Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection.

BACKGROUND: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. METHODS: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins. RESULTS: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. CONCLUSION: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Association of Androgen Hormones, Sex Hormone-Binding Globulin, and the Menopausal Transition With Incident Diabetes Mellitus in Women With and Without HIV.

BACKGROUND: HIV is associated with alterations in androgen hormone levels and sex hormone-binding globulin (SHBG) in women. Higher SHBG has been associated with a lower risk of diabetes in the general population, but the contribution of HIV, androgen hormones, SHBG, and menopausal phase to diabetes is unclear. METHODS: From April 2003 through February 2020, 896 women with HIV (WWH) and 343 women without HIV (WWOH) from the Women's Interagency HIV Study with morning total testosterone, dehydroepiandrosterone sulfate (DHEAS), and SHBG levels were followed to assess for incident diabetes. Parametric regression models were used with age as the time scale and relative times (RT) as the measure of association of hormone level and menopausal phase with incident diabetes. Analyses incorporated time-dependent androgen hormone, SHBG levels, and menopausal phase and were adjusted for race/ethnicity, enrollment year, smoking status, BMI, hepatitis C virus status, and HIV-related factors. RESULTS: In total, 128 (14%) WWH and 47 (14%) WWOH developed diabetes. In WWH, a doubling of SHBG and DHEAS were associated with a 7% (RT = 1.07 [95% CI: 0.82 to 1.40] and 15% (RT = 1.15 [95% CI: 0.95 to 1.39]) longer time to diabetes, respectively; in WWOH, a doubling of SHBG and DHEAS were associated with 84% (RT = 1.84 [95% CI: 0.89 to 3.82]) and 41% (RT= 1.41 [95% CI: 0.82 to 2.44]) longer times to diabetes. Total testosterone was not associated. In WWH, later menopausal phase was associated with shorter times to diabetes. CONCLUSIONS: Despite alterations in androgen hormone and SHBG levels in HIV, regardless of HIV status, higher SHBG and DHEAS were associated with nonstatistically significant slower progression to diabetes. The menopausal transition may be a better hormonal indicator of diabetes risk in WWH.

Mediation analysis of chronic kidney disease risk factors using kidney biomarkers in women living with HIV.

OBJECTIVE: Novel urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in persons living with HIV. However, it is unknown whether these biomarkers provide mechanistic insight into the associations between clinical risk factors for CKD and subsequent CKD risk. METHODS: Among 636 women living with HIV in the Women's Interagency HIV Study with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m 2 , we used a counterfactual approach to causal mediation analysis to evaluate the extent to which systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin a1c (Hba1c) and serum albumin associations with incident CKD were mediated by eight urine proteins. These biomarkers reflect proximal tubular reabsorptive dysfunction (α1-microglobulin [a1m], ß2-microglobulin, trefoil factor 3); tubular injury (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1]); kidney repair (epidermal growth factor); tubular reserve (uromodulin); and glomerular injury (urinary albumin). Incident CKD was defined as eGFR <60 ml/min/1.73 m 2 measured at two consecutive 6-month visits with an average annual eGFR decline ≥3% per year. RESULTS: During a median follow-up of 7 years, 11% developed CKD. Urinary albumin and KIM-1 mediated 32% (95% CI: 13.4%, 76.6%) and 23% (6.9%, 60.7%) of the association between SBP and incident CKD, respectively; and 19% (5.1%, 42.3%) and 22% (8.1%, 45.7%) of the association between DBP and incident CKD, respectively. Urinary albumin, α1m, and IL-18 were significant mediators of the association between Hba1c and incident CKD. None of the eight biomarkers mediated the association between serum albumin and incident CKD. CONCLUSIONS: Among women living with HIV, several urinary biomarkers reflecting distinct dimensions of kidney health may partially explain the associations between SBP, DBP, and Hba1c and subsequent CKD risk.

"As I Grew Older, My Life Got Better": Conceptions of Successful Aging among Older Women Living with or at Risk of HIV.

Successful aging (SA) is an important target for HIV care. However, we have insufficient understanding of how older women living with HIV (OWLH) in the US define SA. We explored conceptions of SA by OWLH and older women at risk of HIV and examined whether SA conceptions differed by (1) HIV serostatus, and (2) participation in the Women's Interagency HIV Study (WIHS). These analyses were part of a larger mixed-methods study with a sequential design. Participants were recruited at two clinical WIHS sites. We enrolled both WIHS participants and non-WIHS clinic patients. Our sample was 84% Black and included 29 OWLH and 15 older women at risk of HIV. We conducted 21 semi-structured interviews and four focus groups. The dataset was analyzed using descriptive, comparative, and relational analysis. We found four interlinked themes: life course perspective, accepting and celebrating aging, taking care of yourself, and looking good. The life course perspective was a core theme: participants assessed their aging in comparison to their earlier life hardships. These themes were similarly present among OWLH and older women at risk of HIV, although OWLH emphasized taking care of HIV. SA conceptualizations by OWLH did not differ whether or not they participated in the WIHS. Women living with or at risk of HIV may experience severe hardships throughout their lives. Overcoming these hardships may be linked to SA. Assessing the needs and connecting women to resources and programs are critical for SA promotion.

Tryptophan metabolism, gut microbiota, and carotid artery plaque in women with and without HIV infection.

OBJECTIVE: The perturbation of tryptophan (TRP) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and atherosclerosis remain unclear in the context of HIV infection. METHODS: We included 361 women (241 HIV+, 120 HIV-) with carotid artery plaque assessments from the Women's Interagency HIV Study, measured 10 plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolite-related gut bacteria were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. Associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression. RESULTS: Although plasma kynurenic acid (KYNA) [odds ratio (OR) = 1.93, 95% confidence interval (CI): 1.12-3.32 per one SD increase; P  = 0.02) and KYNA/TRP [OR = 1.83 (95% CI 1.08-3.09), P  = 0.02] were positively associated with plaque, indole-3-propionate (IPA) [OR = 0.62 (95% CI 0.40-0.98), P  = 0.03] and IPA/KYNA [OR = 0.51 (95% CI 0.33-0.80), P  < 0.01] were inversely associated with plaque. Five gut bacterial genera and many affiliated species were positively associated with IPA (FDR-q < 0.25), including Roseburia spp ., Eubacterium spp., Lachnospira spp., and Coprobacter spp.; but no bacterial genera were found to be associated with KYNA. Furthermore, an IPA-associated-bacteria score was inversely associated with plaque [OR = 0.47 (95% CI 0.28-0.79), P  < 0.01]. But no significant effect modification by HIV serostatus was observed in these associations. CONCLUSION: In a cohort of women living with and without HIV infection, plasma IPA levels and related gut bacteria were inversely associated with carotid artery plaque, suggesting a potential beneficial role of IPA and its gut bacterial producers in atherosclerosis and CVD.

Common antiretroviral combinations are associated with somatic depressive symptoms in women with HIV.

OBJECTIVE: While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms. DESIGN: Analysis of longitudinal data from the Women's Interagency HIV Study. METHODS: Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment. RESULTS: The analysis included 1538 WWH who participated in 12 924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with nonsomatic symptoms in any group. CONCLUSIONS: Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression.

The menopause-related gut microbiome: associations with metabolomics, inflammatory protein markers, and cardiometabolic health in women with HIV.

OBJECTIVE: This study aimed to identify menopause-related gut microbial features, as well as their related metabolites and inflammatory protein markers, and link with cardiometabolic risk factors in women with and without HIV. METHODS: In the Women's Interagency HIV Study, we performed shotgun metagenomic sequencing on 696 stool samples from 446 participants (67% women with HIV), and quantified plasma metabolomics and serum proteomics in a subset (~86%). We examined the associations of menopause (postmenopausal vs premenopausal) with gut microbial features in a cross-sectional repeated-measures design and further evaluated those features in relation to metabolites, proteins, and cardiometabolic risk factors. RESULTS: Different overall gut microbial composition was observed by menopausal status in women with HIV only. We identified a range of gut microbial features that differed between postmenopausal and premenopausal women with HIV (but none in women without HIV), including abundance of 32 species and functional potentials involving 24 enzymatic reactions and lower ß-glucuronidase bacterial gene ortholog. Specifically, highly abundant species Faecalibacterium prausnitzii , Bacteroides species CAG:98 , and Bifidobacterium adolescentis were depleted in postmenopausal versus premenopausal women with HIV. Menopause-depleted species (mainly Clostridia ) in women with HIV were positively associated with several glycerophospholipids, while negatively associated with imidazolepropionic acid and fibroblast growth factor 21. Mediation analysis suggested that menopause may decrease plasma phosphatidylcholine plasmalogen C36:1 and C36:2 levels via reducing abundance of species F. prausnitzii and Acetanaerobacterium elongatum in women with HIV. Furthermore, waist-to-hip ratio was associated with menopause-related microbes, metabolites, and fibroblast growth factor 21 in women with HIV. CONCLUSIONS: Menopause was associated with a differential gut microbiome in women with HIV, related to metabolite and protein profiles that potentially contribute to elevated cardiometabolic risk.

Plasma Biomarkers of Alzheimer Disease in Women With and Without HIV.

Importance: Blood-based biomarkers associated with increased risk of Alzheimer disease (AD) are understudied in people living with and without HIV, particularly women. Objective: To determine whether baseline or 1-year changes in plasma amyloid-ß40 (Aß40), Aß42, ratio of Aß42 to Aß40, total tau (t-tau), phosphorylated tau 231 (p-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NFL) are associated with neuropsychological performance (NP) among women living with HIV (WLWH) and women living without HIV (WLWOH). Design, Setting, and Participants: This longitudinal, prospective, cohort study with 1-year repeated clinical measures (NP only measured once) and biospecimen collection occurred between 2017 and 2019. Participants were women aged 40 years or older from 10 clinical research sites in cities across the US that were part of the Women's Interagency HIV Study. Data analysis was conducted from April to December 2022. Exposure: Laboratory-confirmed HIV status and AD biomarkers. Main Outcomes and Measures: Sociodemographically adjusted NP T-scores (attention and working memory, executive function, processing speed, memory, learning, verbal fluency, motor function, and global performance) were the primary outcomes. Baseline and 1-year fasting plasma Aß40, Aß42, t-tau, p-tau231, GFAP, and NFL levels were measured and analyzed using multivariable linear regression. Results: The study consisted of 307 participants (294 aged ≥50 years [96%]; 164 African American or Black women [53%]; 214 women with a high school education or higher [70%]; 238 women who were current or former smokers [78%]; and 236 women [77%] who were overweight or obese [body mass index >25]) including 209 WLWH and 98 WLWOH. Compared with WLWOH at baseline, WLWH performed worse on learning (mean [SD] T-score 47.8 [11.3] vs 51.4 [10.5]), memory (mean [SD] T-score 48.3 [11.6] vs 52.4 [10.2]), verbal fluency (mean [SD] T-score 48.3 [9.8] vs 50.7 [8.5]), and global (mean [SD] T-score 49.2 [6.8] vs 51.1 [5.9]) NP assessments. Baseline median Aß40, GFAP, and NFL levels were higher among WLWH vs WLWOH. There were no differences in 1-year biomarker change by HIV serostatus. Lower learning, memory, and motor NP were associated with 1-year Aß40 increase; lower learning and motor with Aß42 increase; lower motor with p-tau231 increase; and lower processing speed, verbal fluency and motor with NFL increase in the entire sample. Among WLWH, a 1-year increase in Aß40 from baseline to follow-up was associated with worse learning, memory, and global NP; a 1-year increase in t-tau with worse executive function; and a 1-year increase in NFL with worse processing speed. Among WLWOH, a 1-year increase in Aß40 and Aß42 were associated with poorer memory performance and NFL was associated with poorer motor performance. Conclusions and Relevance: These findings suggest that increases in certain plasma AD biomarkers are associated with NP in WLWH and WLWOH and may be associated with later onset of AD, and measuring these biomarkers could be a pivotal advancement in monitoring aging brain health and development of AD among women with and without HIV.

Gut Microbiota and Cognitive Function Among Women Living with HIV.

BACKGROUND: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer's disease, but little is known among people living with HIV. OBJECTIVE: To examine associations between gut microbiota and cognitive impairment among women with or without HIV. METHODS: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive impairment was defined as two or more domains with T scores < 1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression. RESULTS: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus, and Gemmiger, and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways. CONCLUSIONS: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer's disease.

Association of Gut Microbiota With Objective Sleep Measures in Women With and Without Human Immunodeficiency Virus Infection: The IDOze Study.

BACKGROUND: Poor sleep health is an underrecognized health challenge, especially for people with human immunodeficiency virus (HIV). Gut microbiota related to sleep are underinvestigated. METHODS: The IDOze microbiota substudy included 190 women (114 with HIV and 76 without HIV). Wrist actigraphy measured total sleep duration, sleep efficiency, number of wake bouts, wake after sleep onset, fragmentation index, and sleep timing. 16S rRNA gene sequencing identified gut microbial genera. Analysis of compositions of microbiomes with bias correction was used to investigate cross-sectional associations between gut microbiota and sleep. Abundances of sleep-related gut microbial genera were compared between women with and without HIV. RESULTS: Enrichment of 7 short-chain fatty acid-producing genera (eg, Butyricimonas, Roseburia, and Blautia) was associated with lower fragmentation index. Enrichment of 9 genera (eg, Dorea) was associated with lower sleep efficiency and/or more wake after sleep onset. Enrichment of proinflammatory Acidaminococcus was associated with late sleep midpoint and offset time. These associations were largely consistent regardless of HIV status. The abundance of Butyricimonas was lower among women with HIV compared to those without HIV. CONCLUSIONS: Seventeen genera were identified to be associated with sleep continuity or timing. Butyricimonas, a potentially beneficial genus associated with sleep continuity, was less abundant among women with HIV.

Overnight urinary melatonin levels in women with and without HIV: An observational cohort study.

INTRODUCTION: Despite significant improvements in longevity and quality of life associated with antiretroviral therapy, individuals with HIV still suffer from a higher burden of sleep and circadian disruption and inflammatory-based diseases than individuals without HIV. While melatonin is a hormone that has a role in sleep and circadian regulation and has anti-inflammatory properties, the overnight concentration of the urinary melatonin metabolite has not yet been reported in people with HIV. METHODS: The aim of this study was to compare the overnight urinary melatonin metabolite levels in women aged 35-70 years with HIV (n = 151) to a well-matched comparison group of women without HIV (n = 147). All women wore a wrist actigraphy monitor and completed daily diaries documenting sleep timing and use of medications and drugs or alcohol for 10 days. Participants collected their overnight urine near the end of the monitoring period. RESULTS: Melatonin levels did not differ between women with or without HIV, but more than 40% of women had low levels of melatonin. Higher body mass index predicted lower levels of melatonin, and lower levels of melatonin were associated with lower sleep efficiency as assessed with wrist actigraphy. CONCLUSION: These data lay the foundation for exploration of the longitudinal consequences of endogenous melatonin levels for inflammatory-based diseases in aging women with and without HIV. Future studies should consider the use of supplemental melatonin to improve sleep in women with lower levels of melatonin.

Midlife body mass index, central adiposity and neuropsychological performance over 10 years in women living with and without HIV.

Background and objective: Observations of overweight and obesity in association with neuropsychological performance (NP) vary over the adult life course depending on baseline levels, biological sex, age, race, temporality of measurements, and other factors. Therefore, similar published analyses across cohorts are inconsistent. In our sample of women living with HIV (WLWH) and women without HIV (WWOH), we conducted comparable analyses as those published in men with and without HIV. We examined cross-sectional and longitudinal associations between body mass index (BMI) and waist circumference (WC) and NP. Methods: Four hundred thirty two 432 virologically-suppressed WLWH and 367 WWOH, ≥40 years in the Women's Interagency HIV Study (WIHS) with anthropometry and NP assessments every two years from 2009-2019 were included in the study. Demographically-adjusted T-scores were calculated for six NP domains: learning, memory, executive function, processing speed, attention and working memory, and motor function. Multivariable linear regression models stratified by HIV status were used to examine cross-sectional associations of BMI and WC by NP domain; repeated measures analyses assessed baseline BMI and WC in association with longitudinal change in NP. Covariates included sociodemographic, behavioral, and HIV-related characteristics. Results: At baseline among all women, the median age was 45 years, 65% were Non-Latinx Black women, and 45% were obese women. Obese WLWH (BMI≥30.0 kg/m2) had poorer executive function (ß=-2.27, 95%CI [-4.46, -0.07]) versus WLWH with healthy BMI (18.5-24.9 kg/m2). Longitudinally over ~8 years, obese versus overweight WWOH improved on memory (ß=2.19, 95%CI [0.13, 4.26]), however overweight versus healthy WWOH experienced declining memory (ß= -2.67, 95%CI [-5.40, -0.07]). Increasing WC was associated with declining executive, processing speed, and motor function (p's<0.05); an at-risk WC was associated with improved memory (ß=1.81, 95%CI [0.19, 3.44]) among WWOH. Among WLWH, increasing BMI was associated with improved learning (ß=0.07, 95%CI [0.00, 0.15]. Conclusion: Our cross-sectional and longitudinal analyses evaluating the associations of BMI and WC and NP were mixed compared to previous reports. This illustrates the importance of sociodemographic characteristics, baseline levels of exposures and outcomes, HIV status, temporality of measurements, and other factors when evaluating aging HIV epidemiology study results.

Obesity Modifies the Relationship Between Raltegravir and Dolutegravir Hair Concentrations and Body Weight Gain in Women Living with HIV.

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in women living with HIV (WLH). Relationships between drug exposure, baseline obesity, and INSTI-associated weight gain remain unclear. Data from 2006 to 2016 were analyzed from virally suppressed WLH enrolled in the Women's Interagency HIV Study, who switched/added an INSTI to antiretroviral therapy: [raltegravir (RAL), dolutegravir (DTG), or elvitegravir (EVG)]. Percent body weight change was calculated from weights obtained a median 6 months pre-INSTI and 14 months post-INSTI initiation. Hair concentrations were measured with validated liquid chromatography-mass spectrometry (MS)/MS assays. Baseline (preswitch) weight status evaluated obese (body mass index, BMI, ≥30 kg/m2) versus nonobese (BMI <30 kg/m2). Mixed models examined the drug hair concentration*baseline obesity status interaction for each INSTI. There were 169 WLH included: 53 (31%) switched to RAL, 72 (43%) to DTG, and 44 (26%) to EVG. Women were median age 47-52 years, predominantly Non-Hispanic Black, median CD4 counts >500 cells/mm3, >75% with undetectable HIV-1 RNA. Over ∼1 year, women experienced median increases in body weight: 1.71% (-1.78, 5.00) with RAL; 2.40% (-2.82, 6.50) with EVG; and 2.48% (-3.60, 7.88) with DTG. Baseline obesity status modified the relationship between hair concentrations and percent weight change for DTG and RAL (p's < 0.05): higher DTG, yet lower RAL concentrations were associated with greater weight gain among nonobese women. Additional pharmacologic assessments are needed to understand the role of drug exposure in INSTI-associated weight gain.

Gut microbiota, circulating inflammatory markers and metabolites, and carotid artery atherosclerosis in HIV infection.

BACKGROUND: Alterations in gut microbiota have been implicated in HIV infection and cardiovascular disease. However, how gut microbial alterations relate to host inflammation and metabolite profiles, and their relationships with atherosclerosis, have not been well-studied, especially in the context of HIV infection. Here, we examined associations of gut microbial species and functional components measured by shotgun metagenomics with carotid artery plaque assessed by B-mode carotid artery ultrasound in 320 women with or at high risk of HIV (65% HIV +) from the Women's Interagency HIV Study. We further integrated plaque-associated microbial features with serum proteomics (74 inflammatory markers measured by the proximity extension assay) and plasma metabolomics (378 metabolites measured by liquid chromatography tandem mass spectrometry) in relation to carotid artery plaque in up to 433 women. RESULTS: Fusobacterium nucleatum, a potentially pathogenic bacteria, was positively associated with carotid artery plaque, while five microbial species (Roseburia hominis, Roseburia inulinivorans, Johnsonella ignava, Odoribacter splanchnicus, Clostridium saccharolyticum) were inversely associated with plaque. Results were consistent between women with and without HIV. Fusobacterium nucleatum was positively associated with several serum proteomic inflammatory markers (e.g., CXCL9), and the other plaque-related species were inversely associated with proteomic inflammatory markers (e.g., CX3CL1). These microbial-associated proteomic inflammatory markers were also positively associated with plaque. Associations between bacterial species (especially Fusobacterium nucleatum) and plaque were attenuated after further adjustment for proteomic inflammatory markers. Plaque-associated species were correlated with several plasma metabolites, including the microbial metabolite imidazole-propionate (ImP), which was positively associated with plaque and several pro-inflammatory markers. Further analysis identified additional bacterial species and bacterial hutH gene (encoding enzyme histidine ammonia-lyase in ImP production) associated with plasma ImP levels. A gut microbiota score based on these ImP-associated species was positively associated with plaque and several pro-inflammatory markers. CONCLUSION: Among women living with or at risk of HIV, we identified several gut bacterial species and a microbial metabolite ImP associated with carotid artery atherosclerosis, which might be related to host immune activation and inflammation. Video Abstract.

Tubular Secretory Solute Clearance and HIV Infection.

BACKGROUND: Tubular secretion is an important kidney function responsible for the clearance of numerous medications, including antibiotics and antivirals. It is unknown whether persons living with HIV have lower secretion compared with HIV-uninfected persons, which might predispose them to the risk of progressive kidney disease or adverse drug events. SETTING AND METHODS: We evaluated a panel of 6 endogenous secretory solutes in 199 women living with HIV (WLWH) and 100 women without HIV enrolled in the Women's Interagency HIV Study. Secretory clearance was estimated as the urine-to-plasma ratio of each solute, with adjustment for urine tonicity. Using multivariable linear regression analysis, we compared differences in levels of secretory solute clearance between women with and without HIV and evaluated characteristics associated with secretion. RESULTS: WLWH were older (median 40 vs. 38 years) but had similar estimated glomerular filtration rate (eGFR, 96 vs. 100 mL/minute/1.73 m 2 ) compared with those without HIV. African American and Latino race, diabetes, diastolic blood pressure, smoking, hepatitis C, peak HIV viral load, and current and nadir CD4 count were associated with differences in clearance of at least 1 marker after multivariable adjustment. The secretory clearance of 3 solutes (cinnamoylglycine, kynurenic acid, and pyridoxic acid) were on average 10%-15% lower among WLWH compared with those without HIV independent of eGFR, albuminuria and chronic kidney disease risk factors, including HCV, and injection drug use. CONCLUSIONS: HIV is associated with reduced secretion among women with preserved eGFR. The implications of these findings for drug dosing and adverse events need to be evaluated.

Trauma Across the Life Span and Multisystem Morbidity in Women With HIV.

OBJECTIVE: Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes. METHODS: A total of 1027 WLWH (average age = 48.6 years) in the Women's Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes. RESULTS: Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8. CONCLUSIONS: WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions.

Intersectionality of Socioecological Factors Associated With Cognitive Function Among Older Women With HIV in the United States: A Structural Equation Model Analysis Using Data From the Women's Interagency HIV Study.

ABSTRACT: Increased life expectancy of people with HIV has health implications including the intersection of the long-term use of antiretroviral treatment, inflammatory events, and age-related immunosenescence. In a cross-sectional study utilizing using the Socio-Eecological Model, we identified pathways of cognitive function (CF) among 448 women with HIV, 50 years and older. A structural equation model showed the direct effects of mood (ß = -0.25, p < .01), comorbidities (ß = --0.13, p < .05), race (ß = --0.13, p < .05), and abuse (ß = 0.27, p < .001) on the latent variable CF. Substance and alcohol use, depressive symptoms, cigarette smoking, and the number of comorbidities are important considerations when designing interventions utilizing using a multi-level and intersectional lens to maximize positive CF outcomes.

Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIV.

OBJECTIVE: Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women's Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects(CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35-55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms(P's < 0.01); dolutegravir was also associated with greater re-experiencing symptoms(P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities(P's < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years(P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk-benefit ratio of dolutegravir and elvitegravir in WWH.