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.

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.

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.

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.

Rates of Hospitalization and Infection-Related Hospitalization Among Human Immunodeficiency Virus (HIV)-Exposed Uninfected Children Compared to HIV-Unexposed Uninfected Children in the United States, 2007-2016.

BACKGROUND: Studies from multiple countries have suggested impaired immunity in perinatally human immunodeficiency virus (HIV)-exposed uninfected children (HEU), with elevated rates of all-cause hospitalization and infections. We estimated and compared the incidence of all-cause hospitalization and infection-related hospitalization in the first 2 years of life among HEU and HIV-unexposed uninfected children (HUU) in the United States. Among HEU, we evaluated associations of maternal HIV disease-related factors during pregnancy with risk of child hospitalization. METHODS: HEU data from subjects enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities Study (SMARTT) cohort who were born during 2006-2017 were analyzed. HUU comparison data were obtained from the Medicaid Analytic Extract database, restricted to states participating in SMARTT. We compared rates of first hospitalization, total hospitalizations, first infection-related hospitalization, total infection-related hospitalizations, and mortality between HEU and HUU using Poisson regression. Among HEU, multivariable Poisson regression models were fitted to evaluate associations of maternal HIV factors with risk of hospitalization. RESULTS: A total of 2404 HEU and 3 605 864 HUU were included in the analysis. HEU children had approximately 2 times greater rates of first hospitalization, total hospitalizations, first infection-related hospitalization, and total infection-related hospitalizations compared with HUUs. There was no significant difference in mortality. Maternal HIV disease factors were not associated with the risk of child infection or hospitalization. CONCLUSIONS: Compared with HUU, HEU children in the United States have higher rates of hospitalization and infection-related hospitalization in the first 2 years of life, consistent with studies in other countries. Closer monitoring of HEU infants for infection and further elucidation of immune mechanisms is needed.

Screening and Enrollment by Sex in Human Immunodeficiency Virus Clinical Trials in the United States.

BACKGROUND: Women are underrepresented in human immunodeficiency virus (HIV) research in the United States. To determine if women screening for HIV clinical trials enrolled at lower rates than men, we performed a retrospective, cross-trial analysis. METHODS: We conducted an analysis of screening and enrollment during 2003-2013 to 31 clinical trials at 99 AIDS Clinical Trials Group network research sites in the United States. Random-effects meta regression estimated whether sex differences in not enrolling ("screen out") varied by various individual, trial, or site characteristics. RESULTS: Of 10 744 persons screened, 18.9% were women. The percentages of women and men who screened out were 27.9% and 26.5%, respectively (P = .19); this small difference did not significantly vary by race, ethnicity, or age group. Most common reasons for screening out were not meeting eligibility criteria (30-35%) and opting out (23%), and these did not differ by sex. Trial and research site characteristics associated with variable screen-out by sex included HIV research domain and type of hemoglobin eligibility criterion, but individual associations did not persist after adjustment for multiple testing. CONCLUSIONS: In the absence of evidence of significantly higher trial screen-out for women, approaching more women to screen may increase female representation in HIV trials.

Following young people with perinatal HIV infection from adolescence into adulthood: the protocol for PHACS AMP Up, a prospective cohort study.

INTRODUCTION: The first generation of adolescents born with HIV infection has reached young adulthood due to advances in treatment. It is important to continue follow-up of these individuals to assess their long-term medical, behavioural and mental health and ability to successfully transition to adulthood while coping with a chronic, potentially stigmatising condition. To accomplish this, and to maintain their interest in long-term research participation, we need to accommodate the changing lifestyles and interests of young adult study participants while ensuring valid data collection. We report the protocol for Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) Up, a prospective cohort study enrolling young adult participants for long-term follow-up. METHODS AND ANALYSIS: AMP Up is recruiting 850 young men and women 18 years of age and older-600 perinatally HIV-infected and a comparison group of 250 perinatally HIV-exposed, uninfected-at 14 clinical research sites in the USA and Puerto Rico. Recruitment began in April 2014 and is ongoing, with 305 participants currently enrolled. Planned follow-up is ≥6 years. Data are collected with a flexible hybrid of online and in-person methods. Outcomes include: transition to adult clinical care and retention in care; end-organ diseases; malignancies; metabolic complications; sexually transmitted infections; reproductive health; mental health and neurocognitive functioning; adherence to antiretroviral treatment; sexual behaviour and substance use; hearing and language impairments; and employment and educational achievement. ETHICS AND DISSEMINATION: The study received ethical approval from the Harvard T.H. Chan School of Public Health's institutional review board (IRB), and from the IRBs of each clinical research site. All participants provide written informed consent; for cognitively impaired individuals with legally authorised representatives, legal guardian permission and participant assent is obtained. Findings will be disseminated through peer-reviewed journals, conference presentations and participant summaries.

Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapy in utero.

The use of combination antiretroviral therapy (cART) to prevent HIV mother-to-child transmission during pregnancy and delivery is generally considered safe. However, vigilant assessment of potential risks of these agents remains warranted. Epigenetic changes including DNA methylation are considered potential mechanisms linking the in utero environment with long-term health outcomes. Few studies have examined the epigenetic effects of prenatal exposure to pharmaceutical agents, including antiretroviral therapies, on children. In this study, we examined the methylation status of the LINE-1 and ALU-Yb8 repetitive elements as markers of global DNA methylation alteration in peripheral blood mononuclear cells obtained from newborns participating in the Pediatric HIV/AIDS Cohort Study SMARTT cohort of HIV-exposed, cART-exposed uninfected infants compared to a historical cohort of HIV-exposed, antiretroviral-unexposed infants from the Women and Infants Transmission Study Cohort. In linear regression models controlling for potential confounders, we found the adjusted mean difference of AluYb8 methylation of the cART-exposed compared to the -unexposed was -0.568 (95% CI: -1.023, -0.149) and for LINE-1 methylation was -1.359 (95% CI: -1.860, -0.857). Among those exposed to cART, subjects treated with atazanavir (ATV), compared to those on other treatments, had less AluYb8 methylation (-0.524, 95% CI: -0.025, -1.024). Overall, these results suggest a small but statistically significant reduction in the methylation of these repetitive elements in an HIV-exposed, cART-exposed cohort compared to an HIV-exposed, cART-unexposed historic cohort. The potential long-term implications of these differences are worthy of further examination.

Prevalence of and risk factors for substance use among perinatally human immunodeficiency virus-infected and perinatally exposed but uninfected youth.

PURPOSE: This study examined risk factors associated with recent substance use (SU) among perinatally human immunodeficiency virus (HIV)-infected (PHIV+) and perinatally exposed, uninfected (PHEU) youth and compared SU lifetime prevalence with the general population of United States (U.S.) adolescents. METHODS: We conducted cross-sectional and longitudinal analyses of 511 PHIV+ and PHEU youth (mean age at study entry, 13.2 years; 51% female; 69% PHIV+; and 72% African-American) enrolled in a U.S. multisite prospective cohort study between 2007 and 2009. Substance use data were collected by audio computer-assisted self-interview. Youth Risk Behavior Surveillance System and Monitoring the Future data were used to compare SU lifetime prevalence with U.S. samples. RESULTS: Perinatal HIV infection was not a statistically significant risk factor for alcohol or marijuana use. Risk factors for alcohol use among PHIV+ youth included higher severity of emotional and conduct problems and alcohol and marijuana use in the home by the caregiver or others. Risk factors for marijuana use among PHIV+ youth included marijuana use in the home, higher severity of conduct problems, and stressful life events. Similar SU risk factors among PHEU youth included SU in the home and higher severity of conduct and emotional problems. Overall lifetime prevalence of SU by age was similar to that in national surveys. CONCLUSIONS: Although SU lifetime prevalence and risk factors for PHIV+ and PHEU adolescents were similar to national norms, the negative consequences are potentially greater for PHIV+ youth. Prevention efforts should begin before SU initiation and address the family and social environment and youth mental health status.

Biomarkers from late pregnancy to 6 weeks postpartum in HIV-infected women who continue versus discontinue antiretroviral therapy after delivery.

BACKGROUND: Women who use antiretroviral therapy (ART) solely for the prevention of mother-to-child transmission of HIV discontinue postpartum. We hypothesized that women discontinuing ART by 6 weeks postpartum ("discontinuers") would have elevated postpartum inflammatory biomarker levels relative to women remaining on ART postpartum ("continuers"). METHODS: Data from HIV-infected pregnant women enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1025 with CD4 counts >350 cells per cubic millimeter before initiating ART or first pregnancy CD4 counts >400 cells per cubic millimeter after starting ART and with available stored plasma samples at >20 weeks of gestation, delivery, and 6 weeks postpartum were analyzed. Plasma samples were tested for highly sensitive C-reactive protein, D-dimer, and interleukin-6. We used longitudinal linear spline regression to model biomarkers over time. RESULTS: Data from 128 women (65 continuers and 63 discontinuers) were analyzed. All biomarkers increased from late pregnancy to delivery, then decreased postpartum (slopes different from 0, P < 0.001). Continuers had a steeper decrease in log D-dimer between delivery and 6 weeks postpartum than discontinuers (P = 0.002). CONCLUSIONS: In contrast to results from treatment interruption studies in adults, both ART continuers and ART discontinuers had significant decreases in the levels of D-dimer, highly sensitive C-reactive protein, or interleukin-6 postpartum. Continuation was associated with a more rapid decline in D-dimer levels compared with discontinuation.