Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with 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 IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant 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 post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant 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 non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two 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 non-pregnant 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.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

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 AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 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 AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Self-reported Antiretroviral Adherence: Association With Maternal Viral Load Suppression in Postpartum Women Living With HIV-1 From Promoting Maternal and Infant Survival Everywhere, a Randomized Controlled Trial in Sub-Saharan Africa and India.

INTRODUCTION: Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health. SETTING: Fourteen sites in 7 countries within sub-Saharan Africa and India. METHODS: The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99). CONCLUSIONS: Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01061151; closed to follow-up.

Effects of Initiating Raltegravir-Based Versus Efavirenz-Based Antiretroviral Regimens During Pregnancy on Weight Changes and Perinatal Outcomes: NICHD P1081.

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/m 2 /wk versus 0.11 kg/m 2 /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.

Assessment of minority frequency pretreatment HIV drug-resistant variants in pregnant women and associations with virologic non-suppression at term.

OBJECTIVE: To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term. DESIGN: A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls. METHODS: HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared. RESULTS: PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases' median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085). CONCLUSIONS: We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.

Forty-Eight Week Outcomes of a Site-Randomized Trial of Combined Cognitive Behavioral Therapy and Medication Management Algorithm for Treatment of Depression Among Youth With HIV in the United States.

BACKGROUND: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12-24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. METHODS: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. RESULTS: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). CONCLUSIONS: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.

Pharmacokinetics of Tenofovir Alafenamide With Boosted Protease Inhibitors in Pregnant and Postpartum Women Living With HIV: Results From IMPAACT P1026s.

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.

Pharmacokinetics of Atazanavir Boosted With Cobicistat in Pregnant and Postpartum Women With 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.

Site-Randomized Controlled Trial of a Combined Cognitive Behavioral Therapy and a Medication Management Algorithm for Treatment of Depression Among Youth Living With HIV in the United States.

BACKGROUND: Depression is frequent among youth living with HIV (YLWH). Studies suggest that manualized treatment guided by symptom measurement is more efficacious than usual care. SETTING: This study evaluated manualized, measurement-guided depression treatment among YLWH, aged 12-24 years at 13 US sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Network. METHODS: Using restricted randomization, sites were assigned to either a 24-week, combination cognitive behavioral therapy and medication management algorithm (COMB-R) tailored for YLWH or to enhanced standard of care, which provided standard psychotherapy and medication management. Eligibility included diagnosis of nonpsychotic depression and current depressive symptoms. Arm comparisons used t tests on site-level means. RESULTS: Thirteen sites enrolled 156 YLWH, with a median of 13 participants per site (range 2-16). At baseline, there were no significant differences between arms on demographic factors, severity of depression, or HIV status. The average site-level participant characteristics were as follows: mean age of 21 years, 45% male, 61% Black, and 53% acquired HIV through perinatal transmission. At week 24, youth at COMB-R sites, compared with enhanced standard of care sites, reported significantly fewer depressive symptoms on the Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR score 6.7 vs. 10.6, P = 0.01) and a greater proportion in remission (QIDS-SR score ≤ 5; 47.9% vs. 17.0%, P = 0.01). The site mean HIV viral load and CD4 T-cell level were not significantly different between arms at week 24. CONCLUSIONS: A manualized, measurement-guided psychotherapy and medication management algorithm tailored for YLWH significantly reduced depressive symptoms compared with standard care at HIV clinics.

Brief Report: Vaginal Viral Shedding With Undetectable Plasma HIV Viral Load in Pregnant Women Receiving 2 Different Antiretroviral Regimens: A Randomized Clinical Trial.

BACKGROUND: Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL). METHODS: This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission. RESULTS: A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants. CONCLUSIONS: Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.

Association of Maternal Viral Load and CD4 Count With Perinatal HIV-1 Transmission Risk During Breastfeeding in the PROMISE Postpartum Component.

BACKGROUND: Breastfeeding mothers with HIV infection not qualifying for antiretroviral therapy (ART) based on country-specific guidelines at the time of the Promoting Maternal-Infant Survival Everywhere trial and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) postpartum. HIV transmission proportions were similar (<1%) in the 2 arms. We assessed whether maternal viral load (MVL) and CD4 cell counts were associated with breastfeeding HIV transmission. METHODS: MVL was collected at entry (7-14 days postpartum) and at weeks 6, 14, 26, and 50 postpartum. CD4 cell counts were collected at entry and weeks 14, 26, 38, and 50 postpartum. Infant HIV-1 nucleic acid test was performed at weeks 1 and 6, every 4 weeks until week 26, and then every 12 weeks. The associations of baseline and time-varying MVL and CD4 cell counts with transmission risk were assessed using time-to-event analyses by randomized treatment arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled in the study. Baseline MVL (P = 0.11) and CD4 cell counts (P = 0.51) were not significantly associated with infant HIV-1 infection. Time-varying MVL was significantly associated with infant HIV-1 infection {hazard ratio [95% confidence interval (CI)]: 13.96 (3.12 to 62.45)} in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 1.04 (0.20 to 5.39)]. Time-varying CD4 cell counts were also significantly associated with infant HIV-1 infection [hazard ratio (95% CI): 0.18 (0.03 to 0.93)] in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 0.38 (0.08 to 1.77)]. CONCLUSIONS: In women receiving mART, increased MVL and decreased CD4 cell counts during breastfeeding were associated with increased risk of infant HIV-1 infection.

Pharmacokinetics of darunavir and cobicistat in pregnant and postpartum women with HIV.

OBJECTIVE: To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir 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. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. RESULTS: A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited. CONCLUSION: Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.

Profile of Chronic Comorbid Conditions and Obstetrical Complications Among Pregnant Women With Human Immunodeficiency Virus and Receiving Antiretroviral Therapy in the United States.

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.

Pharmacokinetics of tenofovir alafenamide with and without cobicistat in pregnant and postpartum women living with HIV.

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 cord blood samples were collected at delivery, and washout pharmacokinetic samples were collected in infants. TAF concentrations were quantified using liquid chromatography/mass spectrometry. 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 with postpartum, but comparable with those measured in nonpregnant adults. TAF was below the lower limit of quantitation in 43 of 44 cord blood, 41 of 45 maternal blood at delivery, and all infant washout samples. CONCLUSION: TAF exposures were comparable or higher than those measured in nonpregnant 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.

Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial.

BACKGROUND: Although antiretroviral regimens containing integrase inhibitors rapidly suppress HIV viral load in non-pregnant adults, few published data from randomised controlled trials have compared the safety and efficacy of any integrase inhibitor to efavirenz when initiated during pregnancy. We compared safety and efficacy of antiretroviral therapy with either raltegravir or efavirenz in late pregnancy. METHODS: An open-label, randomised controlled trial was done at 19 hospitals and clinics in Argentina, Brazil, South Africa, Tanzania, Thailand, and the USA. Antiretroviral-naive pregnant women (20-<37 weeks gestation) living with HIV were assigned to antiretroviral regimens containing either raltegravir (400 mg twice daily) or efavirenz (600 mg each night) plus lamivudine 150 mg and zidovudine 300 mg twice daily (or approved alternative backbone regimen), using a web-based, permuted-block randomisation stratified by gestational age and backbone regimen. The primary efficacy outcome was plasma HIV viral load below 200 copies per mL at (or near) delivery. The primary efficacy analysis included all women with a viral load measurement at (or near) delivery who had viral load of at least 200 copies per mL before treatment and no genotypic resistance to any study drugs; secondary analyses eliminated these exclusion criteria. The primary safety analyses included all women who received study drug, and their infants. This trial is registered with Clinicaltrials.gov, number NCT01618305. FINDINGS: From Sep 5, 2013, to Dec 11, 2018, 408 women were enrolled (206 raltegravir, 202 efavirenz) and 394 delivered on-study (200 raltegravir, 194 efavirenz); 307 were included in the primary efficacy analysis (153 raltegravir, 154 efavirenz). 144 (94%) women in the raltegravir group and 129 (84%) in the efavirenz group met the primary efficacy outcome (absolute difference 10%, 95% CI 3-18; p=0·0015); the difference primarily occurred among women enrolling later in pregnancy (interaction p=0·040). Frequencies of severe or life-threatening adverse events were similar among mothers (30% in each group; 61 raltegravir, 59 efavirenz) and infants (25% in each group; 50 raltegravir, 48 efavirenz), with no treatment-related deaths. INTERPRETATION: Our findings support major guidelines. The integrase inhibitor dolutegravir is currently a preferred regimen for the prevention of perinatal HIV transmission with raltegravir recommended as a preferred or alternative integrase inhibitor for pregnant women living with HIV. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Allergy and Infectious Diseases.

Enrollment and transition challenges in the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) network's PROMISE trial for resource-limited regions.

BACKGROUND: We describe enrollment and accrual challenges in the "Promoting Maternal and Infant Survival Everywhere" (PROMISE) trial conducted in resource-limited countries, as well as the challenges in transitioning participants from the antepartum to the postpartum components of the study. METHODS: PROMISE was a large multi-national randomized controlled trial of the safety and efficacy of interventions to reduce perinatal transmission of HIV-1 (HIV) during pregnancy and breastfeeding and of interventions to preserve maternal health after cessation of perinatal transmission risk. The PROMISE study included two protocols for HIV-infected pregnant women in resource-limited countries who intended to either breastfeed or formula-feed their infants and did not meet country criteria for antiretroviral treatment. The PROMISE breastfeeding protocol (1077BF) used a sequential randomization design with up to three randomizations (Antepartum, Postpartum, and Maternal Health). The PROMISE formula-feeding protocol (1077FF) had two randomizations (Antepartum and Maternal Health). Women presenting to the clinic during early or active labor or in the immediate postpartum period were registered as Late Presenters and screened to determine whether eligible to participate in the Postpartum randomization. RESULTS: The study was conducted at 14 sites in seven countries and opened to enrollment in April 2011. A total of 3259 pregnant women intending to breastfeed and an additional 284 pregnant women intending to formula feed were randomized in the Antepartum component. A total of 204 Late Presenters were registered during labor or after delivery. Enrollment was high among breastfeeding women (representing 96% of the target of 3400 women) but was lower than expected among women intending to formula feed (28% of 1000 expected) and late-presenting women (8% of 2500 expected). The successful overall enrollment and final primary study analyses results were attributed to substantial preparation before the study opened, collaboration among all stakeholders, close study monitoring during implementation and the flexibility to change and streamline the protocol. CONCLUSIONS: Experiences from the PROMISE study illustrate the challenges of enrolling in longer term studies in the setting of rapidly evolving prevention and treatment standards priorities. The lessons learned will help the community, site investigators, and study coordinators in the design and implementation of future clinical trials.

Fosamprenavir with Ritonavir Pharmacokinetics during Pregnancy.

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 (27.7 µg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC0-12) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [P < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [P < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC0-12 was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [P = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [P = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [P = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [P = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations (Cmin) of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC50) of 0.146 µg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.

Darunavir Pharmacokinetics With an Increased Dose During Pregnancy.

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 µg × h/mL) of median AUC (62.3 µg × h/mL) in nonpregnant adults on twice daily darunavir-ritonavir 600/100 mg. RESULTS: Twenty-four women were included in the analysis. Darunavir AUC0-12 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 AUC0-12 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.

Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV.

OBJECTIVE: To evaluate elvitegravir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles after 150 mg of elvitegravir and 150 mg of cobicistat given orally in fixed dose combination once-daily were performed during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Elvitegravir and cobicistat were measured in plasma by a validated liquid chromatography with tandem mass spectrometry assay with a lower quantitation limit of 10 ng/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. RESULTS: Thirty pregnant women taking elvitegravir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, elvitegravir AUC0-24 was 24% lower in the second trimester [n = 14, P = 0.058, geometric mean ratios (GMR) = 0.76, 90% confidence interval (CI) 0.57-1.0] and 44% lower in the third trimester (n = 24, P = 0.0001, GMR = 0.56, 90% CI 0.42-0.73), while cobicistat AUC0-24 was 44% lower in the second trimester (n = 14, P = 0.0085, GMR = 0.56, 90% CI 0.37-0.85) and 59% lower in the third trimester (n = 24, P < 0.0001, GMR = 0.41, 90% CI 0.30-0.57). Median cord blood elvitegravir concentration was 540.6 ng/ml and the median ratio of cord blood to maternal plasma elvitegravir concentrations was 0.91. CONCLUSION: Standard elvitegravir and cobicistat dosing during pregnancy results in significantly lower exposure which may increase the risk of virologic failure and mother-to-child transmission. Additional studies are needed to optimize elvitegravir and cobicistat dosing regimens in pregnant women.

Birth Outcomes for Pregnant Women with HIV Using Tenofovir-Emtricitabine.

BACKGROUND: In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r). METHODS: Using data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding. RESULTS: There were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight. CONCLUSIONS: The risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).