Routine Vaccination During Pregnancy Among People Living With HIV in the United States.

Importance: Pregnancy represents a window of opportunity for vaccination due to established maternal and fetal benefits of vaccination. Little is known about receipt of routinely recommended vaccines in pregnancy, specifically tetanus, diphtheria, plus acellular pertussis (Tdap) and influenza, among pregnant people living with HIV (PLHIV). Objective: To estimate prevalence of vaccination receipt among pregnant people with HIV (PLHIV) and identify demographic and clinical characteristics associated with vaccination. Design, Setting, and Participants: This multicenter cohort study included women participating in Women's Health Study (WHS) of the Surveillance Monitoring for ART Toxicities (SMARTT) Study of the Pediatric HIV/AIDS Cohort Study. The network has been enrolling pregnant PLHIV at 22 US sites since 2007. Participants for this study enrolled between December 2017 and July 2019. Data analysis was conducted from October 2021 to March 2022. Exposure: Data on vaccination in pregnancy were collected through medical record abstraction. Main Outcomes and Measures: Vaccination receipt was defined as Tdap vaccination received at less than 36 weeks' gestation and influenza vaccination at any gestational age, based on current guidelines. Log-binomial and modified Poisson regression models with generalized estimating equations were fit to identify factors associated with successful receipt of (1) Tdap, (2) influenza, and (3) both vaccinations. Results: A total of 310 pregnancies among 278 people participating in the WHS were included (mean [SD] age, 29.5 [6.1] years; 220 [71%] Black, 77 [25%] Hispanic, and 77 [25%] race and ethnicity other than Black; 64 [21%] with perinatally acquired HIV). Less than one-third of pregnancies were vaccinated as recommended (Tdap, 32.6% [95% CI, 27.4%-38.1%]; influenza, 31.6% [95% CI, 26.5%-37.1%]; both, 22.6% [95% CI, 18.0%-27.6%]). People living with perinatally acquired HIV, those who did not identify as Black, or those who were multiparous had adjusted risk ratios (aRRs) less than 1, while older PLHIV had aRRs greater than 1, but these differences did not reach statistical significance (perinatally acquired HIV: adjusted risk ratio [aRR], 0.46; 95% CI, 0.21-1.02; race other than Black: aRR, 0.53; 95% CI, 0.26-1.08; multiparous: aRR, 0.59; 95% CI, 0.35-1.00; age 24-29 years: aRR, 2.03; 95% CI, 0.92-4.48). Conclusions and Relevance: In this diverse, multicenter cohort of pregnant PLHIV, receipt of recommended vaccinations was low. Identifying and addressing barriers to vaccination receipt is urgently needed for pregnant people with HIV.

Factors associated with internalized HIV-related stigma among biological mothers living with HIV enrolled in a US cohort study.

Understanding factors associated with internalized HIV-related stigma among mothers living with HIV may improve health outcomes. We examined factors (age, race/ethnicity, education, income, employment, marital status, health limitations, and years since HIV diagnosis) associated with internalized HIV-related stigma among biological mothers of children enrolled in the Surveillance Monitoring for ART Toxicities study of the US-based Pediatric HIV/AIDS Cohort Study. Stigma was measured with the Internalized HIV Stigma Scale (IHSS), completed biennially at their child's 11-17-year visits. Linear regression models were fit with generalized estimating equations to evaluate the association between the factors of interest and internalized HIV-related stigma using all completed IHSS surveys. Among 438 eligible mothers, the mean IHSS score was 43.7 (SD = 19.5). Higher IHSS scores were observed for widowed women compared to married women, with an estimated mean difference of 8.91 (95% CI: 2.25, 15.57) after adjusting for age, education, income, and health limitations. Years since HIV diagnosis was associated with internalized HIV-related stigma. For every year of increase since HIV diagnosis, IHSS scores decreased by 0.54 per year, after adjusting for age (95% CI: -0.92, -0.17). Interventions to reduce internalized HIV-related stigma should target mothers who are widowed and those with a more recent HIV diagnosis.

The role of internalised HIV stigma in disclosure of maternal HIV serostatus to children perinatally HIV-exposed but uninfected: a prospective study in the United States.

INTRODUCTION: Decisions to disclose HIV serostatus may be complicated by internalised HIV stigma. We evaluated the association of internalised HIV stigma in biological mothers living with HIV with disclosure of their serostatus to their children perinatally HIV-exposed but uninfected (CHEU). METHODS: Mothers and their CHEU were enrolled in the United States (U.S.)-based Surveillance Monitoring for Antiretroviral Therapy (ART) Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS), a longitudinal study of outcomes related to in utero exposure to HIV and ART among CHEU. Mothers completing at least one stigma and disclosure assessment starting at the child's age 11-, 13-, 15- and/or 17-year study visits between 16 August 2016 and 1 October 2020 were eligible. Stigma was measured with the 28-item Internalised HIV Stigma Scale (IHSS). Mean stigma scores were linearly transformed to a range of 0-100, with higher scores indicating greater levels of stigma. At each visit, mothers were asked if their child was aware of their HIV diagnosis and at what age the child became aware. The Kaplan-Meier estimator evaluated the cumulative probability of disclosure at each child age. Logistic regression models with generalised estimating equations to account for repeated measures were fit to examine the association between stigma and disclosure, controlling for relevant socio-demographic variables. RESULTS: Included were 438 mothers of 576 children (mean age 41.5 years, 60% U.S.-born, 60% Black/African American and 37% with household income ≤$10,000). The prevalence of disclosure across all visits was 29%. Mothers whose children were aware versus not aware of their serostatus reported lower mean IHSS scores (38.2 vs. 45.6, respectively). The cumulative proportion of disclosure by age 11 was 18.4% (95% CI: 15.5%, 21.8%) and 41% by age 17 (95% CI: 35.2%, 47.4%). At all child ages, disclosure was higher among children of U.S.-born versus non-U.S.-born mothers. After adjusting for age, marital status and years since HIV diagnosis, higher IHSS scores were associated with lower odds of disclosure (OR = 0.985, 95% CI: 0.975, 0.995). CONCLUSIONS: Providing support to women as they make decisions about serostatus disclosure to their children may entail addressing internalised HIV stigma and consideration of community-level factors, particularly for non-U.S.-born mothers.

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.

Association of Perceived Social Support with Viral Suppression Among Young Adults with Perinatally-Acquired HIV in the US-based Pediatric HIV/AIDS Cohort Study (PHACS).

Purpose: To determine the relationship between perceived social support and viral suppression among young adults with perinatally-acquired HIV (YAPHIV). Participants and Methods: We included YAPHIV ≥18 years enrolled in AMP Up, a study of PHACS (Pediatric HIV/AIDS Cohort Study), with social support evaluations and ≥1 HIV viral load (VL) measured over the next year. We evaluated emotional, instrumental, and friendship social support via the NIH Toolbox. We defined social support, measured at study entry and year 3 (if available), as low (T-score ≤40), average (41-59) or high (≥60). We defined viral suppression as all VL <50 copies/mL over the one year after social support measures. We fit multivariable Poisson regression models using generalized estimating equations, and evaluated transition from pediatric to adult care as an effect modifier. Results: Among 444 YAPHIV, low emotional and instrumental support and friendship at entry were reported by 37%, 32% and 36%. Over the next year, 44% were virally suppressed. Of 136 with year 3 data, 45% were suppressed. Average or high levels of all three social support measures were associated with higher likelihood of viral suppression. Instrumental support was associated with viral suppression among those in pediatric (adjusted proportion suppressed among those with average/high vs low support=51.2% vs 28.9%; risk ratio (RR)=1.77, 95% confidence interval (CI)=1.37, 2.29), but not adult care (40.0% vs 40.8%; RR=0.98, 95% CI=0.67, 1.44). Conclusion: Sufficient social support increases likelihood of viral suppression among YAPHIV. Strategies to enhance social support may promote viral suppression as YAPHIV prepare for adult clinical care transition.

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.

Markers of intestinal immune activation and inflammation are not associated with preterm birth among women with low level HIV viremia.

BACKGROUND: Maternal markers of intestinal immune activation may be used to predict preterm birth (PTB) in pregnant women living with HIV. METHODS: This study used de-identified samples from the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) Protocol P1025 study. Singleton pregnancies with ≥3 ml plasma available and HIV viral load ≤400 copies/ml within 4 weeks of specimen collection were included. Frequency matching of PTB cases and term birth controls was performed on basis of maternal race, number of available plasma specimens, and timing of plasma sample collection in a 1:1 ratio. Plasma progesterone, 25-hydroxy vitamin D, soluble CD14, intestinal fatty acid binding protein (I-FABP), Lipopolysaccharide (LPS)-binding protein, and inflammatory cytokines (IL-1B, IFN-gamma, IL-6, TNF-alpha) were measured. Generalized mixed linear regression modeling was used to examine the association between PTB and biomarkers, adjusting for covariates and confounders. Data analyses were performed using SAS 9.4 (Cary, NC). RESULTS: We included 104 PTB compared to 104 controls. Third trimester log2 IL-1B was lower among PTB versus term birth controls by univariate analysis (-1.50 ± 2.26 vs. -.24 ± 2.69, p = .01) though this association was no longer significant by regression modeling. In an uncontrolled, exploratory sub-analysis, subjects with prior PTB had increased odds of PTB with higher I-FABP [aOR 2.72, 95% CI 1.18-6.24] and lower IFN-gamma [aOR .23, 95% CI .12-.41] after adjustment for covariates and confounders. CONCLUSIONS: Intestinal immune activation measured by soluble CD14 or intestinal fatty acid binding protein was not associated with preterm birth among pregnant women with low-level HIV viremia.

Health Insurance Coverage, Clinical Outcomes, and Health-Related Quality of Life Among Youth Born to Women Living With HIV.

BACKGROUND: Although sustained access to health care is essential, little is known about the relationship between insurance coverage and health among people born to women living with HIV (WLHIV). SETTING: Prospective cohort studies of youth and young adults born to WLHIV from 2007 to 2019. METHODS: We used adjusted generalized estimating equation models to estimate mean differences in, and relative risks (RRs) of, health-related quality of life (HR-QoL) and HIV disease measures over time by insurance status. HR-QoL scales with limited variability were dichotomized. Modified Poisson models were used to estimate RRs. RESULTS: Six hundred sixty-nine Adolescent Master Protocol (AMP) youth [66% living with perinatally-acquired HIV (PHIV), 72% Black] and 939 AMP Up/AMP Up Lite young adults (89% PHIV, 68% Black) reported insurance. Most were publicly insured (87% youth, 67% young adults). Privately insured young adults living with PHIV had lower risk of antiretroviral therapy nonadherence [adjusted RR (aRR): 0.82, 95% CI: 0.70 to 0.97] than those with public insurance. There was a lower risk of suboptimal role functioning for young adults with private insurance (aRR: 0.58, 95% CI: 0.35 to 0.97) and those unaware of their coverage (aRR: 0.41, 95% CI: 0.21 to 0.78). Young adults with private insurance had higher health perception scores than those with public insurance (adjusted mean difference: 3.87, 95% CI: 0.37 to 7.38). For youth, we observed no differences in HR-QOL and HIV disease measures by insurance. CONCLUSION: These findings suggest meaningful differences in antiretroviral therapy adherence and some HR-QoL outcomes by health insurance coverage among young adults born to WLHIV.

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.).

Sexually Transmitted Infections in Pregnant People With Human Immunodeficiency Virus: Temporal Trends, Demographic Correlates, and Association With Preterm Birth.

BACKGROUND: We describe trends in prevalence and identify factors associated with Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), syphilis, and Trichomonas vaginalis (TV) diagnosed in pregnancy among US people with human immunodeficiency virus (PWH) and evaluate associations of sexually transmitted infections (STIs) with preterm birth (PTB). METHODS: We included pregnant PWH enrolled in the Surveillance Monitoring for ART Toxicities dynamic cohort of the Pediatric HIV/AIDS Cohort Study network who delivered between 2010 and 2019. Multivariable log-binomial or Poisson generalized estimating equation models were used to estimate the association of calendar year with each STI, controlling for confounders; the association of demographic and clinical factors with each STI; and the association of each STI with PTB. RESULTS: The sample included 2241 pregnancies among 1821 PWH. Median age at delivery was 29.2 years; 71% of participants identified as Black or African American. STI prevalence was: CT 7.7%, NG 2.3%, syphilis 2.4%, and TV 14.5%; 30% had unknown TV status. There were no temporal changes in STI prevalence. Younger age and initial HIV viral load ≥400 copies/mL were associated with increased risk of CT, NG, and TV. Recreational substance use was a risk factor for NG, syphilis, and TV. No STI was associated with PTB. CONCLUSIONS: Unlike nationwide trends, no changes in STI prevalence during the study period were observed. The large proportion with unknown TV status underscores the need for increased adherence to screening guidelines. STIs diagnosed during pregnancy in PWH were not associated with risk of PTB.

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.

Marijuana, Opioid, and Alcohol Use Among Pregnant and Postpartum Individuals Living With HIV in the US.

Importance: Amid the opioid epidemic and evolving legal and social changes with marijuana, little is known about substance use among pregnant and postpartum people living with HIV. Objectives: To evaluate trends in marijuana, alcohol, and opioid use during pregnancy and the first year postpartum among US people living with HIV and the differences in substance use based on marijuana legalization status. Design, Setting, and Participants: Data from the Surveillance Monitoring for Antiretroviral Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study were analyzed. SMARTT-enrolled, pregnant people living with HIV at 22 US sites from January 1, 2007, to July 1, 2019, with self-reported substance use data available in pregnancy, 1 year postpartum, or both were assessed. Exposures: Calendar year and state marijuana legalization status. Main Outcomes and Measures: The prevalence of any use of each of the following substances was calculated by calendar year, separately for pregnancy and postpartum: marijuana, alcohol, opioid, and concomitant alcohol and marijuana. Log binomial models were fit using general estimating equations to evaluate the mean annual change, accounting for repeat pregnancies. The study also evaluated differences in substance use by state recreational or medical marijuana legalization status. Results: Substance use data were available for 2926 pregnancies from 2310 people living with HIV (mean [SD] age, 28.8 [6.1] years; 822 [28.1%] Hispanic, 1859 [63.5%] non-Hispanic Black, 185 [6.3%] White, 24 [0.8%] of more than 1 race, 24 [0.8%] of other race or ethnicity [individuals who identified as American Indian, Asian, or Native Hawaiian or other Pacific Islander], and 12 [0.4%] with unknown or unreported race or ethnicity). Between 2007 and 2019, marijuana use during pregnancy increased from 7.1% to 11.7%, whereas alcohol and opioid use in pregnancy were unchanged. Postpartum alcohol (44.4%), marijuana (13.6%), and concomitant alcohol and marijuana (10.0%) use were common; marijuana use increased from 10.2% to 23.7% from 2007 to 2019, whereas postpartum alcohol use was unchanged. The adjusted mean risk of marijuana use increased by 7% (95% CI, 3%-10%) per year during pregnancy and 11% (95% CI, 7%-16%) per year postpartum. Postpartum concomitant alcohol and marijuana use increased by 10% (95% CI, 5%-15%) per year. Differences in substance use were not associated with recreational legalization, but increased marijuana use was associated with medical marijuana legalization. Conclusions and Relevance: In this cohort study, opioid use among pregnant people living with HIV remained stable, whereas marijuana use during pregnancy and postpartum increased over time and in states with legalized medical marijuana. These patterns of increasing marijuana use among pregnant and postpartum people living with HIV suggest that enhanced clinical attention is warranted, given the potential maternal and child health implications of substance use.

Perinatal Depressive Symptoms, Human Immunodeficiency Virus (HIV) Suppression, and the Underlying Role of Antiretroviral Therapy Adherence: A Longitudinal Mediation Analysis in the IMPAACT P1025 Cohort.

BACKGROUND: Women with HIV have higher risk of depressive symptoms in the perinatal period. Evidence on how perinatal depressive symptoms affect viral suppression (VS) and adherence to antiretroviral therapy (ART) remains limited. METHODS: Perinatal depressive symptoms were assessed using 6 items from the AIDS Clinical Trials Group (ACTG) Quality of Life questionnaire. VS (viral load <400 copies/mL) was the outcome. Adherence was defined as no missed dose in the past 1-4 weeks using the ACTG Adherence Questionnaire. Generalized mixed-effects structural equation models estimated the association of depressive symptoms on VS and the mediating role of ART adherence among women enrolled in the IMPAACT P1025 Perinatal Core Protocol (2002-2013). RESULTS: Among 1869 participants, 47.6% were 21-29 years, 57.6% non-Hispanic Black. In the third trimester, the mean depressive symptoms score was 14.0 (±5.2), 68.0% had consistent adherence, and 77.3% achieved VS. At 6 months postpartum, depressive symptoms declined while adherence and VS fell to 59.8% and 53.0%, respectively. In the fully adjusted model, a 1-SD increase in depressive symptoms was associated with a 3.8-percentage-point (95% CI: -5.7, -1.9) decline in VS. This effect is the sum of the indirect effect of depressive symptoms on VS via ART adherence (-0.4; 95% CI: -.7, -.2) and the direct effect through other pathways (-3.4; -5.2, -1.5). The decline in adherence driven by depressive symptoms accounted for ≥11% of the total negative effect of depressive symptoms on VS. CONCLUSIONS: Perinatal depressive symptoms were associated with decreased adherence and VS, highlighting the need to screen for, diagnose, and treat perinatal depression to optimize maternal outcomes. CLINICAL TRIALS REGISTRATION: NCT00028145.

In-utero exposure to zidovudine-containing antiretroviral therapy and clonal hematopoiesis in HIV-exposed uninfected newborns.

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.

Racial/Ethnic Disparities in Longitudinal Emotional-Behavioral Functioning Among Youth Born to Women Living With HIV.

BACKGROUND: Youth with perinatal HIV exposure have demonstrated high rates of emotional-behavioral problems. Few studies have longitudinally examined racial/ethnic disparities in such functioning across adolescence, a critical time for targeting prevention/intervention efforts. SETTING: The Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol is one of the largest US-based cohort studies of youth with perinatal HIV (YPHIV) infection or HIV exposed but uninfected (YPHEU). METHODS: Youth and caregivers individually completed the Behavior Assessment System for Children, second edition, every 2 years between ages 7 and 19 years. We used adjusted mixed-effects models to evaluate whether mean youth-reported emotional concerns and caregiver-reported behavioral concerns differed by race/ethnicity. We used group-based trajectory models to identify groups having similar emotional-behavioral trajectories, followed by multinomial models to determine which factors predicted group membership. RESULTS: Three hundred ninety-one YPHIV and 209 YPHEU (7% White non-Hispanic, 21% White Hispanic, 66% Black non-Hispanic, and 6% Black Hispanic) completed a median of 4 assessments over follow-up. Adjusted models showed more caregiver-reported behavioral concerns for Black non-Hispanic YPHEU than for Black non-Hispanic YPHIV, White Hispanic YPHIV, and White Hispanic YPHEU, particularly later in adolescence. Race/ethnicity did not predict membership in subgroups of youth-reported emotional or caregiver-reported behavioral functioning identified using group-based trajectory models. However, factors predicting membership in vulnerable youth-reported emotional and caregiver-reported behavioral groups included experiencing a stressful life event and living with a caregiver who was married or screened positive for a psychiatric condition. CONCLUSIONS: Our study revealed that Black non-Hispanic YPHEU are a vulnerable subgroup. Contributing factors that could inform interventions include the caregiver's health, household characteristics, and psychiatric status.

Longitudinal changes in epigenetic age in youth with perinatally acquired HIV and youth who are perinatally HIV-exposed uninfected.

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.

Tenofovir Diphosphate Concentrations in Dried Blood Spots From Pregnant and Postpartum Adolescent and Young Women Receiving Daily Observed Pre-exposure Prophylaxis in Sub-Saharan Africa.

BACKGROUND: Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW). METHODS: Directly observed PrEP was administered for 12 weeks in a pregnancy (14-24 weeks' gestation, n = 20) and postpartum (6-12 weeks postpartum, n = 20) group of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. RESULTS: Median age was 20 (IQR, 19-22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7-12) days in pregnancy and 17 (14-21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691-1166) in pregnancy versus 1406 fmol/punch (1053-1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667-1105) in pregnancy versus 1438 fmol/punch (1178-1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. CONCLUSIONS: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women. CLINICAL TRIALS REGISTRATION: NCT03386578.

Detectable HIV RNA in late pregnancy associated with low tenofovir hair levels at time of delivery among women living with HIV in the United States.

OBJECTIVE: We evaluated peripartum tenofovir (TFV) exposure via hair measures among women living with HIV in the United States. DESIGN: Observational cohort study. METHODS: Hair samples were collected at or shortly after childbirth among mothers enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities Study of the Pediatric HIV/AIDS Cohort Study between 6/2014 and 7/2016. Among mothers receiving TFV disoproxil fumarate (TDF)-based regimens during pregnancy, TFV hair concentrations were analyzed using liquid chromatography/tandem mass spectrometry. Weight-normalized TFV concentrations were log10 transformed. Multivariable linear regression assessed correlates of TFV concentrations. RESULTS: Overall, 121 mothers on TDF-based antiretroviral therapy during pregnancy had hair specimens tested for TFV concentrations and were included in the analysis. Median age at delivery was 31 years [interquartile range (IQR) 26-36]; 71% self-identified as non-Hispanic black, and 10% had unsuppressed viral loads in late pregnancy (HIV RNA ≥ 400 copies/ml). Median time from birth to hair collection was 3 days (IQR 1-14) and median TFV hair concentration was 0.02 ng/mg (IQR 0.01-0.04). In multivariable models, an unsuppressed viral load in late pregnancy was associated with 80% lower adjusted mean peripartum TFV concentrations than pregnancies with viral suppression (95% confidence interval: -90% to -59%, P < 0.001). Use of TDF only in the first trimester and attaining high school graduation were also associated with lower TFV hair concentrations. CONCLUSION: Unsuppressed viral load during late pregnancy was strongly associated with lower maternal TFV hair concentrations at birth, though viremia was rare. Efforts to improve maternal virological outcomes and eliminate vertical HIV transmission could incorporate drug exposure monitoring using hair or other metrics.

Extent of In Utero Transfer of Tenofovir From Mother to Fetus: A Paired Analysis of Hair Specimens Collected at Birth From a Cohort in the United States.

Understanding in utero transfer of antiretrovirals is critical for interpreting safety. Hair levels measure cumulative exposure. We measured tenofovir (TFV) concentrations in hair at delivery among women living with human immunodeficiency virus receiving TFV disoproxil fumarate-based treatment and their infants, using liquid chromatography-tandem mass spectrometry. Among 103 mother-infant pairs, the mean log10 ratio of infant-to-maternal TFV levels was 1.08 (95% confidence interval, .97-1.20). TFV transfer was 60% lower from mothers who had preterm compared with term deliveries and 42% lower from mothers who had cesarean compared with vaginal deliveries. Like prior studies assessing transfer via short-term measures (plasma, cord blood, amniotic fluid), we found high cumulative transfer using hair.