF 10 mg with cobicistat or TAF 25 mg without boosting as part of clinical care had intensive pharmacokinetic assessments performed during the second and third trimesters, and 6-12 weeks postpartum. Maternal and infant blood samples were collected at delivery, and washout pharmacokinetic samples were collected in infants. TAF concentrations were quantified using LC/MS. Comparisons between pregnancy and postpartum were made using geometric mean ratios (90% confidence intervals) and Wilcoxon signed-rank tests. RESULTS Thirty-one pregnant women receiving TAF 10 mg with cobicistat-boosting and 27 women receiving TAF 25 mg without boosting were enrolled. TAF exposures did not significantly differ between pregnancy and postpartum when administered as 10 mg with cobicistat. Antepartum TAF exposures with the 25 mg dose were 33-43% lower in comparison to postpartum, but comparable to those measured in non-pregnant adults. TAF was below the lower limit of quantitation in 43/44 cord blood, 41/45 maternal blood at delivery, and all infant washout samples. CONCLUSIONS TAF exposures were comparable or higher than those measured in non-pregnant adults during pregnancy and postpartum. These findings provide reassurance on adequate TAF exposures during pregnancy, and support efforts to expand the use of TAF in pregnant women with HIV.

To evaluate the frequency and associated characteristics of chronic comorbid conditions and obstetrical complications among pregnant women living with HIV on antiretroviral therapy, and in comparison to those without HIV. We assessed two concurrent U.S cohorts of pregnant women with and without HIV: 1) International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1025, 2002-2013; and 2) Consortium for Safe Labor Study, 2002-2008. The primary outcomes were ≥2 chronic comorbid conditions per the WHO, and obstetrical complications. For women with HIV, we assessed whether a detectable viral load at delivery (≥400 copies/mL), starting ART earlier (less effective era, 2002-2008), and late entry to prenatal care (≥14 weeks) were associated with study outcomes. We assessed 2,868 deliveries (n=2,574 women) with HIV on antiretroviral therapy, and 211,910 deliveries (n=193,170 women) without HIV. Women with HIV were more likely to have ≥2 chronic comorbid conditions versus those without (10 vs. 3%; AOR: 2.96), including the most frequent comorbid groups, psychiatric (16 vs. 4%; AOR: 5.13), pulmonary (12 vs. 8%; AOR: 1.66), and cardiovascular (9 vs. 5%; AOR: 1.27). Women with HIV were slightly less likely to have obstetrical complications versus those without (both 17%; AOR: 0.84), including preeclampsia (both 6%; AOR: 0.80), very preterm birth <34 weeks (4 vs. 5%; AOR: 0.76), and gestational diabetes (both 4%; AOR: 0.70), but not preterm birth <37 weeks (17 vs. 13%; AOR: 1.31). Late entry to prenatal care and starting antiretroviral therapy earlier were associated with a lower likelihood of ≥2 chronic comorbidities (AORs: 0.65 and 0.72) and obstetrical complications (AORs: 0.76 and 0.76), and detectable viral load with a higher likelihood of obstetrical complications (AOR: 1.32). Chronic comorbid conditions were more frequent among pregnant women with HIV in an era of antiretroviral therapy, but not most obstetrical complications, compared to those without HIV, reinforcing the continued importance of high-risk interdisciplinary pregnancy care for this population.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Tenofovir exposure is increased in non‐pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy.

Background. To evaluate the frequency and associated characteristics of chronic comorbid conditions and obstetrical complications among pregnant women with human immunodeficiency virus (HIV) and receiving antiretroviral therapy (ART) in comparison to those without HIV. Methods. We compared 2 independent concurrent US pregnancy cohorts: (1) with HIV (International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1025, 2002-2013) and (2) without HIV (Consortium for Safe Labor Study, 2002-2007). Outcomes were >= 2 chronic comorbid conditions and obstetrical complications. For women with HIV, we assessed whether late prenatal care (>= 14 weeks), starting ART in an earlier era (2002-2008), and a detectable viral load at delivery (>= 400 copies/mL) were associated with study outcomes. Results. We assessed 2868 deliveries (n = 2574 women) with HIV and receiving ART and 211 910 deliveries (n = 193 170 women) without HIV. Women with HIV were more likely to have >= 2 chronic comorbid conditions versus those without HIV (10 vs 3%; adjusted OR [AOR]: 2.96; 95% CI: 2.58-3.41). Women with HIV were slightly less likely to have obstetrical complications versus those without HIV (both 17%; AOR:.84; 95% CI:.75-.94), but secondarily, higher odds of preterm birth <37 weeks. Late entry to prenatal care and starting ART in an earlier era were associated with a lower likelihood of >= 2 chronic comorbidities and obstetrical complications; detectable viral load at delivery was associated with a higher likelihood of obstetric complications. Conclusions. Pregnant women with HIV receiving ART have more chronic comorbid conditions, but not necessarily obstetrical complications, than their peers without HIV.

Background: This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples. Setting: A nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children. Methods: Intensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons. Results: A total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0 –24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 μg/mL (0.16–0.28) in the second trimester, 0.21 μg/mL (0.11–0.56) in the third trimester, and 0.61 μg/mL (0.42–1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited. Conclusions: Standard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.

Background: This study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum. Methods: Darunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2-3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography. Target darunavir area under the concentration time curve (AUC) was >70% (43.6 mu g x h/mL) of median AUC (62.3 mu g x h/mL) in nonpregnant adults on twice daily darunavir-ritonavir 600/100 mg. Results: Twenty-four women were included in the analysis. Darunavir AUC(0-12) was lower with the increased dose during the second {[geometric mean ratio (GMR) of 0.62 (IQR 0.44-0.88); P = 0.055]} and third trimesters [GMR 0.64 (IQR 0.55-0.73); P = <0.001] compared with postpartum. Darunavir apparent clearance was higher during the second [GMR 1.77 (IQR 1.24-2.51); P = 0.039] and third trimesters [GMR 2.01 (IQR 1.17-2.35); P = <0.001] compared with postpartum. Similarly, ritonavir AUC(0-12) was lower during the third trimester [GMR 0.65 (IQR 0.52-0.82); P = 0.007] compared with postpartum, whereas its apparent clearance was higher during the third trimester [GMR 1.53 (IQR 1.22-1.92); P = 0.008] compared with postpartum. No major drug-related safety concerns were noted. Conclusions: Increasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared with 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.

The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.