Pharmacokinetics and Safety of Remdesivir in Pregnant and Nonpregnant Women With COVID-19: Results From IMPAACT 2032

Abstract

Pregnant people are at high risk of severe coronavirus disease 2019 (COVID-19) disease and adverse pregnancy outcomes [1–3]. Several studies have shown higher risks of hospitalization, intensive care unit admissions, mechanical ventilation, and death in comparison to nonpregnant persons [1, 2], and these risks are higher in unvaccinated persons [4] and those with comorbidities [2]. Higher rates of hypertensive disorders, cesarean delivery, preterm birth, and stillbirth have also been observed in comparison to pregnant people without COVID-19 [1–3, 5]. These poor outcomes demonstrate a critical need for safe and effective COVID-19 therapeutics in pregnant people, but data supporting their use in pregnancy continue to lag data in nonpregnant persons.

Remdesivir is an intravenously administered nucleoside prodrug analog indicated for treatment of COVID-19. Early in the pandemic, remdesivir was used for the treatment of hospitalized patients with severe COVID-19 infection [6], with clinical use later expanding to those at risk for severe disease in the outpatient setting [7]. Remdesivir is moderately protein bound (88%–94%) and hydrolyzed to the alanine intermediate, GS-704277, and then the nucleotide monophosphate (MP) analog, GS-441524-MP [8]. GS-441524-MP can either be dephosphorylated to the main metabolite, GS-441524, or phosphorylated to the active triphosphate form, GS-443902, which blocks severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication through competitive inhibition of RNA-dependent RNA polymerase. Pregnancy-specific remdesivir data are limited to clinical and birth outcomes from case series, cohort, and compassionate use studies [9, 10]. The potential impact of pregnancy-related physiologic changes on the pharmacokinetics (PK) of remdesivir and its metabolites have not been studied and need to be examined.

We report findings from IMPAACT 2032, which examined the PK and safety of intravenous remdesivir in pregnant and nonpregnant women with COVID-19. The primary objectives of this study were to describe the PK of remdesivir and its plasma metabolites and to describe clinical and safety outcomes through 4 weeks after last infusion in pregnant women. Secondary objectives were to describe these same outcomes in nonpregnant women. Other objectives included comparisons of the PK of remdesivir and its metabolites between pregnant and nonpregnant women, in addition to describing and comparing GS-443902 in peripheral blood mononuclear cells (PBMCs) and remdesivir protein binding. Birth and infant outcomes were also summarized.

METHODS

Study Design

IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women with COVID-19 prescribed remdesivir as part of clinical care in the United States (NCT04582266). The decision to prescribe remdesivir and provision of all clinical care was under the direction of the clinicians at each site who were not members of the site research team. Enrollment could occur through the day of the fourth remdesivir infusion. The study enrolled pregnant and nonpregnant women in separate arms and comprised 3 data collection periods: preinfusion, infusion, and safety follow-up (Figure 1). Written informed consent was obtained from either participants or a legally authorized representative in cases where participants of legal age were unable to directly provide written informed consent. Consent was also obtained to collect limited information on birth and infant outcomes. The study protocol (Supplementary material) was reviewed and approved by the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, US National Institutes of Health, and site institutional review boards.

Figure 1.

Study design. The preinfusion period provided baseline data collection for 48 hours prior to initiating remdesivir. The infusion period included the initiation of RDV (200 mg on day 1 and 100 mg every 24 hours thereafter) for up to 5 or 10 days as clinically indicated. The safety follow-up period was inclusive of the time from discontinuing or completing remdesivir through 4 weeks after the last infusion. Among pregnant women (Arm 1), safety and birth outcomes were collected from the onset of labor or start of the cesarean delivery through 24 hours after delivery. The delivery visit could occur during remdesivir treatment, safety follow-up, or afterward. Except for PK sampling, study procedures and data collections were largely performed by medical chart abstraction or remote contact. Abbreviations: EOI, end of infusion; IV, intravenous; PBMC, peripheral blood mononuclear cell; PK, pharmacokinetics; RDV, remdesivir.

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Eligibility Criteria

Inclusion criteria for both study arms included hospitalization with confirmed or suspected COVID-19, and either receiving or expected to receive remdesivir as part of clinical care. Pregnant women with a viable intrauterine pregnancy of any gestational age were eligible. Nonpregnant women were required to be 18 to 45 years of age, female sex at birth, not taking gender-affirming hormone therapy, and not suspected to be pregnant. Exclusion criteria for both arms included starting or having received the fourth remdesivir dose; contraindications to remdesivir treatment; receipt of disallowed medications within 48 hours prior to entry (eg, chloroquine, hydroxychloroquine); and any other condition that would compromise participant safety or interpretation of study outcomes.

Pharmacokinetic Assessments

Intensive PK assessments were performed on a single day between infusion days 3 and 5 (Figure 1 and Supplementary Methods). PBMC cell counts were determined based on cellular DNA content [11]. Remdesivir, GS-704277, GS-441524, and GS-443902 were quantified using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods as previously described [12, 13]. The remdesivir free fraction was determined ex vivo and α-1-acid glycoprotein (AAG) was quantified using an enzyme-linked immunosorbent assay (ELISA) method (Supplementary Methods). Plasma PK parameters were determined using noncompartmental methods (Phoenix WinNonlin version 8.3; Certara).

Clinical and Safety Outcomes

Clinical management of participants was overseen by each participant's health care team. The protocol team's clinical management committee (CMC) monitored safety reports monthly, including listings of adverse events (AEs). Safety assessments in pregnant and nonpregnant participants were inclusive of vital signs, respiratory status, and clinical laboratory results (hepatic, renal, hematologic, and any other grade 3 or 4 abnormalities). Only the most abnormal results were recorded during the 48 hours prior to initiating remdesivir (baseline), daily over each 24-hour dosing interval during the infusion period, and through the last data collection time point during the safety period. AEs were assessed by the site investigator with guidance from the treating physician, where possible, with further review and confirmation of AE assessments by the CMC. In cases where AE relationships could not be determined by the site or discordant assessments between the site and CMC existed and could not be resolved, the CMC assessment was used. The CMC adjudication was used for AE summaries. AE relationship assessments to the study drug were categorized as either related or not related, with the former being defined as a reasonable possibility that the AE was related to remdesivir, and the latter being defined as there not being a reasonable possibility. AE severity was graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (corrected version 2.1, July 2017) [14]. For pregnant participants, serum creatinine, creatinine clearance, and estimated glomerular filtration rate (eGFR) were graded based on measured values and not change from baseline.

Statistical Analysis

Two populations were defined for the purposes of analyses: the safety-evaluable population, inclusive of enrolled participants who received any amount of remdesivir, and the PK-evaluable population. PK-evaluable participants received the full remdesivir dose on the day of intensive sampling and had both adequate sample collection—defined as meeting the following criteria: (1) at least 3 of 4 samples from end of infusion through 3 hours postdose, (2) either the 5- or 7-hour sample, and (3) either the predose or 23-hour after end of infusion sample—and concentration results for remdesivir and GS-441524 (ie, at least 2 drug concentrations greater than the lower limit of quantitation). The target sample size of 20 PK-evaluable participants per arm was chosen to assess whether a greater than 30% difference in PK parameters was detected between pregnant and nonpregnant participants and provided sufficiently narrow confidence intervals (CIs) for a coefficient of variation up to 40%.

PK, clinical, safety, and birth outcomes were summarized using descriptive statistics by study arm, with further stratification of PK results by trimester in pregnant participants. Plasma PK parameters were compared using geometric mean ratios (GMR) with 90% CIs between pregnant and nonpregnant participants. Sparse GS-443902 concentrations in PBMCs were analyzed using generalized linear mixed effects models to account for repeated measures across multiple infusions. Safety outcomes were summarized through the end of the infusion period; 48 hours, 7 days, and 4 weeks after last infusion; and at delivery. The primary safety outcomes were any renal, hepatic, or hematologic abnormality through 7 days after last infusion, and grade 3 or higher AEs, drug-related AEs, and serious AEs through 4 weeks after last infusion. Analyses of AEs with missing data used an available case approach, wherein participants who discontinued follow-up before the time point of interest and had a relevant event were included. Birth outcomes were summarized using a complete case approach for missing data, wherein only participants with delivery data available were included in analyses. Statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc).

RESULTS

Study Population

Fifty-four participants were enrolled (26 pregnant and 28 nonpregnant) between March 2021 and December 2021. Participant disposition is outlined in Supplementary Figure 1. One pregnant participant withdrew prior to receiving remdesivir. The remaining 53 participants comprised the safety population. Baseline demographics and clinical characteristics are presented in Table 1. Most (98%) had confirmed COVID-19 by diagnostic polymerase chain reaction testing prior to initiation of remdesivir. Among pregnant participants, median (interquartile range; IQR) gestational age was 27.6 weeks (interquartile range [IQR], 24.9–31.0 weeks); 13 (52%) were enrolled during the second trimester, and 12 (48%) were enrolled during the third trimester. Compared to nonpregnant participants at baseline, pregnant participants were slightly younger and had lower weights/body mass indices. Most were on low- (64%) or high-flow oxygen therapy (30%), and none were receiving vasopressor or inotropic support at baseline.

Clinical Outcomes

Median length of hospitalization was slightly longer in pregnant versus nonpregnant participants (10 [IQR, 7–12] versus 7 [IQR, 5–10] days). Most participants remained on low- (range, 41%–58%) or high-flow (range, 36%–53%) oxygen therapy throughout treatment. Four participants worsened during this period: 3 pregnant participants, 1 requiring mechanical ventilation on infusion days 2–4 and the other 2 requiring vasopressor/inotropic support on infusion days 2–5; and 1 nonpregnant participant requiring nasal intermittent positive pressure ventilation. Most participants (70%) completed remdesivir through 5 days of therapy, 1 (2%) each completed 6 and 10 days, and 9 (17%) were discontinued in alignment with treatment guidelines at their clinical provider's discretion. All participants were on at least 1 other concomitant medication during remdesivir treatment, with several on dexamethasone, oral or intravenous antibiotics, immune modulators, and various other medications to manage COVID-19 symptoms (Supplementary Table 1). Of remaining participants, 2 (4%) discontinued due to AEs, 2 (4%) withdrew, and 1 (2%) was lost to follow-up.

Pharmacokinetics

Concentration-time profiles for all 3 plasma analytes were comparable between pregnant and nonpregnant women (Figure 2A–D). Remdesivir area under the concentration-time curve over the 24-hour dosing interval (AUC_0-24h) and volume of distribution did not significantly differ in pregnant versus nonpregnant participants, but the lower bounds of the GMR 90% CIs were not contained within the 30% equivalence margin of 70%–143% (Table 2). All other GMR 90% CIs of plasma PK parameters for remdesivir, GS-704277, and GS-441524 were contained within the predefined equivalence margin. Albumin and AAG were 30% and 27% lower in pregnant versus nonpregnant participants, respectively (Table 2). However, the free fraction of remdesivir was similar between arms (Table 2). Further stratification of plasma PK and protein binding results by trimester did not identify significant differences within or between arms (Supplementary Table 2), but plasma AUCs of remdesivir and its metabolites were numerically lower in the second trimester compared to the third trimester and nonpregnant women. GS-443902 concentrations in PBMCs appeared to plateau in pregnant participants over time, whereas concentrations in nonpregnant participants increased by 2.04-fold with each additional infusion relative to pregnant participants (Figure 3).

Figure 2.

Concentration-time profiles for total remdesivir (A), free remdesivir (B) GS-704277 (C), and GS-441524 (D). Data presented as median concentrations for each nominal time point by arm assuming a 1-hour infusion duration. Total remdesivir plot overlaid with half maximal effective concentration (EC₅₀) in human airway epithelial (HAE) cells [15].

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Figure 3.

GS-443902 concentrations in PBMCs. Data presented as geometric mean (geometric SD) by study arm across nominal time points and overall. Gray shaded area shows 25th and 75th percentile concentrations measured in healthy volunteers on days 5 and 10 following administration of a 200-mg dose on day 1 with 100-mg daily thereafter for 5 or 10 days (6.7 and 12.4 µM, respectively). The GMR for GS-443902 in nonpregnant versus pregnant participants increased by 2.04-fold (90% CI, 1.35–3.03) with each additional infusion. Comparisons at each time point reflect GMR (90% CI) for nonpregnant versus pregnant participants from the same generalized linear mixed effects model. Pooled results reflect up to 2 observations per participant but were overlaid to show comparisons by arm. Abbreviations: CI, confidence interval; GMR, geometric mean ratio; PBMC, peripheral blood mononuclear cell.

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Safety Outcomes

Most participants (60%) had at least 1 AE of any grade and the majority of these occurred during the infusion period (Table 3 and Supplementary Table 3). Through 7 days after last infusion, 26% (95% CI, 10%–48%) and 20% (95% CI, 7%–41%) of pregnant and nonpregnant participants, respectively, had hematologic abnormalities comprising grade 3 or higher lymphocyte, leukocyte, or hemoglobin decreases. Several pregnant and nonpregnant participants had grade 3 or higher AEs (24% [95% CI, 8%–47%] and 17% [95% CI, 5.0%–38.8%], respectively) and serious AEs (SAE) (63% [95% CI, 41%–81%] and 54% [95% CI, 33%–74%], respectively) through 4 weeks after last infusion (Table 3 and Supplementary Table 4). No SAEs were deemed related to remdesivir. Three AEs deemed related to remdesivir occurred in nonpregnant participants. These included 1 grade 3 eGFR decrease based on actual values that later resolved, and 2 grade 2 bradycardia AEs (1 after dose 2 and the other after dose 4) resulting in treatment discontinuation.

Labor and Delivery Outcomes

Delivery outcomes were available for 17 of 25 (68%) participants (Supplementary Table 5). Three maternal participants experienced AEs of any grade (17.6% [95% CI, 3.8%–43.4%]), of which 2 were hematologic abnormalities (grade 3 hemoglobin decreases). Two maternal participants experienced grade 3 or higher SAEs, including fetal heart deceleration (grade 3) and respiratory failure (grade 3), the latter of which overlapped with the safety follow-up period. One participant experienced an intrauterine fetal demise at 26.7 weeks (5.9% [95% CI, .1–28.7%]). Of the remaining live births, the median gestational age at birth was 38.5 weeks (range, 34–41 weeks). Four infants (25% [95% CI, 7.3%–52.4%]) were delivered preterm (before 37 weeks of gestation) and 2 (12.5% [95% CI, 1.6%–38.3%]) were small for gestational age (<10th percentile birth weight for gestational age). No AEs or adverse pregnancy outcomes were deemed related to remdesivir. No maternal deaths occurred, and no congenital anomalies were reported.

DISCUSSION

The plasma PK of remdesivir and its major metabolites were similar between hospitalized pregnant and nonpregnant women with COVID-19. GS-443902 concentrations in PBMCs increased by 2-fold in nonpregnant versus pregnant participants. Albumin and AAG were lower in pregnancy, but the free remdesivir fraction was similar between pregnant and nonpregnant women. Based on our limited data, no safety concerns were identified. Our PK findings collectively support use of standard adult dosing of remdesivir in pregnant individuals when clinically indicated.

Plasma PK parameters for remdesivir and its metabolites were largely comparable between arms. The AUC of remdesivir was not contained within the 70%–143% bounds, which may be due in part to the greater variability with differing infusion durations and a sicker patient population. Post hoc comparisons by trimester initially suggested some PK differences, but these did not reach statistical significance, likely due to limited sample sizes. Separate PK analyses in persons with COVID-19 have shown a variety of factors can influence the PK of remdesivir and its metabolites [16–18]. Further evaluation of demographic and clinical factors that may affect remdesivir and metabolite PK is underway, and continued refinements of physiologically based PK modeling in pregnancy should be pursued [19]. Plasma exposures were comparable between study arms and to other PK studies in nonpregnant persons with COVID-19 [16, 17]. Consistent with other PK studies in pregnancy, albumin and AAG were lower in pregnancy, but no differences in the remdesivir free fraction were detected. The free fraction measured in this study was lower than what has been reported (6%–12%) [20]. Binding preference for albumin versus AAG is not known, but a molecular docking study has suggested moderate binding potential for remdesivir by albumin [21]. AAG concentrations in our participants were also high, which may be explained in part by AAG being an acute phase reactant [22, 23]. Median measures during pregnancy in this study were elevated compared to historical data in pregnant persons without COVID-19 (approximately 95 vs approximately 45–60 mg/dL) [24–26].

The accumulation of GS-443902 concentrations in PBMCs differed between arms, appearing to plateau in pregnant participants while nonpregnant participants continued to increase with each infusion. The continued accumulation in nonpregnant women was consistent with the previously published half-life of approximately 43 hours in PBMCs [8]. The underlying mechanisms and clinical relevance behind the differing accumulation is unclear. GS-443902 concentrations in PBMCs serve as a measure of drug activation within cells [8]. Compared with healthy volunteers, GS-443902 concentrations were comparable but more variable in nonpregnant women [8], and lower in pregnant women. However, all GS-443902 concentrations in this study were above the in vitro half maximal effective concentration (EC₅₀) of approximately 0.01 µM in human airway and lung epithelial cells [15]. Additionally, it is unknown how reflective PBMCs are of drug activation in other tissue types. Multiple factors have been shown to affect cellular concentrations of other nucleos(t)ide analogs in PBMCs, many of which overlap with the changes seen in pregnancy and COVID-19 infection [27–30]. Further investigation of factors that may affect GS-443902 concentrations, relationships between plasma and cellular concentrations, and understanding the clinical significance of this finding are warranted [19, 31].

No safety concerns were identified, and few participants discontinued remdesivir due to an AE. There were several grade 3 or higher SAEs unrelated to remdesivir use. These were largely consistent with outcomes in severe COVID-19 infection, and our enrolled population reflected known demographic and clinical risk factors for progression to severe disease [1, 2, 9, 32]. Of events related to remdesivir, bradycardia has been reported [33], which may be due in part to its adenosine analog structure and ability to bind to adenosine/P2Y purinoreceptors receptors [18]. However, COVID-19 infection has also been associated with several other adverse cardiovascular outcomes [34, 35]. No adverse pregnancy outcomes related to remdesivir were identified, and no congenital abnormalities were detected. However, pregnancy outcomes were unknown for 8 of 25 (32%) participants, and our study did not include any pregnant people in the first trimester of pregnancy. The proportion of adverse birth outcomes based on our limited data were consistent with prior literature in pregnant people with COVID-19, particularly the risk of preterm birth [1, 2]. Furthermore, collective data have not identified a higher risk of adverse pregnancy outcomes, major birth defects, or miscarriage when remdesivir is initiated in the second or third trimester [20, 36, 37]. However, there are currently insufficient data to evaluate the risk of remdesivir use when initiated during the first trimester [20].

There were strengths and limitations in this study. At the start of the pandemic, PK data with remdesivir were limited to healthy volunteers who were primarily male [8, 13]. This necessitated enrolling nonpregnant women for direct comparison of drug exposures in persons with COVID-19. However, to ensure that enrollment proceeded in a timely manner, participants were not matched based on demographic or clinical factors. Differences in baseline factors, such as weight and race/ethnicity, were apparent between arms. Given the opportunistic design with enrollment permitted through the fourth remdesivir dose, this design may have selected for participants who were already tolerating therapy compared to individuals who had poorer outcomes at treatment initiation. Alternatively, potential patients who recovered quickly may have stopped drug early and not been enrolled, thereby leading to underestimation of positive outcomes. This study was also not designed to compare clinical, safety, or adverse pregnancy outcomes. The median time to remdesivir initiation was 8 days across both arms, and earlier treatment initiation is associated with improved clinical outcomes in nonpregnant [7] and pregnant populations [10, 36]. The longer hospitalization duration in pregnant women may have contributed additional bias in reporting of safety follow-up outcomes. Overall outcomes in our study were consistent with the known disease course of severe COVID-19 infection. Pregnancy outcome data were also missing for 8 participants. As adverse outcomes occurred earlier in the safety observation period, missing outcomes may be more representative of uncomplicated births, but this is unknown.

The COVID-19 pandemic has continued to highlight the exclusion of pregnant people from treatment and vaccine studies [38]. Pregnancy PK and safety studies are key to determining drug dosing, safety, and efficacy of medications in this population. Unfortunately, pregnancy studies for new drugs are often not performed or are delayed for multiple years after initial regulatory approvals [39]. These exclusions can result in effective drugs not being used during pregnancy or used at suboptimal doses. There is a critical need to generate pregnancy PK and safety data in a timely manner, particularly during public health emergencies. IMPAACT 2032 was rapidly developed in response to the known delays in drug development that can occur in pregnant people. Ultimately, PK and safety results from this study were included in recent labeling updates for use of intravenous remdesivir during pregnancy [20], illustrating the critical role these studies have in informing appropriate treatment of pregnant people with new medications.

In conclusion, the plasma PK of remdesivir, its metabolites, and the free fraction of remdesivir were comparable between hospitalized pregnant and nonpregnant women with COVID-19, suggesting remdesivir does not require dose adjustment in pregnancy. This study addressed a significant knowledge gap in the pharmacology of COVID-19 therapeutics in pregnant people.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

Notes

Acknowledgments. We thank the study participants and families, clinical providers, the IMPAACT 2032 Protocol Team, and the following study sites and personnel: Lurie Children's Hospital of Chicago (Emanuela Lartey, RN; Rohit Kalra, MS, CCRP; Lynn Yee, MD, MPH; James Etta Stewart); Bronx-Lebanon Hospital Center (Martha Cavallo, PNP; Mirza Baig, MD); Johns Hopkins University Baltimore (Aleisha Collinson-Streng, BSN, RN; Thuy Anderson, BSN, RN; Bonnie Addison, BA); SUNY Stony Brook (Barsha Chakraborty, MPH; Cecilia Avila, MD, MPH; Giuseppe Caso, MD, PhD); David Geffen School of Medicine at UCLA (Carla Janzen, MD, PhD; Michele F. Carter, BS, RN); Baylor College of Medicine/Texas Children's Hospital (Mary Paul, MD; Ruth Eser-Jose, MSN, RN, CPN; Mariam Pontifes, CCRP; Chivon McMullen Jackson, RN); Pediatric Perinatal HIV Clinical Trials Unit, Miami Fl (Nicolette Gomez, CCRP; Grace Alvarez FMD, CCRP; Charles Mitchell, MD; JoNell Potter, PhD); Emory University School of Medicine (Martina L. Badell, MD; Sierra Jordan-Thompson, MPH; Riaun Floyd, BA; LaTeshia Thomas-Seaton, MS, APRN, CCRC); University of Colorado Denver (Adriana Weinberg, MD; Shane Curran-Hays, MS; Christine Kwon, BS; Carrie Glenny, RN, BSN; ); Rush University Cook County Hospital Chicago (Mariam Aziz, MD; Maureen McNichols, RN CCRC). We also thank Gilead Sciences, Inc and the following representatives: Rich Clark, Heather Maxwell, Gina Brown, Chris Blair, and James Rooney. The University of Colorado is a Certara Center of Excellence. The Center of Excellence program supports leading institutions with Certara's state-of-the-art model-informed drug development software.

Author contributions. K. M. B., K. B., D. F. C., S. N., K. M. P., A. M. S., A. C. E., D. E. S., E. C., E. G., K. G., D. E. Y., P. J. P., N. C., B. M. B., M. M., and J. D. M. contributed to the conception, design, and oversight of the study. K. M. B., J. D. M., E. C., and B. M. B. had access to, analyzed, verified, and interpreted pharmacokinetic data. J. J., M. U. P., A. A., C. B., and J. G. D. were involved in implementation, recruitment, and oversight of study conduct at their respective study sites. K. B., D. S., F. B., K. B., B. J., and C. R. had access to data and were involved in data management and oversight. K. B. and D. E. S. performed statistical analyses and interpreted results. K. M. B., K. B., D. F. C., S. N., K. M. P., A. M. S., A. C. E., D. E. S., E. C., E. G., K. G., D. E. Y., P. J. P., N. C., K. K., R. H., B. M. B., M. M., and J. D. M. reviewed and interpreted data. All authors contributed to manuscript development and approved the final manuscript version.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH).

Data availability. The data cannot be made publicly available due to the ethical restrictions in the study's informed consent documents and in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network's approved human subjects protection plan; public availability may compromise participant confidentiality. However, data are available to all interested researchers upon request to the IMPAACT Statistical and Data Management Center's data access committee (email address: sdac.data@fstrf.org) with the agreement of the IMPAACT Network.

Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health, all components of the NIH (grant numbers UM1AI068632 to International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) Leadership and Operations Center (LOC), UM1AI068616 to IMPAACT Statistical and Data Management Center (SDMC), and UM1AI106716 to IMPAACT Laboratory Center (LC); and NICHD contract number HHSN275201800001I). Additional support was provided by Gilead Sciences, Inc.

References

Author notes