Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals (HOPE) study protocol: a prospective observational cohort study of reproductive-aged women living with HIV.

INTRODUCTION: Over 265 000 women are living with HIV in the USA, but limited research has investigated the physical, mental and behavioural health outcomes among women living with HIV of reproductive age. Health status during the reproductive years before, during and after pregnancy affects pregnancy outcomes and long-term health. Understanding health outcomes among women living with HIV of reproductive age is of substantial public health importance, regardless of whether they experience pregnancy. The Health Outcomes around Pregnancy and Exposure to HIV/Antiretrovirals (HOPE) study is a prospective observational cohort study designed to investigate physical and mental health outcomes of young women living with HIV as they age, including HIV disease course, engagement in care, reproductive health and choices and cardiometabolic health. We describe the HOPE study design, and characteristics of the first 437 participants enrolled as of 1 January 2024. METHODS AND ANALYSIS: The HOPE study seeks to enrol and follow 1630 women living with HIV of reproductive age, including those with perinatally-acquired HIV, at 12 clinical sites across 9 US states and Puerto Rico. HOPE studies multilevel dynamic determinants influencing physical, mental and social well-being and behaviours of women living with HIV across the reproductive life course (preconception, pregnancy, post partum, not or never-pregnant), informed by the socioecological model. Key research areas include the clinical course of HIV, relationship of HIV and antiretroviral medications to reproductive health, pregnancy outcomes and comorbidities and the influence of racism and social determinants of health. HOPE began enrolling in April 2022. ETHICS AND DISSEMINATION: The HOPE study received approval from the Harvard Longwood Campus Institutional Review Board, the single institutional review board of record for all HOPE sites. Results will be disseminated through conference presentations, peer-reviewed journals and lay summaries.

How much could anemia-related interventions reduce the HIV disparity in adverse birth outcomes?

Women and other people of childbearing potential living with HIV (WLHIV) have a higher risk of adverse birth outcomes than those without HIV (WWHIV). A higher risk of anemia in WLHIV could partially explain this disparity. Using a birth outcomes surveillance study in Botswana, we emulated target trials corresponding to currently available or feasible interventions on anemia. The first target trial evaluated two interventions: initiate multiple micronutrient supplementation (MMS), and MMS or iron and folic acid supplementation by 24 weeks gestation. The remaining target trials evaluated the interventions: eliminate anemia before pregnancy; and jointly eliminate anemia before pregnancy and initiate MMS. We estimated the observed disparity in adverse birth outcomes between WLHIV and WWHIV and compared the observed disparity measure (ODM) to the counterfactual disparity measure (CDM) under each intervention. Of 137,499 individuals (22% WLHIV), the observed risk of any adverse birth outcome was 26.0% in WWHIV and 34.5% in WLHIV (ODM, 8.5% [95% CI, 7.9-9.1%]). CDMs (95% CIs) ranged from 6.6% (4.8-8.4%) for the intervention to eliminate anemia and initiate MMS to 8.4% (7.7-9.1%) for the intervention to eliminate anemia only. Preventing anemia and expanding MMS may reduce HIV disparities in birth outcomes, but interventions with greater impact should be identified.

Dolutegravir- Versus Efavirenz-Based Treatment in Pregnancy: Impact on Red Blood Cell Folate Concentrations in Pregnant Women and Their Infants.

In IMPAACT 2010/VESTED, pregnant women were randomized to initiate dolutegravir (DTG)+emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG+FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF. We assessed red blood cell folate concentrations (RBC-folate) at maternal study entry and delivery, and infant birth. RBC-folate outcomes were: 1) maternal change entry to delivery (trajectory), 2) infant, 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-GMRT) of each arm comparison in 340 mothers and 310 infants. 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/mm3 and log10HIV 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%CI 1.00, 1.06). The DTG+FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92, 95%CI 0.78, 1.09) versus EFV/FTC/TDF. 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- vs. EFV-based ART.

Phosphaturia in HIV-exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown. METHODS: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure. RESULTS: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers. CONCLUSIONS: Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

Gut permeability is associated with lower insulin sensitivity in youth with perinatally acquired HIV.

The relationships between alterations in the intestinal barrier, and bacterial translocation with the development of metabolic complications in youth with perinatally acquired HIV (YPHIV) have not been investigated. The PHACS Adolescent Master Protocol enrolled YPHIV across 15 U.S. sites, including Puerto Rico, from 2007 to 2009. For this analysis, we included YPHIV with HIV viral load 1000 c/ml or less, with at least one measurement of homeostatic assessment of insulin resistance (HOMA-IR) or nonhigh density lipoprotein (non-HDLc) between baseline and year 3 and plasma levels of intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin levels at baseline. We fit linear regression models using generalized estimating equations to assess the association of baseline log 10 gut markers with log 10 HOMA-IR and non-HDLc at all timepoints. HOMA-IR or non-HDLc was measured in 237, 189, and 170 PHIV at baseline, Yr2, and Yr3, respectively. At baseline, median age (Q1, Q3) was 12 years (10, 14), CD4 + cell count was 762 cells/µl (574, 984); 90% had HIV RNA less than 400 c/ml. For every 10-fold higher baseline I-FABP, HOMA-IR dropped 0.85-fold at baseline and Yr2. For a 10-fold higher baseline zonulin, there was a 1.35-fold increase in HOMA-IR at baseline, 1.23-fold increase in HOMA-IR at Yr2, and 1.20-fold increase in HOMA-IR at Yr3 in adjusted models. For a 10-fold higher baseline LBP, there was a 1.23-fold increase in HOMA-IR at baseline in the unadjusted model, but this was slightly attenuated in the adjusted model. Zonulin was associated with non-HDLc at baseline, but not for the other time points. Despite viral suppression, intestinal damage may influence downstream insulin sensitivity in YPHIV.

Longitudinal changes in body fat and metabolic complications in young people with perinatally acquired HIV.

BACKGROUND: The role of body fat on metabolic complications remains poorly understood in young people living with perinatally acquired HIV (YPHIV). OBJECTIVE: Our objective was to assess the association of changes in adiposity over 2 years with metabolic outcomes in YPHIV. METHODS: The PHACS Adolescent Master Protocol (AMP) study enrolled YPHIV from 2007 to 2009 across 15 US sites, including Puerto Rico. We included YPHIV aged 7-19 years with body composition data assessed by whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 2 years later. Metabolic outcomes included homeostatic model assessment of insulin resistance (HOMA-IR) and non-high-density lipoprotein cholesterol (non-HDL-C). We fitted linear regression models to assess the association of increase in body fat over 2 years with metabolic outcomes at years 2 and 3. RESULTS: In all, 232 participants had a second DXA and either HOMA-IR or non-HDL-C measured at year 2. Participant characteristics at the first DXA were: age 12 years (9-14) [median (Q1-Q3)], 69% Black, and median CD4 count 714 cells/µL; 70% with HIV RNA <400 copies/mL. In adjusted analyses for every 1% increase in body fat from baseline to year 2, HOMA-IR was higher by 1.03-fold at year 3 (95% CI: 1.00, 1.05). We observed that for every 1% increase in body fat from baseline to year 2, non-HDL-C was 0.72 mg/dL higher at year 2 (95% CI: -0.04-1.49) and 0.81 mg/dL higher at year 3 (95% CI: -0.05-1.66). CONCLUSIONS: Increases in adiposity over time may lead to downstream decreased insulin sensitivity and dyslipidaemia in YPHIV.

Association of Fatty Acid Signatures with HIV Viremia in Pregnancy.

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are vital for fetal metabolic programming and immunomodulation. Higher n-6:n-3 ratios, reflecting a proinflammatory eicosanoid profile, are associated with adverse perinatal outcomes. Limited data exist, however, on n-6 and n-3 PUFAs specifically in the context of HIV and pregnancy. Our objective was to assess HIV clinical factors associated with PUFA signatures in pregnant persons with HIV (PWH). In this observational cohort, third trimester plasma PUFA concentrations (six n-6 PUFAs, four n-3 PUFAs) were measured, each as a percent of total fatty acid content, via esterification and gas chromatography in pregnant PWH enrolled from 2009 to 2011 in the Nutrition substudy of the Pediatric HIV/AIDS Cohort Study. PUFA ratios (n-6:n-3) were calculated. Exposures assessed were first/second trimester CD4 count (<200 vs. >200 cells/mm3), HIV RNA viral load (VL) (VL >400 vs. <400 copies/mL), and protease inhibitor (PI) versus non-PI antiretroviral therapy (ART). Linear regression models using generalized estimating equations were fit to assess mean differences and their 95% confidence intervals (CIs) in n-6:n-3 by each exposure, adjusted for potential confounders. Of 264 eligible pregnant PWH, the median age was 27 years, 12% had CD4 counts <200 cells/mm3, and 56% had VL ≥400 copies/mL in the first/second trimesters. PUFA concentrations and ratios were similar by CD4 count and PI exposure. n-3 concentrations were lower in PWH with VL ≥400 versus <400 copies/mL (median 2.8% vs. 3.0%, p < .01, respectively); no differences were observed for n-6 concentrations by VL. In models adjusted for age, education, tobacco use, body mass index, and PI-based ART, n-6:n-3 was higher in those with VL ≥400 copies/mL (mean difference: 1.6; 95% CI: 0.79-2.48, p = .0001). Therefore, PUFA signatures in viremic pregnant PWH reflect a proinflammatory eicosanoid milieu. Future studies should evaluate associations of proinflammatory PUFA signatures with adverse perinatal outcomes in PWH.

Evaluating the association of antiretroviral therapy and immune status with hypertensive disorders of pregnancy among people with HIV.

OBJECTIVE: The aim of this study was to examine the association of timing of antiretroviral therapy (ART) initiation and ART class with risk of new-onset hypertensive disorders of pregnancy (HDP) among people with HIV (PWH). DESIGN: An observational study of participants in the multisite Surveillance Monitoring for ART Toxicities (SMARTT) study. METHODS: Data were abstracted from medical records of pregnant PWH enrolled in SMARTT (January 30, 2015 to March 25, 2019). New-onset HDP included gestational hypertension, preeclampsia/eclampsia, or HELLP syndrome. We examined the associations of clinical risk factors and three exposures of interest, each in a separate model, with risk of new-onset HDP. Log-binomial regression models were fit using generalized estimating equations to account for correlations within people. Exposures included timing of ART initiation, antiretroviral class among those on therapy at conception, and antiretroviral class among those initiating treatment during pregnancy. RESULTS: Of 1038 pregnancies in this cohort, 973 were singletons with complete data on HDP, with ART use in 948. Overall, 9% had a new-onset HDP, 10% had chronic hypertension, and 81% had no hypertension. Diabetes [adjusted relative risk (aRR) 2.44, 95% confidence interval (95% CI) 1.42-4.21] and first/second trimester CD4 + cell count less than 200 cells/µl (aRR 1.99, 95% CI 1.21-3.27) were associated with a greater risk of new-onset HDP. Risk of new-onset HDP was similar by antiretroviral class, but those initiating ART after 20 weeks' gestation had a greater risk (aRR 1.93, 95% CI 1.12-3.30) compared with those receiving ART at conception. CONCLUSION: In this large, diverse cohort of pregnant PWH, worse early pregnancy immune status and later ART initiation were associated with an increased risk of HDP while ART class was not.

Dual trajectories of antiretroviral therapy adherence and polypharmacy in women with HIV in the United States.

BACKGROUND: Polypharmacy, using five or more medications, may increase the risk of nonadherence to prescribed treatment. We aimed to identify the interrelationship between trajectories of adherence to antiretroviral therapy (ART) and polypharmacy. METHODS: We included women with HIV (aged ≥ 18) enrolled in the Women's Interagency HIV Study in the United States from 2014 to 2019. We used group-based trajectory modeling (GBTM) to identify trajectories of adherence to ART and polypharmacy and the dual GBTM to identify the interrelationship between adherence and polypharmacy. RESULTS: Overall, 1,538 were eligible (median age of 49 years). GBTM analysis revealed five latent trajectories of adherence with 42% of women grouped in the consistently moderate trajectory. GBTM identified four polypharmacy trajectories with 45% categorized in the consistently low group. CONCLUSIONS: The joint model did not reveal any interrelationship between ART adherence and polypharmacy trajectories. Future research should consider examining the interrelationship between both variables using objective measures of adherence.

Dual Trajectories of Antiretroviral Therapy Adherence and Polypharmacy in Women with HIV in the United States.

Background Polypharmacy, using five or more medications, may increase the risk of nonadherence to prescribed treatment. We aimed to identify the interrelationship between trajectories of adherence to antiretroviral therapy (ART) and polypharmacy. Methods We included women with HIV (aged ≥ 18) enrolled in the Women's Interagency HIV Study in the United States from 2014 to 2019. We used group-based trajectory modeling (GBTM) to identify trajectories of adherence to ART and polypharmacy and the dual GBTM to identify the interrelationship between adherence and polypharmacy. Results Overall, 1,538 were eligible (median age of 49 years). GBTM analysis revealed five latent trajectories of adherence with 42% of women grouped in the consistently moderate trajectory. GBTM identified four polypharmacy trajectories with 45% categorized in the consistently low group. Conclusions The joint model did not reveal any interrelationship between ART adherence and polypharmacy trajectories. Future research should consider examining the interrelationship between both variables using objective measures of adherence.

Trajectories of Antiretroviral Therapy Adherence and Virologic Failure in Women With HIV in the United States.

BACKGROUND: Women with HIV (WHIV) in the United States face many challenges with adherence to antiretroviral therapy (ART), and suboptimal adherence often leads to virologic failure. This study aimed to determine the association between ART adherence trajectories and the risk of virologic failure. METHODS: We included WHIV (aged 18 years or older) enrolled in the Women's Interagency HIV Study in the United States from April 2014 to September 2019 who had at least 2 consecutive measurements of HIV RNA and ≥3 measurements of self-reported adherence. Group-based trajectory modeling was used to identify adherence trajectories. Cox proportional hazard ratios were used to measure the association. MAIN OUTCOME MEASURE: Virologic failure was defined as HIV RNA ≥200 copies/mL at 2 consecutive visits. RESULTS: We included 1437 WHIV (median age 49 years). Of all women, 173 (12.0%) experienced virologic failure. Four adherence trajectories were identified, namely "consistently high" (26.3%), "moderate increasing" (9.5%), "moderate decreasing" (30.6%), and "consistently low" (33.5%). Women in the consistently low adherence group consumed alcohol and experienced depression more than other groups. Compared with the "consistently high" trajectory, the risk of virologic failure was higher among women with "consistently low" [adjusted hazard ratio (aHR) 2.8; 95% confidence interval (CI): 1.6 to 4.9; P < 0.001] and "moderate decreasing" adherence trajectories (aHR 1.8; 95% CI: 1.0 to 3.2; P = 0.04), but it was similar to those with "moderate increasing" adherence trajectory (aHR 1.0; 95% CI: 0.4 to 2.5; P = 0.94). CONCLUSIONS: Adherence to ART remains a challenge among WHIV. Multilevel behavioral interventions to address poor adherence, alcohol consumption, and depression are needed.

Gestational weight gain in persons with HIV in the United States.

OBJECTIVE: We evaluated gestational weight gain (GWG) in pregnant persons with HIV (PWH) enrolled in the Surveillance Monitoring for ART Toxicities study. DESIGN: This was a cohort study. METHODS: GWG was classified as excessive, adequate, or inadequate; weekly GWG in second and third trimesters was calculated using National Academy of Medicine standards. Adjusted modified Poisson and linear regression models were fit with generalized estimating equations to assess the association of antiretroviral treatment (ART) with GWG outcomes stratified by timing of ART initiation [at conception (ART-C) and initiating during pregnancy (ART-I)]. RESULTS: We included 1477 pregnancies (847 ART-C, 630 ART-I) from 1282 PWH. The proportion of excessive, adequate, and inadequate GWG was 44, 24, and 32%, respectively. No associations of ART class with excessive GWG were observed overall. However, among ART-I pregnancies with overweight prepregnancy BMI-based, protease inhibitor-based, nonnucleoside reverse transcriptase inhibitor-based, and nucleoside reverse transcriptase inhibitor-based ART were associated with significantly lower GWG per week than integrase inhibitor (INSTI)-based ART [mean differences: -0.14, -0.27, and -0.29 kg/week, respectively]. Among ART-I pregnancies with obese prepregnancy BMI, lower weekly GWG was also observed for protease inhibitor-based vs. INSTI-based ART (mean difference: -0.14 kg/week). CONCLUSION: ART class type was not associated with excessive GWG. However, PWH entering pregnancy already overweight/obese and initiating INSTI-based ART had higher weekly GWG in second and third trimesters vs. other ART classes. Further studies to understand how increases in weekly GWG for overweight/obese PWH impinges on long-term maternal/child health are warranted.

Unique Profile of Inflammation and Immune Activation in Pregnant People With HIV in the United States.

BACKGROUND: Little is known about inflammation/immune activation during pregnancy in people with HIV (PWH) and growth in their children who are HIV-exposed and uninfected (CHEU). METHODS: Using data from the Pediatric HIV/AIDS Cohort Study and an HIV-seronegative comparison group, we assessed associations of (1) HIV status, mode of HIV acquisition (perinatally vs nonperinatally acquired), and type of antiretroviral therapy (ART) with inflammation/immune activation in pregnancy; and (2) inflammation/immune activation in pregnancy with growth of CHEU at 12 months. Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble(s) TNF-α receptor 1 and 2 (sTNFR1, sTNFR2), sCD14, and sCD163 were measured between 13 and 27 weeks' gestation. Linear regression models were fit to estimate differences between groups for each log-transformed biomarker, adjusted for confounders. RESULTS: Pregnant PWH (188 total, 39 perinatally acquired, 149 nonperinatally acquired) and 76 HIV-seronegative persons were included. PWH had higher IL-6, sTNFR1, sCD14, and sCD163 and lower sTNFR2 compared to HIV-seronegative persons in adjusted models. Among PWH, sCD163 was higher in those with perinatally versus nonperinatally acquired HIV and on PI-based versus INSTI-based ART. Higher maternal concentrations of IL-6, sTNFR2, and hs-CRP were associated with poorer growth at 12 months. CONCLUSIONS: Maternal HIV status is associated with a distinct profile of inflammation/immune activation during pregnancy, which may influence child growth.

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States.

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.).

Gut Dysfunction Markers Are Associated With Body Composition in Youth Living With Perinatally Acquired Human Immunodeficiency Virus.

BACKGROUND: The association between gut dysfunction and body fat composition in youth living with perinatal human immunodeficiency virus infection (YPHIV) has not been investigated. METHODS: We included YPHIV aged 7-19 years from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol with plasma available within 6 months of baseline whole-body dual energy x-ray absorptiometry (DXA) and HIV RNA ≤1000 copies/mL within 3 months of baseline DXA and a second DXA 2 years later. Plasma markers of bacterial translocation and gut barrier dysfunction (lipopolysaccharide binding protein [LBP], zonulin, and intestinal fatty acid binding protein [I-FABP]) were measured at baseline by enzyme-linked immunosorbent assay and log10 transformed. Adiposity outcomes included percentage total body, truncal, and extremity fat in kilograms from DXA. Linear regression models were fit using generalized estimating equations to assess associations of baseline gut markers (log10) on adiposity outcomes at baseline and 2 years, adjusted for demographic variables, current antiretroviral therapy exposure, and physical activity. RESULTS: Two hundred sixty-one youth were included; 128 had a second DXA. Median age at first DXA was 12 years (interquartile range, 10-14 years), 49% were female, and 69% were Black. After adjustment for potential confounders, log10 LBP was positively associated with percentage total body fat at baseline (ß = 4.08, P < .01) and zonulin with adiposity measures at both time points (ß = .94 to 6.50, P ≤ .01). I-FABP was inversely associated with percentage total body fat at baseline and year 2 (ß = -2.36 and -3.01, respectively, P ≤ .02). CONCLUSIONS: Despite viral suppression, gut damage and the resultant bacterial translocation are associated with body composition measures in YPHIV.

Growth patterns of uninfected children born to women living with perinatally versus nonperinatally acquired HIV.

OBJECTIVE: The aim of this study was to compare long-term growth between HIV-exposed uninfected children (CHEU) born to women with perinatally acquired HIV (CHEU-PHIV) and CHEU born to women with nonperinatally acquired HIV (CHEU-NPHIV). DESIGN: A longitudinal analysis of anthropometric measurements from a U.S.-based multisite prospective cohort study enrolling CHEU and their mothers since April 2007. METHODS: CHEU were evaluated for growth annually from birth through age 5 and again at age 7 years. Z-scores were calculated using U.S. growth references for weight (WTZ), height (HTZ), and weight-for-length or BMI-for-age (WLZ/BMIZ). Mid-upper arm circumference (MUACZ) and triceps skinfold thickness (TSFZ) Z-scores were obtained from ages 1 and 2, respectively, through age 7 years. Piecewise mixed-effects models, overall and stratified by race and sex, were fit to assess differential growth patterns across age by maternal PHIV status. RESULTS: One thousand four hundred fifty-four singleton infants (286 CHEU-PHIV and 1168 CHEU-NPHIV) were included. CHEU-PHIV had slower growth rates than CHEU-NPHIV for WTZ and WLZ/BMIZ at earlier ages and continued to have lower mean WTZ [-0.27, 95% confidence interval (95% CI): -0.50, -0.04] and WLZ/BMIZ (-0.39, 95% CI: -0.67, -0.11) through age 7. Among non-Black boys, CHEU-PHIV had slightly lower WTZ and WLZ/BMIZ at birth than CHEU-NPHIV and these growth deficits persisted through age 7 years. CONCLUSION: Compared with CHEU-NPHIV, CHEU-PHIV had diminished growth in early childhood with differences most pronounced among non-Black male children. Further longitudinal follow-up of CHEU-PHIV into young adulthood is needed to understand whether these early effects of maternal PHIV status on growth persist and have other health consequences.

Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C.

BACKGROUND: In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV). SETTING: Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2-4 as "possible" MD. METHODS: Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression. RESULTS: Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06-25.92] for FGF21 and 3.5 (95%CI: 1.19-10.25) for GDF15. Relationships persisted after covariate adjustments. CONCLUSION: FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.

Prevalence and outcomes of twin pregnancies in Botswana: a national birth outcomes surveillance study.

OBJECTIVES: This study aims to evaluate the prevalence and outcome of twin pregnancies in Botswana. SETTING: The Tsepamo Study conducted birth outcomes surveillance at 8 government-run hospitals (~45% of all births in Botswana) from August 2014 to June 2018 and expanded to 18 hospitals (~70% of all births in Botswana) from July 2018 to March 2019. PARTICIPANTS: Data were collected for all live-born and stillborn in-hospital deliveries with a gestational age (GA) greater than 24 weeks. This analysis included 117 593 singleton and 3718 twin infants (1859 sets (1.6%)) born to 119 477 women between August 2014 and March 2019 and excluded 73 higher order multiples (23 sets of triplets and 1 set of quadruplets). OUTCOMES MEASURED: Our primary outcomes were preterm delivery (<37 weeks GA), very preterm delivery (<32 weeks GA) and stillbirth (APGAR (Appearance, Pulse, Grimace, Activity, Respiration) score of 0, 0, 0). RESULTS: Women with twin pregnancies had a similar median number of antenatal care visits (9 vs 10), but were more likely to deliver in a tertiary centre (54.8% vs 45.1%, p<0.001) and more likely to have a cesarean-section (54.6% vs 22.0%, p<0.001) than women with singletons. Compared with singletons, twin pregnancies had a higher risk of preterm delivery (<37 weeks GA) (47.6% vs 16.7%, adjusted risk ratio (aRR) 2.8, 95% CI 2.7 to 2.9) and very preterm delivery (<32 weeks) (11.8% vs 4.0%, aRR 3.0 95% CI 2.6 to 3.4). Among all twin pregnancies, 128 (6.9%) had at least one stillborn infant compared with 2845 (2.4%) stillbirths among singletons (aRR 2.8, 95% CI 2.3 to 3.3). CONCLUSION: Adverse birth outcomes are common among twins in Botswana, and are often severe. Interventions that allow for earlier identification of twin gestation and improved antenatal management of twin pregnancies may improve infant and child survival.

Components of metabolic syndrome associated with lower neurocognitive performance in youth with perinatally acquired HIV and youth who are HIV-exposed uninfected.

We investigated the association of metabolic syndrome (MetS) and its components [abdominal obesity, elevated triglycerides (TG), low HDL cholesterol, elevated blood pressure (BP), and impaired fasting glycemia (IFG)] with neurocognitive impairment in youth with perinatally acquired HIV (YPHIV) or who are perinatally HIV-exposed uninfected (YPHEU). This was an observational study with a comparison group of 350 YPHIV and 68 YPHEU ages 10-19 years. Youth with MetS components measured between 1 year before and 3 months after a baseline neurocognitive assessment (Wechsler Intelligence Scale) were selected from the Pediatric HIV/AIDS Cohort Study (PHACS). A sub-group completed another assessment 3 years later. We assessed the association of each baseline MetS component with five standardized neurocognitive indices at baseline and changes in indices over time. At baseline, 15% of YPHIV and 18% of YPHEU met criteria for ≥ 2 MetS components. Among YPHIV, there was no association between MetS components and neurocognitive indices at baseline; however, over time, elevated baseline BP was associated with a greater decrease in mean Perceptual Reasoning scores (-4.3;95%CI: -8.8,0.3) and ≥ 2 MetS components with a greater decrease in mean Processing Speed scores (-5.1;95%CI: -9.4, -0.8). Among YPHEU, elevated TG was associated with lower mean Verbal Comprehension, Perceptual Reasoning, and Full-scale IQ scores at baseline, and IFG with lower mean Verbal Comprehension scores. Components of MetS in YPHIV (elevated BP) and YPHEU (elevated TG and IFG) were associated with lower neurocognitive performance index scores. Studies to elucidate how modifying metabolic risk factors early in life may improve neurocognitive outcomes in this population are warranted.

Perinatally acquired HIV infection is associated with abnormal blood mitochondrial function during childhood/adolescence.

OBJECTIVE: We assessed differences in mitochondrial function between youth living with perinatal HIV (YPHIV) and youth perinatally HIV-exposed but uninfected (YPHEU). DESIGN: Cross-sectional analysis. METHODS: We measured lactate and pyruvate values, as well as mitochondrial Complex I and Complex IV activity in peripheral blood mononuclear cells. Logistic or linear regression models were fit, as appropriate, to assess the association between PHIV status and each mitochondrial parameter, adjusted for confounders. We introduced interaction terms to assess effect modification of PHIV status on the relationship between anthropometric factors and each mitochondrial parameter. Among YPHIV, similar regression models were fit to assess the relationship between HIV-associated factors and each mitochondrial outcome. RESULTS: A total of 243 YPHIV and 118 YPHEU were compared. On average, YPHIV had higher lactate/pyruvate ratio (ß: 7.511, 95% confidence interval [95% CI]: 0.402, 14.620) and Complex IV activity (ß: 0.037, 95% CI: 0.002, 0.072) compared to YPHEU, adjusted for confounders. Among YPHIV, body mass index Z score (BMIZ) and Complex I activity were inversely associated, whereas, among YPHEU, there was a positive association (ß for interaction: -0.048, P = 0.003). Among YPHIV, current (ß: -0.789, 95% CI: -1.174, -0.404) and nadir CD4+% (ß: -0.605, 95% CI: -1.086, -0.125) were inversely associated with lactate/pyruvate ratio; higher current (4.491, 95% CI: 0.754, 8.229) and peak (7.978, 95% CI: 1.499, 14.457) HIV RNA levels were positively associated with lactate/pyruvate ratio in adjusted models. CONCLUSIONS: Mitochondrial function and substrate utilization appear perturbed in YPHIV compared to YPHEU. Increasing immunosuppression and viremia are associated with mitochondrial dysfunction among YPHIV.