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Objective: To describe postpartum bone mineral density (BMD) change among breastfeeding African women living with HIV (WLHIV) on life-long antiretroviral therapy (ART)., Design: In IMPAACT P1084 s, postpartum BMD declines were greater in WLHIV randomized to ART to prevent breastmilk transmission compared to infant nevirapine prophylaxis). This analysis extends the observation period through entry to a follow-on observational study, PROMOTE., Methods: Lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD were assessesd using dual energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74 in P1084 s, and at PROMOTE entry. Participants were included if DXA data were available from PROMOTE entry and > 1 earlier timepoint. Country-specific Z-scores were created by internal standardization to week 1 values. Linear mixed models, adjusted for country, estimated the annualized rate of change in BMD z-scores between postpartum week 1 and PROMOTE entry. Linear regression assessed the association between maternal characteristics and BMD z-score rate of change., Results: We included BMD data from 519 participants between postpartum week 1 through PROMOTE entry (median (IQR) 4.6 (3.5-5.1) years postpartum). For every 5 years passed, LS BMD Z-scores increased by + 0.250 units, while TH and FN BMD z-scores decreased by -0.173 and -0.141 units, respectively. LS, TH and FN BMD increased between postpartum week 74 and PROMOTE entry, but only LS BMD fully recovered to week 1 values., Conclusion: Given dampened TH and FN BMD recovery post-breastfeeding, longer term monitoring is needed to assess peri-/post-menopausal fracture risk, and interventions to optimize bone health among WLHIV on life-long ART., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2010/VESTED study, pregnant women were randomized to initiate dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG + FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF., Methods: We assessed red blood cell (RBC) folate concentrations at maternal study entry and delivery, and infant birth. RBC folate outcomes were (1) maternal change entry to delivery (trajectory), (2) infant, and (3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRTs) of each arm comparison in 340 mothers and 310 infants., Results: Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/μL, and log10 HIV RNA was 3 copies/mL. Entry RBC folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG + FTC/TAF versus EFV/FTC/TDF arm (1.03 [95% confidence interval {CI}, 1.00-1.06]). The DTG + FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92 [95% CI, .78-1.09]) versus EFV/FTC/TDF., Conclusions: Results are consistent, with no clinically meaningful differences between arms for all RBC folate outcomes, and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- versus EFV-based antiretroviral therapy., Clinical Trials Registration: NCT03048422., Competing Interests: Potential conflicts of interest. P. D. and S. B. have received funds from ViiV/GSK that were paid to Harvard. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Safety data from randomized trials of antiretrovirals in pregnancy are scarce. We evaluated maternal bone and renal data from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 trial, which compared the safety and efficacy of 3 antiretroviral therapy regimens started in pregnancy: dolutegravir + emtricitabine/tenofovir alafenamide (DTG + FTC/TAF), dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG + FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)., Methods: A subset of participants underwent dual-energy X-ray absorptiometry scans at postpartum week 50 only. Maternal bone mineral density (BMD) Z-scores were compared between arms. Maternal creatinine was measured at enrolment and periodically through week 50 postpartum, and by-arm differences in average weekly change in estimated creatinine clearance were compared., Results: Six hundred forty-three participants were randomized to DTG + FTC/TAF (N = 217) or DTG + FTC/TDF (N = 215) or EFV/FTC/TDF (N = 211). Median age = 27 years (IQR 23, 32), median CD4 count = 466 cells/mm3 (IQR 308, 624); 564 (88%) women enrolled in Africa and 479 (74%) breastfed. Week 50 postpartum dual-energy X-ray absorptiometry results from 154 women were included in the analysis. Hip and spine BMD was on average higher in women in the DTG + FTC/TAF and lower in the DTG + FTC/TDF and EFV/FTC/TDF arms, but no significant differences in BMD Z-scores were observed between treatment groups. The weekly rate of change in estimated creatinine clearance differed among treatment groups during the antepartum period, but not over the full study follow-up., Conclusions: Markers of bone and renal toxicity did not differ significantly through week 50 postpartum among women randomized to start DTG + FTC/TAF or DTG + FTC/TDF or EFV/FTC/TDF in pregnancy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Women with HIV (WHIV) have higher risks of adverse pregnancy outcomes, particularly in the absence of antiretroviral treatment(ART), and timing of ART may impact risk., Methods: In IMPAACT 2010 (VESTED), 643 pregnant WHIV in 9 countries were randomized 1:1:1 to initiate ART: dolutegravir (DTG)+emtricitabine(FTC)/tenofovir alafenamide(TAF); DTG+FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. We describe adverse pregnancy outcomes in women with a subsequent pregnancy during 50 weeks of postpartum follow-up: spontaneous abortion (<20 weeks), stillbirth (≥20 weeks), preterm delivery (<37 weeks) and small-for-gestational-age (SGA)., Results: Of 643 women, 19 (3%) had 20 subsequent pregnancies while receiving ART at conception: DTG/FTC/TAF(3), DTG/FTC/TDF(2), EFV/FTC or lamivudine(3TC)/TDF(12), EFV/abacavir/3TC (1) and no ART(1). Four spontaneous abortions, 3 stillbirths, and 1 induced abortion occurred. Three (25%) of 12 liveborn infants were preterm (24-, 26- and 36-weeks' gestation). Only 12 (60%) subsequent pregnancies resulted in live birth, and at least 1 adverse pregnancy outcome occurred in 11/19 (58%) (induced abortion excluded). Of 7 women who experienced spontaneous abortion/stillbirth in the subsequent pregnancy, 4 experienced a stillbirth and 1 a neonatal death as outcomes of their earlier index pregnancy. No congenital anomalies were reported., Conclusions: Adverse pregnancy outcomes were common in this cohort of WHIV who conceived on ART shortly after an index pregnancy, 35% ended in stillbirth or spontaneous abortion. The majority of fetal losses occurred in women with recent prior pregnancy loss. Data from larger cohorts of WHIV conceiving on ART and surveillance are needed to elucidate rates and predictors of adverse pregnancy outcome. (249 words)., Competing Interests: Competing interests SB and LZ received NIH funding and ViiV Healthcare funding, both paid to their institution. RH serves on the editorial board for Elsevier’s Clinical Key, a clinical resource for clinicians.

Background: Children born to women with HIV but who do not become HIV infected experience increased morbidity and mortality compared with children born to women without HIV. The basis of this increased vulnerability is unknown. The microbiome, specifically the infant gut microbiome, likely plays an important role in infant immune development. The human milk microbiome is thought to have an important role in the development of the infant gut and therefore, if perturbed, may contribute to this increased vulnerability. We investigated the effects of HIV and its therapies on the milk microbiome and possible changes in the milk microbiome before or after infant HIV infection., Results: Seven-hundred fifty-six human milk samples were selected from three separate studies conducted over a 15-year period to investigate the role of HIV and its therapies on the human milk microbiome. Our data reveal that the milk microbiome is modulated by parity (R 2  = 0.006, p = 0.041), region/country (R 2  = 0.014, p = 0.007), and duration of lactation (R 2  = 0.027-0.038, all p < 0.001). There is no evidence, however, using 16S rRNA V4 amplicon sequencing, that the human milk microbiome is altered by HIV infection (R 2  = 0.003, p = 0.896), by combination antiretroviral therapy (R 2  = 0.0009, p = 0.909), by advanced maternal disease (R 2  = 0.003, p = 0.263), or in cases of infant infection either through isolated early mucosal (R 2  = 0.003, p = 0.197) or early mucosal and breast milk transmission (R 2  = 0.002, p = 0.587)., Conclusions: The milk microbiome varies by stage of lactation, by parity, and by region; however, we found no evidence that the human milk microbiome is altered by maternal HIV infection, disease severity, or antiretroviral therapy. Additionally, we found no association between the milk microbiome and transmission of HIV to the infant. Investigations including higher resolution microbiome approaches or into other potential mechanisms to understand why the approximately one million children born annually to women with HIV escape infection, but do not escape harm, are urgently needed. Video Abstract., (© 2024. The Author(s).)

Context: Low bone mineral density (BMD) has been reported in children and adolescents living with perinatally-acquired HIV (PHIV). Little is known about their bone accrual through puberty compared to an uninfected healthy cohort., Objective: To compare bone accrual in PHIV and healthy children., Design: PHIV children aged 7-16 years had dual energy X-ray absorptiometry (DXA) at entry, 2 years, and then at least 2 years later. Bone accrual was compared to healthy children from the Bone Mineral Density in Childhood Study (BMDCS)., Setting: United States academic clinical research centers., Patients: 172 PHIV; 1321 BMDCS., Analysis: We calculated height-adjusted whole-body and spine BMD and bone mineral content (BMC) Z-scores in PHIV using BMDCS reference curves. We fit piecewise weighted linear mixed effects models with change points at 11 and 15 years, adjusted for age, sex, race, height Z-score, and Tanner stage, to compare BMD and BMC Z-scores across actual age by cohort.Main Outcome Measure: BMD/BMC Z-scores., Results: Height-adjusted whole-body BMD and BMC Z-scores in PHIV were lower across age compared to BMDCS children. Spine BMD Z-score across age was higher in PHIV after height adjustment. Whole-body and spine bone area tended to be lower in PHIV. PHIV had slower accrual in whole-body and spine bone area before 14 years. After 15 years, bone area accruals were similar, as were height-adjusted spine BMC Z-scores, across age., Conclusions: PHIV had persistent deficits in all measures except height-adjusted spine BMD and BMC Z-scores. Data are needed on PHIV followed to adulthood., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy is limited. We evaluated metabolic markers in pregnant women with HIV after starting TAF- vs TDF-based ART., Methods: We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC+DTG; n=217) or TDF/FTC+DTG (n=215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected eight weeks after enrollment. We employed linear regression models to estimate by-arm mean differences., Results: 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC+DTG and 110 in the TDF/FTC+DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By eight weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/FTC+DTG versus TDF/FTC+DTG (95% CI 3.8, 21.1). Pregnant women in the TAF/FTC+DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI 0.2, 14.0), triglycerides (12.3 mg/dL, 95% CI 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI 0.1, 5.6) compared to the TDF/FTC+DTG arm., Conclusion: Pregnant women randomized to start TAF/FTC+DTG had higher lipids than those randomized to TDF/FTC+DTG within eight weeks of ART initiation. However, lipid levels were within normal reference ranges., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment ( ART ) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate ( TDF ); efavirenz/emtricitabine/TDF. Vertical HIV transmission ( VT ) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance ( HIVDR ) and other risk factors., Setting: In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum., Methods: HIV sequences derived by single genome amplification ( SGA ) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract ( 3'PPT )., Results: The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor ( NNRTI ) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero , one peripartum, one early, and one late breastfeeding transmission., Conclusions: VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis., Competing Interests: Conflicts of Interest: All authors declare no conflicts of interest.

Background: IMPAACT 1077BF/FF (PROMISE) compared the safety/efficacy of two HIV antiretroviral therapy (ART) regimens to zidovudine (ZDV) alone during pregnancy for HIV prevention. PROMISE found an increased risk of preterm delivery (<37 weeks) with antepartum triple ART (TDF/FTC/LPV+r or ZDV/3TC/LPV+r) compared with ZDV alone. We assessed the impact of preterm birth, breastfeeding, and antepartum ART regimen on 24-month infant survival., Methods: We compared HIV-free and overall survival at 24 months for liveborn infants by gestational age, time-varying breastfeeding status, and antepartum ART arm at 14 sites in Africa and India. Kaplan-Meier survival probabilities and Cox proportional hazards ratios were estimated., Results: Three thousand four hundred and eighty-two live-born infants [568 (16.3%) preterm and 2914 (83.7%) term] were included. Preterm birth was significantly associated with lower HIV-free survival [0.85; 95% confidence interval (CI) 0.82-0.88] and lower overall survival (0.89; 95% CI 0.86-0.91) versus term birth (0.96; 95% CI 0.95-0.96). Very preterm birth (<34 weeks) was associated with low HIV-free survival (0.65; 95% CI 0.54-0.73) and low overall survival (0.66; 95% CI 0.56-0.74). Risk of HIV infection or death at 24 months was higher with TDF-ART than ZDV-ART (adjusted hazard ratio 2.37; 95% CI 1.21-4.64). Breastfeeding initiated near birth decreased risk of infection or death at 24 months (adjusted hazard ratio 0.05; 95% CI 0.03-0.08) compared with not breastfeeding., Conclusion: Preterm birth and antepartum TDF-ART were associated with lower 24-month HIV-free survival compared with term birth and ZDV-ART. Any breastfeeding strongly promoted HIV-free survival, especially if initiated close to birth. Reducing preterm birth and promoting infant feeding with breastmilk among HIV/antiretroviral drug-exposed infants remain global health priorities., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: SARS-CoV-2 seropositivity data in women living with HIV (WLHIV), their infants and associated factors in this subpopulation remain limited. We retrospectively measured SARS-CoV-2 seropositivity from 07/2020-11/2021 among WLHIV and their children in the PROMOTE observational cohort in Uganda, Malawi, and Zimbabwe prior to widespread SARS-CoV-2 vaccination in those countries., Methods: Plasma stored during 3 waves of the COVID-19 pandemic in East/Southern Africa were tested for SARS-CoV-2 specific IgG antibodies (Ab) using serological assays that detect adaptive immune responses to SARS-CoV-2 spike protein. (EUROIMMUN, Mountain Lakes, New Jersey and Roche Diagnostics, Indianapolis, IN). Modified-Poisson regression models were used to calculate prevalence rate ratios (PRR) and 95% confidence intervals (CI) to identify sociodemographic and clinical risk factors., Results: PROMOTE samples from 918 mothers and 1237 children were analysed. Overall, maternal SARS-CoV-2 seropositivity was 60.1% (95% CI: 56.9 -63.3) and 41.5% (95%CI: 38.8 - 44.2) for children. Non-breastfeeding mothers had a 31% higher risk of SARS-CoV-2 seropositivity compared to breastfeeding mothers (aPRR=1.31, 95%CI: 1.08-1.59). WLHIV with undetectable viral load had a 10% increased risk of SARS-CoV-2 seropositivity (aPRR=1.10, 95%CI: 0.89-1.37). Moreover, those who were normotensive had 12% increased risk SARS-CoV-2 seropositivity (aPRR= 1.12, 95% CI: 0.68-1.85) compared to women with hypertension. Children between 2 and 5 years had a 19% reduced risk of SARS-CoV-2 seropositivity (aPRR=0.81, 95%CI: 0.64-1.02) when compared to younger children. Mother/infant SARS-CoV-2 serostatuses were discordant in 346/802 (43.1%) families tested: mothers+/children- in 72.3%; mothers-/children+ in 26.3%; child+/sibling+ concordance was 34.6%., Conclusions: These SARS-CoV-2 seropositivity data indicate that by late 2021, about 60% of mothers and about 40% of children in a cohort of HIV-affected families in eastern/southern Africa had been infected with SARS-CoV-2. More mothers than their infants tested SARS-CoV-2+, likely due to a greater external exposure for mothers linked to daily routines/employment, and school closures. Breastfeeding was protective for mothers, likely because of higher likelihood of staying home with young children, and thus less exposure. Discordant results between children within the same families underscores the need to further understand transmission dynamics within households., (© 2024. The Author(s).)

Objective: HIV treatment regimen during pregnancy was associated with preterm delivery (PTD) in the PROMISE 1077 BF trial. Systemic inflammation among pregnant women with HIV could help explain differences in PTD by treatment regimen. We assessed associations between inflammation, treatment regimen, and PTD., Design/methods: A nested 1 : 1 case-control study ( N  = 362) was conducted within a multicountry randomized trial comparing three HIV regimens in pregnant women: zidovudine alone, or combination antiretroviral therapy (ART) with lopinavir/ritonavir and either zidovudine or tenofovir. Cases were women with PTD (<37 weeks of gestational age). The following inflammatory biomarkers were measured in plasma samples using immunoassays: soluble CD14 (sCD14) and sCD163, intestinal fatty acid-binding protein, interleukin (IL)-6, interferon γ, and tumor necrosis factor α. We fit regression models to assess associations between second trimester biomarkers (measured before ART initiation at 13-23 weeks of gestational age and 4 weeks later), treatment regimen, and PTD. We also assessed whether inflammation was a mediator in the relationship between ART regimen and PTD., Results: Persistently high interleukin-6 was associated with increased PTD. Compared with zidovudine alone, the difference in biomarker concentration between week 0 and week 4 was significantly higher ( P  < 0.05) for both protease inhibitor-based regimens. However, the estimated proportion of the ART effect on increased PTD mediated by persistently high biomarker levels was 5% or less for all biomarkers., Conclusion: Persistently high IL-6 during pregnancy was associated with PTD. Although protease inhibitor-based ART was associated with increases in inflammation, factors other than inflammation likely explain the increased PTD in ART-based regimens compared with zidovudine alone., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: We evaluated associations between antepartum weight change and adverse pregnancy outcomes and between antiretroviral therapy (ART) regimens and week 50 postpartum body mass index in IMPAACT 2010., Methods: Women with human immunodeficiency virus (HIV)-1 in 9 countries were randomized 1:1:1 at 14-28 weeks' gestational age (GA) to start dolutegravir (DTG) + emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) versus DTG + FTC/tenofovir disoproxil fumarate (TDF) versus efavirenz (EFV)/FTC/TDF. Insufficient antepartum weight gain was defined using Institute of Medicine guidelines. Cox-proportional hazards regression models were used to evaluate the association between antepartum weight change and adverse pregnancy outcomes: stillbirth (≥20 weeks' GA), preterm delivery (<37 weeks' GA), small size for GA (<10th percentile), and a composite of these endpoints., Results: A total of 643 participants were randomized: 217 to the DTG + FTC/TAF, 215 to the DTG + FTC/TDF, and 211 to the EFV/FTC/TDF arm. Baseline medians were as follows: GA, 21.9 weeks; HIV RNA, 903 copies/mL; and CD4 cell count, 466/μL. Insufficient weight gain was least frequent with DTG + FTC/TAF (15.0%) versus DTG + FTC/TDF (23.6%) and EFV/FTC/TDF (30.4%). Women in the DTG + FTC/TAF arm had the lowest rate of composite adverse pregnancy outcome. Low antepartum weight gain was associated with higher hazard of composite adverse pregnancy outcome (hazard ratio, 1.44 [95% confidence interval, 1.04-2.00]) and small size for GA (1.48 [.99-2.22]). More women in the DTG + FTC/TAF arm had a body mass index ≥25 (calculated as weight in kilograms divided by height in meters squared) at 50 weeks postpartum (54.7%) versus the DTG + FTC/TDF (45.2%) and EFV/FTC/TDF (34.2%) arms., Conclusions: Antepartum weight gain on DTG regimens was protective against adverse pregnancy outcomes typically associated with insufficient weight gain, supportive of guidelines recommending DTG-based ART for women starting ART during pregnancy. Interventions to mitigate postpartum weight gain are needed., Competing Interests: Potential conflicts of interest. R. M. H. is an Elsevier ClinicalKey editorial board member. R. M. H. also reports honoraria for lectures on this topic from the Los Angeles County Division of HIV and STI Programs and the UCLA CARE Center’s continuing medical education seminars. S. B. and L. Z. reports support for the present work from the NIH Division of AIDS/Eunice Kennedy Shriver National Institute of Child Health and Human Development and ViiV/GSK, paid to their institution. L. F. reports grants or contracts for the current study through NIH/IMPAACT. S. H. reports grants or contracts from UKZN Developing Research Innovation, Localisation and Leadership in South Africa (DRILL), the Fogarty International Center, the NIH Common Fund, Office of Strategic Coordination, Office of the Director, Office of AIDS Research, the NIH Office of the Director, the National Institute of Mental Health, NIH (award D43TW010131, paid to their institution, from January 2018 to July 2023), and the SA National Research Foundation (Thuthuka funding grant, paid to their institution, from January 2019 to December 2021). R. Z. reports receipt of study medication from ViiV healthcare for a federally funded research study (as principal investigator); ViiV is donating long-acting cabotegravir for an implementation study of preexposure prophylaxis in Botswana, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. J. S. C. is a scientific advisor for Merck, participating on its advisory board, and reports royalties or licenses from UpToDate. P. S. reports grants or contracts from Gilead and ViiV; consulting fees from Gilead, Janssen, Merck, and ViiV; and participation on a data safety monitoring board or advisory board for Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Integration of cardiovascular disease SCreening and prevention in the HIV MAnagement plan for women of reproductive age study set out to determine the effectiveness of screening and lifestyle modification in modifying cardiovascular disease (CVD) risk factors in women living with HIV (WLHIV)., Methods: In this prospective, quasiexperimental, intervention study, WLHIV aged 18-<50 years were enrolled from 2 clinics (intervention [I-arm]) and (control arms [C-arm]) in Umlazi, South Africa, between November 2018 and May 2019. Women in the I-arm received lifestyle modification advice on diet, physical activity, alcohol use, and smoking cessation and underwent annual screening for CVD risk. The CVD risk factors were assessed through standardized questionnaires and clinical and laboratory procedures at baseline and at end of 3 years of follow-up. Prevalence of metabolic syndrome and other CVD indices were compared between arms at end-of-study (EOS)., Results: Total of 269 WLHIV (149 I-arm and 120 C-arm) with a mean ± SD age of 36 ± 1 years were included in the EOS analyses after 32 ± 2 months of follow-up. The metabolic syndrome prevalence at EOS was 16.8% (25/149) in the I-arm and 24% (24/120) in the C-arm (risk ratio 0.9; 95% CI: 0.5 to 1.1; P 0.86). Proportion of women with fasting blood glucose >5.6 mmol/L in the I-arm and C-arm were 2.7% (4/149) and 13.3% (16/120) respectively (risk ratio 0.2; 95% CI: 0.069 to 0.646; P < 0.01). High-density lipoprotein improved with the intervention arm from baseline to EOS (95% CI: -0.157 to -0.034; P < 0.05)., Conclusions: Although there was no significant difference in the prevalence of metabolic syndrome between study arms, we observed decreased blood glucose levels in the I-arm compared with the C-arm and improved high-density lipoprotein within the I-arm, following lifestyle modification and regular screening for CVD risk factors in WLHIV., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined., Methods: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model., Results: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts., Conclusions: Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lifelong antiretroviral treatment (ART) use is recommended for pregnant and breastfeeding (BF) women living with HIV (WLWH) to prevent perinatal HIV transmission and improve maternal health. We address 2 objectives in this analysis: (1) determine timing and factors associated with BF cessation and (2) assess the impact of BF on health of WLWH on ART., Setting: This multicountry study included 8 sites in Uganda, Malawi, Zimbabwe, and South Africa., Methods: This was a prospective study of WLWH on lifelong ART. These women initially participated from 2011 to 2016 in a randomized clinical trial (PROMISE) to prevent perinatal HIV transmission and subsequently reenrolled in an observational study (PROMOTE, 2016-2021) to assess ART adherence, safety, and impact., Results: The PROMOTE cohort included 1987 women on ART. Of them, 752 breastfed and were included in analyses of objective 1; all women were included in analyses of objective 2. The median time to BF cessation varied by country (11.2-19.7 months). Country of residence, age, and health status of women were significantly associated with time to BF cessation (compared with Zimbabwe: Malawi, adjusted hazard ratio [aHR] 0.50, 95% confidence interval [95% CI]: 0.40 to 0.62, P < 0.001; South Africa, aHR 1.49, 95% CI: 1.11 to 2.00, P = 0.008; and Uganda, aHR 1.77, 95% CI: 1.37 to 2.29, P < 0.001). Women who breastfed had lower risk of being "unwell" compared with women who never breastfed (adjusted rate ratio 0.87, 95% CI: 0.81 to 0.95 P = 0.030)., Conclusion: Women on lifelong ART should be encouraged to continue BF with no concern for their health. Time to BF cessation should be monitored for proper counseling in each country., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive., Objectives: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens., Methods: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth., Results: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context., Conclusion: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation., (© 2023. The Author(s).)

Background: Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1., Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422., Findings: Between Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per μL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups., Interpretation: Safety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy., Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health., Competing Interests: Declaration of interests JvW is an employee of ViiV Healthcare and JFR is an employee of Gilead Sciences. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Antiretroviral therapy (ART) is associated with high rates of adverse birth outcomes, including preterm birth and low birthweight. Studies suggest that progesterone and prolactin may play important intermediary roles., Methods: We analyzed data from the Antenatal Component of the PROMISE trial, a multi-center study of pregnant women taking antiretroviral regimens (lopinavir/ritonavir-containing ART or zidovudine alone) to prevent mother-to-child HIV transmission. In a nested case-control study, we compared data from women who gave birth to preterm (<37 weeks gestation) and/or low birthweight (<2500 g) infants to matched individuals who did not. We measured serum progesterone and prolactin at 24-34 weeks gestation. We used conditional logistic regression to describe relationships between hormone levels, birth outcomes, and antiretroviral regimens., Results: 299 women and their newborns were included (146 cases, 153 controls). When compared to women receiving zidovudine alone, those on ART had higher odds of progesterone levels under the 10th percentile (adjusted odds ratio [AOR]:2.34, 95%CI:1.41-3.89) and 25th percentile (AOR:2.07, 95%CI:1.46-2.94). However, higher levels of progesterone-rather than lower levels-were associated with our composite case outcome at the 10th percentile (AOR:1.88, 95%CI:0.77-4.59) and 25th percentile (AOR:1.96, 95%CI:1.06-3.61). Associations were not observed between prolactin, antiretroviral regimen, and birth outcomes., Conclusion: We observed lower progesterone levels among women allocated to ART regimens; however, higher progesterone levels were associated with preterm birth and/or low birthweight. While features of the study design may have contributed to these findings, they nevertheless highlight the potentially complex mechanisms underpinning adverse birth outcomes and HIV., Competing Interests: The study products in the PROMISE trial were provided free of charge by Abbott, Gilead Sciences, Boehringer Ingelheim, and GlaxoSmithKline. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Chi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human immunodeficiency virus (HIV) viral load (VL) is an important quantitative marker of disease progression and treatment response in people living with HIV infection, including children with perinatally acquired HIV. Measures of VL are often used to predict different outcomes of interest in this population, such as HIV-associated neurocognitive disorder. One popular approach to summarizing historical viral burden is the area under a time-VL curve (AUC). However, alternative historical VL summaries (HVS) may better answer the research question of interest. In this article, we discuss and contrast the AUC with alternative HVS, including the time-averaged AUC, duration of viremia, percentage of time with suppressed VL, peak VL, and age at peak VL. Using data on youth with perinatally acquired HIV infection from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, we show that HVS and their associations with full-scale intelligence quotient depend on when the VLs were measured. When VL measurements are incomplete, as can be the case in observational studies, analysis results may be subject to selection bias. To alleviate bias, we detail an imputation strategy, and we present a simulation study demonstrating that unbiased estimation of a historical VL summary is possible with a correctly specified imputation model., (© Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited., Methods: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results., Results: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar., Conclusions: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: Given the roll out of maternal antiretroviral therapy (ART) for prevention-of-perinatal-HIV-transmission, increasing numbers of children are perinatally HIV/antiretroviral exposed but uninfected (CAHEU). Some studies suggest CAHEU may be at increased risk for neurodevelopmental (ND) deficits. We aimed to assess ND performance among preschool CAHEU., Design: This cross-sectional study assessed ND outcomes among 3-6-year-old CAHEU at entry into a multicountry cohort study., Methods: We used the Mullen Scales of Early Learning (MSEL) and Kaufman Assessment Battery for Children (KABC-II) to assess ND status among 3-6-year-old CAHEU at entry into the PROMISE Ongoing Treatment Evaluation (PROMOTE) study conducted in Uganda, Malawi, Zimbabwe and South Africa. Statistical analyses (Stata 16.1) was used to generate group means for ND composite scores and subscale scores, compared to standardized test score means. We used multivariable analysis to adjust for known developmental risk factors including maternal clinical/socioeconomic variables, child sex, growth-for-age measurements, and country., Results: 1647 children aged 3-6 years had baseline ND testing in PROMOTE; group-mean unadjusted Cognitive Composite scores on the MSEL were 85.8 (standard deviation [SD]: 18.2) and KABC-II were 79.5 (SD: 13.2). Composite score group-mean differences were noted by country, with South African and Zimbabwean children having higher scores. In KABC-II multivariable analyses, maternal age >40 years, lower education, male sex, and stunting were associated with lower composite scores., Conclusions: Among a large cohort of 3-6 year old CAHEU from eastern/southern Africa, group-mean composite ND scores averaged within the low-normal range; with differences noted by country, maternal clinical and socioeconomic factors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies., Discussion: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias., Conclusions: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: We report the long-term impact of ART in women of reproductive age (15-49 years) in Africa who have been using ART for up to 10 years. We assess outcomes of retention, adherence, maternal health, fertility intentions, and safety., Methods: This longitudinal, multicountry study (PROMOTE) enrolled women who initiated ART in an earlier perinatal clinical trial, PROMISE. PROMISE occurred from 2011 to 2016 and PROMOTE follow-up started in 2016 and is ongoing. The PROMOTE study was done at eight sites in four countries: Malawi (Blantyre and Lilongwe), South Africa (Durban and Soweto), Uganda (Kampala), and Zimbabwe (Harare, Seke North, and St Mary's). After baseline enrolment, women and their children are followed up every 6 months to collect information on medical history, antiretroviral therapy (ART) use, adherence, and health information, and to do physical examinations and laboratory tests. Obesity was defined as a body-mass index of 30 kg/m 2 or more. Data analyses were restricted to summaries of the main long-term outcomes (retention, adherence, maternal health, fertility intentions, and safety). We used descriptive and stratified analyses, and estimated rates using person-years of follow-up and computed probabilities based on Kaplan-Meier methods., Findings: PROMOTE enrolled 1987 mothers and 2522 children. The median follow-up time for mothers was 41·8 (IQR 35·8-42·0) months and for children was 35·7 (23·8-42·0) months. Overall retention rates were 96·5% for mothers and 94·3% for children at 12 months, and, at 42 months, were 88·9% for mothers and 85·4% for children. 1115 (89·1%) of 1252 women had an undetectable viral load at 42 months, which varied by site (81·7-93·8%). Reported maternal health improved over time, with the proportion of women with excellent to very good health increasing from 67·5% at baseline to 87·5% at 42 months, the proportion of unwell participants who visited a health centre declining from 14·7% to 2·8%, and the proportion of those admitted to hospital declining from 1·5% to 1·0%. The desire to have more children was consistently high at some sites. The proportion of women with obesity was high in South Africa and increased over time from 40·2% at baseline to 52·8% at 42 months. The overall pregnancy rate was 17·6 (95% CI 16·5-18·7) per 100 women-years, and mortality rates were 2·4 (1·4-3·9) per 1000 person-years for mothers and 3·4 (2·2-5·10) per 1000 person-years for children (0-9 years)., Interpretation: The findings from this multicountry study are reassuring. These findings show that African women can consistently use ART for a long period after initiation, and long-term benefits can be maintained. Services to support maternal HIV care, treatment, and reproductive health should be strengthened., Funding: US President's Emergency Plan for AIDS Relief., Competing Interests: Declaration of interests SH was supported by Developing Research Innovation, Localization and Leadership in South Africa (DRILL), Fogarty International Center, US National Institutes of Health Common Fund, US Office of Strategic Coordination, US Office of the Director, US Office of AIDS Research, US Office of the Director, National Institute of Mental Health of the US National Institutes of Health (D43TW010131). All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study examined associations of self-regulatory behavior and cognitive functioning with substance use (SU) to inform interventions for youth with perinatal HIV infection (YPHIV) or exposure but uninfected (YPHEU). Youth aged 7-15 years (YPHIV, n = 390; YPHEU, n = 211) were followed longitudinally with cognitive testing and behavioral questionnaires including self-report of alcohol, marijuana, tobacco, and other SU. Cox proportional hazards analyses were used to examine correlates of initiating each substance for those without prior use at baseline and generalized estimating equation analyses were used to address associations of cognitive/behavioral measurements with SU prevalence for the entire sample. Lower self-reported self-regulation skills, but higher cognitive functioning abilities, were associated with initiation and prevalent use of alcohol and marijuana regardless of HIV status. Our findings suggest SU screening tools and self-regulation interventions developed for general adolescent populations should be implemented for those with PHIV, who may be at heightened risk for SU-related health consequences., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children., Methods: Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA) < 70 and 247 CSA ≥ 70 (discovery cohort [DC]). SNVs identified in DC were evaluated in 2 validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes., Results: Twenty-nine SNVs in 24 genes reaching P ≤ .002 and OR ≥ 1.5 comparing CSA < 70 to CSA ≥ 70 were identified in the DC, of which 3 SNVs were identified in VCs for further study. Combining the 3 cohorts, SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (P < .0001); RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (P < .0001 and P < .001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1β following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1β release., Conclusions: Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: Zidovudine (ZDV) has been extensively used in pregnant women to prevent vertical transmission of HIV but few studies have evaluated potential mutagenic effects of ZDV during fetal development., Design: Our study investigated clonal hematopoiesis in HIV-exposed uninfected (HEU) newborns, 94 of whom were ZDV-exposed and 91 antiretroviral therapy (ART)-unexposed and matched for potential confounding factors., Methods: Utilizing high depth sequencing and genotyping arrays, we comprehensively examined blood samples collected during the first week after birth for potential clonal hematopoiesis associated with fetal ZDV exposure, including clonal single nucleotide variants (SNVs), small insertions and deletions (indels), and large structural copy number or copy neutral alterations., Results: We observed no statistically significant difference in the number of SNVs and indels per person in ZDV-exposed children (adjusted ratio [95% confidence interval, CI] for expected number of mutations = 0.79 [0.50--1.22], P = 0.3), and no difference in the number of large structural alterations. Mutations in common clonal hematopoiesis driver genes were not found in the study population. Mutational signature analyses on SNVs detected no novel signatures unique to the ZDV-exposed children and the mutational profiles were similar between the two groups., Conclusion: Our results suggest that clonal hematopoiesis at levels detectable in our study is not strongly influenced by in-utero ZDV exposure; however, additional follow-up studies are needed to further evaluate the safety and potential long-term impacts of in-utero ZDV exposure in HEU children as well as better investigate genomic aberrations occurring late in pregnancy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Globally, the number of infected women of childbearing age living with human immunodeficiency virus (HIV) and conceiving on antiretroviral therapy (ART) is increasing. Evidence of ART safety at conception and during pregnancy and adverse pregnancy outcomes remains conflicting. The Promoting Maternal and Infant Survival Everywhere (PROMISE) 1077 breastfeeding (BF) and formula feeding (FF) international multisite trials provide an opportunity to examine the impact of ART at conception on pregnancy outcomes with subsequent pregnancies., Methods: The PROMISE 1077BF/1077FF trials were designed to address key questions in the management of HIV-infected women who did not meet clinical guidelines for ART treatment during the time of the trials. After the period of risk of mother-to-child transmission was over, women were randomized to either continue or discontinue ART. We compared subsequent pregnancy outcomes of nonbreastfeeding women randomized to continue ART following delivery, or breastfeeding women randomized to continue ART following breastfeeding cessation who conceived while on ART to women randomized to discontinue ART, who restarted ART after pregnancy was diagnosed., Results: Pregnancy outcomes of 939 subsequent pregnancies of 826 mothers were recorded. The intention-to-treat analyses showed increased incidence of low birth weight (<2500 g) for women who conceived while on ART (relative risk, 2.65 [95% confidence interval {CI}, 1.20-5.81]), and also a higher risk of spontaneous abortion, stillbirth, or neonatal death (hazard ratio, 1.40 [95% CI, .99-1.98]) compared to women who restarted ART after they were found to be pregnant during trial follow-up., Conclusions: We found an increased risk for adverse pregnancy outcomes in women conceiving on ART, emphasizing the need for improved obstetric and neonatal care for this group., Clinical Trials Registration: NCT01061151., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction: Untargeted metabolomics holds significant promise for biomarker detection and development. In resource-limited settings, a dried blood spot (DBS)-based platform would offer significant advantages over plasma-based approaches that require a cold supply chain., Objectives: The primary goal of this study was to compare the ability of DBS- and plasma-based assays to characterize maternal metabolites. Utility of the two assays was also assessed in the context of a case-control predictive model in pregnant women living with HIV., Methods: Untargeted metabolomics was performed on archived paired maternal plasma and DBS from n = 79 women enrolled in a large clinical trial., Results: A total of 984 named biochemicals were detected across both plasma and DBS samples, of which 627 (63.7%), 260 (26.4%), and 97 (9.9%) were detected in both plasma and DBS, plasma alone, and DBS alone, respectively. Variation attributable to study individual (R 2  = 0.54, p < 0.001) exceeded that of the sample type (R 2  = 0.21, p < 0.001), suggesting that both plasma and DBS were capable of differentiating individual metabolomic profiles. Log-transformed metabolite abundances were strongly correlated (mean Spearman rho = 0.51) but showed low agreement (mean intraclass correlation of 0.15). However, following standardization, DBS and plasma metabolite profiles were strongly concordant (mean intraclass correlation of 0.52). Random forests classification models for cases versus controls identified distinct feature sets with comparable performance in plasma and DBS (86.5% versus 91.2% mean accuracy, respectively)., Conclusion: Maternal plasma and DBS samples yield distinct metabolite profiles highly predictive of the individual subject. In our case study, classification models showed similar performance albeit with distinct feature sets. Appropriate normalization and standardization methods are critical to leverage data from both sample types. Ultimately, the choice of sample type will likely depend on the compounds of interest as well as logistical demands.

Background: Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate., Methods: This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422., Findings: Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per μL (308-624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of -10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference -8·8% [95% CI -17·3 to -0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; -8·6% [-17·1 to -0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; -6·3% [-11·8 to -0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050)., Interpretation: When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths., Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health., Competing Interests: Declaration of interests JDM reports receiving research support from Gilead, paid to his institution. NKT is an employee of ViiV Healthcare. JFR is an employee and stockholder of Gilead Sciences. KRA reports receiving fees from Gilead Sciences for expert consultation. JC reports receiving fees from Merck & Co for service on a scientific advisory board. PES reports receiving research support and fees for service on scientific advisory boards from Gilead Sciences and ViiV Healthcare. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To quantify the rate of change in epigenetic age compared with chronological age over time in youth with perinatally acquired HIV (YPHIV) and youth who are perinatally HIV-exposed uninfected (YPHEU)., Design: Longitudinal study of 32 YPHIV and 8 YPHEU with blood samples collected at two time points at least 3 years apart., Methods: DNA methylation was measured using the Illumina MethylationEPIC array and epigenetic age was calculated using the Horvath method. Linear mixed effects models were fit to estimate the average change in epigenetic age for a 1-year change in chronological age separately for YPHIV and YPHEU., Results: Median age was 10.9 and 16.8 years at time 1 and 2, respectively. Groups were balanced by sex (51% male) and race (67% black). Epigenetic age increased by 1.23 years (95% CI 1.03--1.43) for YPHIV and 0.95 years (95% CI 0.74--1.17) for YPHEU per year increase in chronological age. Among YPHIV, in a model with chronological age, a higher area under the curve (AUC) viral load was associated with an increase in epigenetic age over time [2.19 years per log10 copies/ml, (95% CI 0.65--3.74)], whereas a higher time-averaged AUC CD4+ T-cell count was associated with a decrease in epigenetic age over time [-0.34 years per 100 cells/μl, (95% CI -0.63 to -0.06)] in YPHIV., Conclusion: We observed an increase in the rate of epigenetic aging over time in YPHIV, but not in YPHEU. In YPHIV, higher viral load and lower CD4+ T-cell count were associated with accelerated epigenetic aging, emphasizing the importance of early and sustained suppressive treatment for YPHIV, who will receive lifelong ART., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: IMPAACT PROMISE 1077BF/FF was a sequentially randomized study of pregnant and postpartum women living with HIV to investigate the efficacy and safety of antiretroviral therapy (ART). This Maternal Health Component investigated efficacy for the risk of developing AIDS or death; and safety among women randomized to continue ART (CTART: N = 289) or discontinue ART (N = 268) after cessation of breastfeeding or after confirmation of infant infection. No AIDS-defining illnesses were reported during follow-up in either arm. Adverse events of grade 3 or higher were more frequent in the CTART arm [hazard ratio = 1.78, 95% confidence interval: (1.05 to 3.02), P-value = 0.03]. The difference in adverse events in the 2 groups was mostly driven by moderate weight loss for women on the CTART arm., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS)., Methodology: Lifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr)., Results: PHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis., Conclusions: Among children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood., Summary: Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents., Competing Interests: Declaration of competing interest Denise L. Jacobson, No conflict. Wendy Yu, No conflict. Rohan Hazra, No conflict. Sean Brummel, No conflict. Mitchell E. Geffner, No conflict. Kunjal Patel, No conflict. William Borkowsky, No conflict. Jiajia Wang, No conflict. Janet S. Chen, No conflict. Ayesha Mirza, No conflict. Linda A. DiMeglio, No conflict. for the Pediatric HIV/AIDS Cohort Study, No conflict., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

Background: Intensified viral load monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies., Methods: We used an individual Monte Carlo simulation to describe longitudinal ART adherence and viral load from conception until 2 years' postpartum. We applied national and international guidelines for viral load monitoring to the simulated data. We compared guidelines on the percentage of women receiving viral load monitoring and the percentage of women monitored at the time of elevated viral load., Results: Coverage of viral load monitoring in pregnancy and breastfeeding varied markedly, with between 14% and 100% of women monitored antenatally and 38-98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved more than 95% testing in pregnancy but this was much lower (14-83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated viral load more than 1000 copies/ml were successfully detected by monitoring (range, 20-50%)., Discussion: Although further research is needed to understand optimal viral load frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated viral load in pregnant and breastfeeding women.

Background: Given well documented challenges faced by pregnant women living with HIV taking lifetime ART, it is critical to understand the impact of short-term ART exposure followed by treatment interruption on maternal health outcomes., Methods: HIV+ breastfeeding (BF) and Formula Feeding (FF) women with CD4 counts > 350 cells/mm3, enrolled in the 1077BF/1077FF PROMISE trial were followed to assess the effect of ART during pregnancy and breastfeeding respectively. The first analysis compared ART use limited to the antepartum period (AP-only) relative to women randomized to Zidovudine. The second analysis included women with no pregnancy combination ART exposure; and compared women randomized to either ART or no ART during postpartum (PP-only). Both analyses included follow-up time beyond breastfeeding period. The primary outcome was progression to AIDS and/or death. Secondary outcomes included adverse events and HIV-related events., Results: 3490 and 1137 HIV+ women were enrolled from 14 sites in Africa and India from April 2011 through September 2014 in cohort AP-only and PP-only, respectively. Most were Black African (96%); median age was 27 years; 97% were WHO Clinical Stage I; and most had a screening CD4 count ≥500 cells/mm3 (78%). The rate of progression to AIDS and/or death was similar and low across all comparison arms (AP comparison, HR = 1.14, 95%CI (0.44, 2.96), p-value = 0.79). In the PP-only cohort, the rate of WHO stage 2-3 events was lower for women randomized to ART(HR = 0.65, 95% CI 0.42, 1.01, p-value = 0.05)., Conclusion: The incidence of AIDS and/or death was low in pregnant/postpartum HIV+ women with highCD4 cell counts for all comparison arms. This provides some reassurance that there were limited consequences for short term ART interruption in this group of asymptomatic HIV+ women during up to 4 years of follow up; and underscores that even short term ART exposure postpartum may reduce the risk of WHO grade 2-3 disease progression., Competing Interests: The authors have declared that no competing interests exist.

Objective(s): The short-term safety of treatment interruptions, a necessary part of cure studies, is not well established, particularly in women. We explored viral rebound kinetics and safety in a group of postpartum women discontinuing ART and compared results to men in historical interruption trials., Design: Prospective evaluation of time to virologic rebound., Methods: One thousand and seventy-six asymptomatic, virally suppressed, postpartum women living with HIV enrolled in the PROMISE trial with baseline CD4 cell counts at least 350 cells/μl underwent antiretroviral treatment (ART) discontinuation. Proportion with virologic suppression at weeks 4 and 12 were compared with participants in ACTG treatment interruption trials (91% male population)., Results: In PROMISE, using interval censored methods, the estimated median time to HIV viral rebound was 2 weeks. An estimated 6% of women would remain virally suppressed at 30 weeks. Of those who had viral rebound by 30 weeks (N = 993), less than 4% experienced grade 3 or higher laboratory events, and 1% experienced WHO stage 2 or higher clinical events. Overall, less than 1% of participants progressed from WHO Stage 1 to Stage 2 or higher after discontinuation of ART, and 3.9% experienced a decline in CD4 cell count to less than 350 cells/μl or local treatment guidelines. A significantly higher proportion of women in PROMISE (25.4%) were virologically suppressed (<400 copies/ml) at 12 weeks compared with ACTG NWCS 371 participants (6.4%)., Conclusion: Temporary treatment interruptions in healthy, HIV-infected women with high CD4 cell counts can be well tolerated. Potential sex differences need to be considered in cure studies examining time to virologic rebound.

Objectives: Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length at birth in HIV-exposed-uninfected (HEU) newborns., Methods: We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative telomere length in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative telomere length between ZDV-exposed and ART-unexposed children. We additionally evaluated relative telomere length according to maternal and infant characteristics., Results: Relative telomere length was longer in ZDV-exposed children compared with ART-unexposed individuals (adjusted mean ratio difference 0.21, 95% confidence interval 0.15-0.28, P < 0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative telomere length (-0.06 per log10 copies, 95% confidence interval -0.08 to -0.03, P < 0.001). Relative telomere length was not associated with maternal CD4 cell count, maternal age, gestational age, sex, sample storage time, or maternal substance use (P > 0.05)., Conclusion: Relative telomere length was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of ART during pregnancy, as we observed an inverse association with maternal HIV RNA levels.

To design immune interventions that can synergize with antiretroviral therapy (ART) to reduce the rate of HIV mother-to-child transmission (MTCT), it is essential to characterize maternal immune responses in the setting of ART during pregnancy and breastfeeding and define their effect on MTCT. Prior studies reported an association between breast milk envelope (Env)-specific antibodies and antibody-dependent cell cytotoxicity (ADCC) activity with reduced postnatal transmission. In this study, we investigated whether these immune correlates were similarly associated with protection in a matched case-control study of mother-infant pairs receiving maternal ART or infant nevirapine prophylaxis during breastfeeding in the International Maternal-Pediatric-Adolescent AIDS Clinical Trials Network Promoting Maternal-Infant Survival Everywhere (PROMISE) trial, assessing postnatal transmission risk in 19 transmitting and 57 nontransmitting mothers using conditional logistic regression models adjusted for maternal plasma viral load. The odds ratios of postnatal MTCT for a 1-unit increase in an immune correlate were 3.61 (95% confidence interval [CI], 0.56, 23.14) for breast milk Env-specific secretory IgA (sIgA), 2.32 (95% CI, 0.43, 12.56) for breast milk and 2.16 (95% CI, 0.51, 9.14) for plasma Env-specific IgA, and 4.57 (95% CI, 0.68, 30.48) for breast milk and 0.96 (95% CI, 0.25, 3.67) for plasma ADCC activity, with all CIs spanning 1.0. Interestingly, although mucosal IgA responses are poor in untreated HIV-infected women, there was a strong correlation between the magnitudes of breast milk and plasma Env-specific IgA in this cohort. In this analysis of the small number of postnatal virus transmissions in the landmark PROMISE study, no single antibody response was associated with breast milk transmission risk. IMPORTANCE Each year, >150,000 infants become newly infected with HIV-1 through MTCT despite ART, with up to 42% of infections occurring during breastfeeding. Several factors contribute to continued pediatric infections, including ART nonadherence, the emergence of drug-resistant HIV strains, acute infection during breastfeeding, and poor access to ART in resource-limited areas. A better understanding of the maternal humoral immune responses that provide protection against postnatal transmission in the setting of ART is critical to guide the design of maternal vaccine strategies to further eliminate postnatal HIV transmission. In this study, we found that in women treated with antiretrovirals during pregnancy, there was a positive correlation between plasma viral load and breast milk and plasma IgA responses; however, conclusions regarding odds of MTCT risk were limited by the small sample size. These findings will inform future studies to investigate maternal immune interventions that can synergize with ART to eliminate MTCT during breastfeeding., (Copyright © 2019 Hompe et al.)

Background: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies., Methods: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals., Results: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87)., Conclusions: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Antiretroviral treatment (ART) adherence is often suboptimal in the perinatal period. We measured hair tenofovir (TFV) concentrations as a metric of adherence in postpartum women to understand patterns and predictors of adherence throughout this critical period. In addition, we examined the association between hair TFV concentrations and virologic outcomes., Methods: Between 12/2012 and 09/2016, hair samples were collected longitudinally from delivery through breastfeeding from women on ART in the Promoting Maternal and Infant Survival Everywhere study (NCT01061151) in sub-Saharan Africa. Hair TFV levels were measured using validated methods. Using generalized estimating equations, we estimated the association between hair TFV levels and virologic suppression (<400 copies/ml) over time and assessed predictors of hair TFV levels., Results: Hair TFV levels were measured at 370 visits in 71 women from delivery through a median of 14 months (interquartile range 12-15) of breastfeeding. Levels ranged from below detection (0.002) to 1.067 ng/mg (geometric mean: 0.047). After at least 90 days on ART, 69 women had at least one viral load measured (median 5 measures, range 1-9); 18 (26%) experienced viremia at least once. Each doubling of TFV level more than doubled odds of concurrent virologic suppression [odds ratio 2.35, 95% confidence interval (CI): 1.44-3.84, P = 0.0006] and was associated with 1.43 times the odds of future suppression (95% CI: 0.75-2.73, P = 0.28). Relative to the first 3 months after delivery, hair levels were highest in months 6-12 (1.42-fold higher, 95% CI: 1.09-1.85, P = 0.01)., Conclusion: Hair TFV levels strongly predicted concurrent virologic suppression among breastfeeding women. Objective adherence metrics can supplement virologic monitoring to optimize treatment outcomes in this important transition period.

Background: Adverse pregnancy outcomes for women who conceive on antiretroviral therapy (ART) may be increased, but data are conflicting., Methods: Human immunodeficiency virus-infected, nonbreastfeeding women with pre-ART CD4 counts ≥400 cells/μL who started ART during pregnancy were randomized after delivery to continue ART (CTART) or discontinue ART (DCART). Women randomized to DCART were recommended to restart if a subsequent pregnancy occurred or for clinical indications. Using both intent-to-treat and as-treated approaches, we performed Fisher exact tests to compare subsequent pregnancy outcomes by randomized arm., Results: Subsequent pregnancies occurred in 277 of 1652 (17%) women (CTART: 144/827; DCART: 133/825). A pregnancy outcome was recorded for 266 (96%) women with a median age of 27 years (interquartile range [IQR], 24-31 years) and median CD4+ T-cell count 638 cells/μL (IQR, 492-833 cells/μL). When spontaneous abortions and stillbirths were combined, there was a significant difference in events, with 33 of 140 (23.6%) in the CTART arm and 15 of 126 (11.9%) in the DCART arm (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.1-3.5]; P = .02). In the as-treated analysis, the RR was reduced and no longer statistically significant (RR, 1.4 [95% CI, .8-2.4])., Conclusions: Women randomized to continue ART who subsequently conceived were more likely to have spontaneous abortion or stillbirth, compared with women randomized to stop ART; however, the findings did not remain significant in the as-treated analysis. More data are needed on pregnancy outcomes among women conceiving on ART, particularly with newer regimens.

Background: The PROMOTE study aims to measure long-term antiretroviral treatment (ART) safety and adherence; compare HIV disease progression; assess subsequent adverse pregnancy outcomes; evaluate effect of ART exposure on growth and development in HIV-exposed uninfected children; and assess long-term survival of mothers and children. This report primarily describes cohort characteristics at baseline to better understand long-term outcomes., Methods and Findings: This is a prospective study. HIV-infected mothers and their children originally recruited in a multisite randomized clinical trial for prevention of perinatal HIV transmission were re-enrolled in PROMOTE. A total of 1987 mothers and 1784 children were enrolled from eight sites in Uganda, Malawi, Zimbabwe and South Africa. Most women (≥75%) reported being married in Malawi and Zimbabwe compared to low proportions in South Africa (4.4% in Durban and 15% in Soweto), and 43.5% in Uganda (p<0.001). There were variabilities in contraceptive practices: injectable contraceptive was the commonest reported method (40.9% overall); implant was the second commonest (15.7% overall); oral contraceptives were common in Zimbabwe; and tubal ligation was common in Malawi and South Africa. At baseline, 97.8% of women reported currently using ART; 96.4% were in WHO clinical class 1 or 2; median CD4 cell count was 825 cells per uL; and viral load was undetectable in 1637 (~85%) of the women. Approximately, 14% of women did not inform their primary partners of their own HIV status, 18% reported that they knew their partners were not HIV tested, and 9% did not know if partner was tested. Overall mean age of children at enrollment was 3.5 years; and 5.7% and 25.0% had weight-for-age and height-for-age z-scores <2 standard deviations, respectively., Conclusions: These baseline data show high adherence to ART use. However, issues of HIV disclosure and reproductive intentions remain important. In addition to ART and ensuring high adherence, other preventive measures should be included., Competing Interests: The authors have declared that no competing interests exist

Background: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery., Methods: Women with pre-ART CD4+ cell counts ≥350 cells/mm 3 who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat., Findings: 1611 women were enrolled (June 2011-October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm 3 and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61)., Interpretation: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.

Background: Perinatally HIV-infected (PHIV) children have, on average, lower bone mineral density (BMD) than perinatally HIV-exposed uninfected (PHEU) and healthy children. Low 25-hydroxy vitamin D [25(OH)D] and elevated parathyroid hormone (PTH) concentrations may lead to suboptimal bone accrual., Methods: PHIV and PHEU children in the Pediatric HIV/AIDS Cohort Study had total body (TB) and lumbar spine (LS) BMD and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry; BMD z-scores (BMDz) were calculated for age and sex. Low 25(OH)D was defined as ≤20 ng/mL and high PTH as >65 pg/mL. We fit linear regression models to estimate the average adjusted differences in BMD/BMC by 25(OH)D and PTH status and log binomial models to determine adjusted prevalence ratios of low 25(OH)D and high PTH in PHIV relative to PHEU children., Results: PHIV children (n = 412) were older (13.0 vs. 10.8 years) and more often black (76% vs. 64%) than PHEU (n = 207). Among PHIV, children with low 25(OH)D had lower TB-BMDz [SD, -0.38; 95% confidence interval (CI), -0.60 to -0.16] and TB-BMC (SD, -59.1 g; 95% CI, -108.3 to -9.8); high PTH accompanied by low 25(OH)D was associated with lower TB-BMDz. Among PHEU, children with low 25(OH)D had lower TB-BMDz (SD, -0.34; 95% CI, -0.64 to -0.03). Prevalence of low 25(OH)D was similar by HIV status (adjusted prevalence ratio, 1.00; 95% CI, 0.81 to 1.24). High PTH was 3.17 (95% CI, 1.25 to 8.06) times more likely in PHIV children., Conclusions: PHIV and PHEU children with low 25(OH)D may have lower BMD. Vitamin D supplementation trials during critical periods of bone accrual are needed.

Background: Medication adherence is a critical but challenging developmental task for children and adolescents with perinatally acquired HIV (PHIV). Understanding how medication responsibility, executive functions (EFs) and adaptive functioning (AF) influence adherence may help prepare adolescents for transition to adulthood., Methods: Participants included PHIV children and adolescents 7-16 years of age enrolled in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, who were prescribed antiretroviral medications. Measures included caregiver report and child self-report measures of adherence, medication responsibility and EF, caregiver report of child AF, examiner-administered tests of EF and processing speed and demographic and health characteristics., Results: Two hundred fifty-six participants with PHIV (mean age: 12 years old) were 51% female, 80% black and 79% non-Hispanic. Per 7-day recall, 72% were adherent (no missed doses). Children/adolescents self-reported that 22% had sole and 55% had shared medication responsibility. Adjusted logistic models revealed significantly higher odds of adherence with sole caregiver responsibility for medication [odds ratio (OR): 4.10, confidence interval (CI): 1.43-11.8, P = 0.009], child nadir CD4% <15% (OR: 2.26, CI: 1.15-4.43, P = 0.018), better self-reported behavioral regulation (OR: 0.65, CI: 0.44-0.96, P = 0.029) and slower processing speed (OR: 0.54, CI: 0.38-0.77, P < 0.001), adjusting for demographic variables (age, race and caregiver education)., Conclusions: Among children and adolescents with PHIV, continued caregiver medication management, especially during adolescence, is essential. Although global EF and AF were not significantly associated with adherence, behavioral regulation was. Given that EF and AF develop throughout adolescence, their relationships to adherence should be evaluated longitudinally, especially as youth transition to adulthood and caregiver responsibility diminishes.

Background.: Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown., Methods.: We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS., Results.: In the first 2 years following VS, HIV-1 DNA levels decreased by -0.25 (95% confidence interval [CI], -.36 to -.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (-0.50 and -0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by -0.05 (95% CI, -.06 to -.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates., Conclusions.: Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Health benefits of postpartum antiretroviral therapy (ART) for human immunodeficiency virus (HIV) positive women with high CD4+ T-counts have not been assessed in randomized trials., Methods: Asymptomatic, HIV-positive, non-breastfeeding women with pre-ART CD4+ T-cell counts ≥ 400 cells/mm3 started on ART during pregnancy were randomized up to 42 days after delivery to continue or discontinue ART. Lopinavir/ritonavir plus tenofovir/emtricitabine was the preferred ART regimen. The sample size was selected to provide 88% power to detect a 50% reduction from an annualized primary event rate of 2.07%. A post-hoc analysis evaluated HIV/AIDS-related and World Health Organization (WHO) Stage 2 and 3 events. All analyses were intent to treat., Results: 1652 women from 52 sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand and the US were enrolled (1/2010-11/2014). Median age was 28 years and major racial categories were Black African (28%), Asian (25%) White (15%). Median entry CD4 count was 696 cells/mm3 (IQR 575-869), median ART exposure prior to delivery was 19 weeks (IQR 13-24) and 94% had entry HIV-1 RNA < 1000 copies/ml. After a median follow-up of 2.3 years, the primary composite endpoint rate was significantly lower than expected, and not significantly different between arms (continue arm 0.21 /100 person years(py); discontinue 0.31/100 py, Hazard ratio (HR) 0.68, 95% CI: 0.19, 2.40). WHO Stage 2 and 3 events were significantly reduced with continued ART (2.08/100 py vs. 4.36/100 py in the discontinue arm; HR 0.48, 95%CI: 0.33, 0.70). Toxicity rates did not differ significantly between arms. Among women randomized to continue ART, 189/827 (23%) had virologic failure; of the 155 with resistance testing, 103 (66%) failed without resistance to their current regimen, suggesting non-adherence., Conclusions: Overall, serious clinical events were rare among young HIV-positive post-partum women with high CD4 cell counts. Continued ART was safe and was associated with a halving of the rate of WHO 2/3 conditions. Virologic failure rates were high, underscoring the urgent need to improve adherence in this population., Trial Registration: ClinicalTrials.gov NCT00955968.

The Pediatric HIV/AIDS Cohort Study (PHACS), the largest ongoing longitudinal study of perinatal HIV-infected (PHIV) and HIV-exposed, uninfected (PHEU) children in the United States, comprises the Surveillance Monitoring of Antiretroviral Therapy [ART] Toxicities (SMARTT) Study in PHEU children and the Adolescent Master Protocol (AMP) that includes PHIV and PHEU children ≥7 years. Although race/ethnicity is often used to assess health outcomes, this approach remains controversial and may fail to accurately reflect the backgrounds of ancestry-diverse populations as represented in the PHACS participants.In this study, we compared genetically determined ancestry (GDA) and self-reported race/ethnicity (SRR) in the PHACS cohort. GDA was estimated using a highly discriminative panel of 41 single nucleotide polymorphisms and compared to SRR. Because SRR was similar between the PHIV and PHEU, and between the AMP and SMARTT cohorts, data for all unique 1958 participants were combined.According to SRR, 63% of study participants identified as Black/African-American, 27% White, and 34% Hispanic. Using the highest percentage of ancestry/ethnicity to identify GDA, 9.5% of subjects were placed in the incorrect superpopulation based on SRR. When ≥50% or ≥75% GDA of a given superpopulation was required, 12% and 25%, respectively, of subjects were placed in the incorrect superpopulation based on SRR, and the percent of subjects classified as multiracial increased. Of 126 participants with unidentified SRR, 71% were genetically identified as Eurasian.GDA provides a more robust assessment of race/ethnicity when compared to self-report, and study participants with unidentified SRR could be assigned GDA using genetic markers. In addition, identification of continental ancestry removes the taxonomic identification of race as a variable when identifying risk for clinical outcomes., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Ancestry informative markers (AIMs) measure genetic admixtures within an individual beyond self-reported racial/ethnic (SRR) groups. Here, we used genetically determined ancestry (GDA) across SRR groups and examine associations between GDA and HIV-1 RNA and CD4 counts in HIV-positive children in the United States., Methods: Forty-one AIMs, developed to distinguish 7 continental regions, were detected by real-time PCR in 994 HIV-positive, antiretroviral naive children. GDA was estimated comparing each individual's genotypes to allele frequencies found in a large set of reference individuals originating from global populations using STRUCTURE. The means of GDA were calculated for each category of SRR. Linear regression was used to model GDA on CD4 count and log10 RNA, adjusting for SRR and age., Results: Subjects were 61% black, 25% Hispanic, 13% white, and 1.3% Unknown. The mean age was 2.3 years (45% male), mean CD4 count of 981 cells per cubic millimeter, and mean log10 RNA of 5.11. Marked heterogeneity was found for all SRR groups with high admixture for Hispanics. In adjusted linear regression models, subjects with 100% European ancestry were estimated to have 0.33 higher log10 RNA levels (95% CI: 0.03 to 0.62, P = 0.028) and 253 CD4 cells per cubic millimeter lower (95% CI: -517 to 11, P = 0.06) in CD4 count, compared to subjects with 100% African ancestry., Conclusion: Marked continental admixture was found among this cohort of HIV-infected children from the United States. GDA contributed to differences in RNA and CD4 counts beyond SRR and should be considered when outcomes associated with HIV infection are likely to have a genetic component.