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.).

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.

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.

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.

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.

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.

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.

Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana.

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.).

Safety and Efficacy of 48 and 96 Weeks of Alendronate in Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection and Low Bone Mineral Density for Age.

No safety concerns were identified in a randomized, crossover study of alendronate/placebo in youth with perinatal HIV infection and low bone mineral density (BMD). BMD improved with 48 weeks of alendronate and continued to improve with an additional 48 weeks of therapy. Gains were largely maintained 48 weeks after stopping alendronate.

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.

Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age.

BACKGROUND: Children and adolescents with perinatal human immunodeficiency virus (HIV) infection and with low bone mineral density (BMD) may be at higher risk of osteoporosis and fractures in later life than their uninfected peers. Bisphosphonate therapy has been shown to reduce fractures in adults with osteoporosis, but has not been formally studied in youths living with HIV. METHODS: Fifty-two children and adolescents (aged 11-24 years) perinatally infected with HIV with low lumbar spine (LS) BMD (Z score < -1.5) were randomized to receive once-weekly alendronate or placebo in a double-blind cross-over study designed to assess the safety and efficacy of 48 and 96 weeks of alendronate in the United States and Brazil. All participants received daily calcium carbonate and vitamin D supplementation and were asked to engage in regular weight-bearing exercise. Safety and efficacy are summarized for the initial 48 weeks of the trial. RESULTS: Grade 3 or higher abnormal laboratory values, signs, or symptoms developed in 5 of 32 (16%) participants on alendronate and 2 of 18 (11%) on placebo (P > .99). No cases of jaw osteonecrosis, atrial fibrillation, or nonhealing fractures were reported. Mean increases (95% confidence interval) in LS BMD over 48 weeks were significantly larger on alendronate (20% [14%-25%]) than placebo (7% [5%-9%]) (P < .001). Similar improvements were seen for whole body BMD. CONCLUSIONS: In this small study in children and adolescents perinatally infected with HIV with low LS BMD, 48 weeks of alendronate was well-tolerated, showed no safety concerns, and significantly improved LS and whole body BMD compared to participants on vitamin D/calcium supplementation and exercise alone. CLINICAL TRIALS REGISTRATION: NCT00921557.

Human Papillomavirus Antibody Levels and Quadrivalent Vaccine Clinical Effectiveness in Perinatally Human Immunodeficiency Virus-infected and Exposed, Uninfected Youth.

BACKGROUND: Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth. METHODS: This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts. RESULTS: Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively. CONCLUSION: Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

A multicenter study of diet quality on birth weight and gestational age in infants of HIV-infected women.

We determined factors associated with diet quality and assessed the relationship between diet quality, birth weight, and gestational age in a prospective national multicenter cohort study. We evaluated diet quality with the Healthy Eating Index (HEI, scale 0-100) in the third trimester of pregnancy with three 24-hr multiple-pass dietary recalls in 266 HIV+ women enrolled in the Pediatric HIV/AIDS Cohort Study. Covariates included demographics, food security, pre-pregnancy body mass index, HIV disease severity, substance use, and antiretroviral exposures. A two-stage multivariate process using classification and regression trees (CART) followed by multiple regression described HEI tendencies, controlled possible confounding effects, and examined the association of HEI with birth weight and gestational age. To assess the stability of the CART solution, both the HEI 2005 and 2010 were evaluated. The mean HEI scores were 56.1 and 47.5 for the 2005 and 2010 HEI, respectively. The first-stage CART analysis examined the relationship between HEI and covariates. Non-US born versus US-born mothers had higher HEI scores (15-point difference, R2  = 0.28). There was a secondary partition due to alcohol/cigarette/illicit drug usage (3.5-point difference, R2  = 0.03) among US-born women. For the second-stage CART adjusted multiple regression, birth weight z-score was positively related to HEI 2005 and 2010 (partial r's > 0.13, P's ≤ 0.0398), but not gestational age (r = 0.00). We conclude that diet quality among HIV+ women is associated with higher birth weight. Despite the influence of a large cultural effect and poor prenatal behaviors, interventions to improve diet in HIV+ women may help to increase birth weight.

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

Lower Newborn Bone Mineral Content Associated With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy.

BACKGROUND: Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. METHODS: We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. RESULTS: Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (-0.41 vs -0.18) or weight (-0.71 vs -0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, -9.5, -1.2; P = .013) in the tenofovir-exposed infants. CONCLUSIONS: Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01310023.

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.

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 mitochondrial-associated measures and insulin resistance in youth with perinatally-acquired HIV in the U.S.

HIV infection and its treatment are associated with mitochondrial dysfunction and metabolic derangement. However, longitudinal changes in oxidative phosphorylation activities [Complex I (C1) and Complex IV (C4)], or venous lactate/pyruvate ratios (LPR), and their relationships with insulin resistance (IR), remain unclear in youth living with perinatally-acquired HIV (YPHIV). We measured venous LPR, C1, and C4 activities in blood cells and homeostatic model assessment for IR (HOMA-IR) over two years. Limited longitudinal differences in mitochondrial-related measures and IR were observed in YPHIV vs youth perinatally HIV-exposed but uninfected. There were no systematic differences in C1, C4, or HOMA-IR between the groups.