Comparison of Cardiovascular Disease Risk Factors Between 2 Subclinical Atherosclerosis Measures in Healthy Postmenopausal Women: Carotid Artery Wall Thickness and Echogenicity: Carotid Artery Wall Thickness and Echogenicity.

OBJECTIVES: Although carotid artery intima media thickness (CIMT) is a widely used determinant of subclinical atherosclerosis, gray-scale median of the intima-media complex (IM-GSM) of the common carotid artery is a relatively novel measure of echogenicity reflecting composition of the arterial wall. It is important to compare cardiovascular disease (CVD) risk factor correlates across CIMT and IM-GSM to determine whether these measures reflect distinct aspects of atherosclerosis. METHODS: Baseline information from a completed randomized clinical trial of 643 healthy postmenopausal women without clinically apparent CVD was included in this cross-sectional study. The women were on average ± SD 61 ± 7 years old, and predominantly non-Hispanic White. CIMT and IM-GSM were measured by high-resolution B-mode ultrasonogram in the far wall of the right common carotid artery. CVD risk factors including age, race, body mass index (BMI), smoking, weekly hours of physical activity, systolic (SBP) and diastolic blood pressure (DBP), lipids, glucose, and inflammatory markers were measured at baseline. Linear regression models were used to assess associations of CVD risk factors with CIMT and IM-GSM. Multivariable models included groups of risk factors added one at a time with and withoutbasic demographic factors (age, race, BMI, physical activity) with model R2 values compared between CIMT and IM-GSM. RESULTS: In multivariable analysis, age, Black race, BMI, SBP, and DBP were associated with CIMT (all P < .05), whereas age, Hispanic race, BMI, SBP, physical activity, LDL-cholesterol, and leptin were correlates of IM-GSM (all P < .05). Adjusted for age, race, BMI, and physical activity, the R2 value for SBP was greater for CIMT association, whereas R2 values for lipids, glucose, inflammatory markers, and adipokines were greater for IM-GSM associations. CONCLUSIONS: CIMT and IM-GSM assess different attributes of subclinical atherosclerosis. Integrating both measures may provide improved assessment of atherosclerosis in asymptomatic individuals.

Regulatory CD4+ T Cells Recognize Major Histocompatibility Complex Class II Molecule-Restricted Peptide Epitopes of Apolipoprotein B.

BACKGROUND: CD4+ T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules. METHODS: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E-deficient ( Apoe-/-) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined. RESULTS: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4+ T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3+ regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe-/- mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4+ T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-Ab-p18 tetramer identified the expansion of p18-specific CD4+ T cells on vaccination, which were enriched for interleukin-10-producing Tregs. CONCLUSIONS: These findings show that APOB p18-specific CD4+ T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.

Miscarriage among women in the United States Women's Interagency HIV Study, 1994-2017.

BACKGROUND: Relatively little is known about the frequency and factors associated with miscarriage among women living with HIV. OBJECTIVE: The objective of the study was to evaluate factors associated with miscarriage among women enrolled in the Women's Interagency HIV Study. STUDY DESIGN: We conducted an analysis of longitudinal data collected from Oct. 1, 1994, to Sept. 30, 2017. Women who attended at least 2 Women's Interagency HIV Study visits and reported pregnancy during follow-up were included. Miscarriage was defined as spontaneous loss of pregnancy before 20 weeks of gestation based on self-report assessed at biannual visits. We modeled the association between demographic, behavioral, and clinical covariates and miscarriage (vs live birth) for women overall and stratified by HIV status using mixed-model logistic regression. RESULTS: Similar proportions of women living with and without HIV experienced miscarriage (37% and 39%, respectively, P = .638). In adjusted analyses, smoking tobacco (adjusted odds ratio, 2.0), alcohol use (adjusted odds ratio, 4.0), and marijuana use (adjusted odds ratio, 2.0) were associated with miscarriage. Among women living with HIV, low HIV viral load (<4 log10 copies/mL) (adjusted odds ratio, 0.5) and protease inhibitor (adjusted odds ratio, 0.4) vs the nonuse of combination antiretroviral therapy use were protective against miscarriage. CONCLUSION: We did not find an increased odds of miscarriage among women living with HIV compared with uninfected women; however, poorly controlled HIV infection was associated with increased miscarriage risk. Higher miscarriage risk among women exposed to tobacco, alcohol, and marijuana highlight potentially modifiable behaviors. Given previous concern about antiretroviral therapy and adverse pregnancy outcomes, the novel protective association between protease inhibitors compared with non-combination antiretroviral therapy and miscarriage in this study is reassuring.

Effect of antiretroviral therapy on allele-associated Lp(a) level in women with HIV in the Women's Interagency HIV Study.

We previously demonstrated an association between lipoprotein (a) [Lp(a)] levels and atherosclerosis in human immunodeficiency virus (HIV)-seropositive women. The effects of antiretroviral therapy (ART) on Lp(a) levels in relation to apo(a) size polymorphism remain unclear. ART effects on allele-specific apo(a) level (ASL), an Lp(a) level associated with individual apo(a) alleles within each allele-pair, were determined in 126 HIV-seropositive women. ART effects were tested by a mixed-effects model across pre-ART and post-ART first and third visits. Data from 120 HIV-seronegative women were used. The mean age was 38 years; most were African-American (∼70%). Pre-ART ASLs associated with the larger (4.6 mg/dl vs. 8.0 mg/dl, P = 0.024) or smaller (13 mg/dl vs. 19 mg/dl, P = 0.041) apo(a) sizes were lower in the HIV-seropositive versus HIV-seronegative group, as was the prevalence of a high Lp(a) level (P = 0.013). Post-ART ASL and prevalence of high Lp(a) or apo(a) sizes and frequency of small size apo(a) (22 kringles) did not differ between the two groups. ART increased Lp(a) level (from 18 to 24 mg/dl, P < 0.0001) and both ASLs (P < 0.001). In conclusion, regardless of genetic control, Lp(a) can be modulated by HIV and its treatment. ART initiation abrogates HIV-induced suppression of Lp(a) levels and ASLs, contributing to promote CVD risk in HIV-seropositive individuals.

Lipoprotein(a) and HIV: Allele-Specific Apolipoprotein(a) Levels Predict Carotid Intima-Media Thickness in HIV-Infected Young Women in the Women's Interagency HIV Study.

OBJECTIVE: In the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV)-related elevated cardiovascular disease risk remain unclear. APPROACH AND RESULTS: The associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima-media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women's Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ≈31 years), with the majority being Blacks (≈70%). The prevalence of a small size apo(a) (≤22 Kringle repeats) or a high Lp(a) level (≥30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (P=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.022) were significantly associated with carotid artery intima-media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4+ T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (P=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima-media thickness. CONCLUSIONS: Lp(a) and allele-specific apo(a) levels predict carotid artery intima-media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection.

Use of antimüllerian hormone to predict the menopausal transition in HIV-infected women.

BACKGROUND: HIV infection has been associated with early menopausal onset, which may have adverse long-term health consequences. Antimüllerian hormone, a biomarker of ovarian reserve and gonadal aging, is reduced in HIV-infected women. OBJECTIVE: We sought to assess the relationship of antimüllerian hormone to age of menopause onset in HIV-infected women. STUDY DESIGN: We used antimüllerian hormone levels measured in plasma in 2461 HIV-infected participants from the Women's Interagency HIV Study to model the age at final menstrual period. Multivariable normal mixture models for censored data were used to identify factors associated with age at final menstrual period. RESULTS: Higher antimüllerian hormone at age 40 years was associated with later age at final menstrual period, even after multivariable adjustment for smoking, CD4 cell count, plasma HIV RNA, hepatitis C infection, and history of clinical AIDS. Each doubling of antimüllerian hormone was associated with a 1.5-year increase in the age at final menstrual period. Median age at final menstrual period ranged from 45 years for those in the 10th percentile of antimüllerian hormone to 52 years for those in the 90th percentile. Other factors independently associated with earlier age at final menstrual period included smoking, hepatitis C infection, higher HIV RNA levels, and history of clinical AIDS. CONCLUSION: Antimüllerian hormone is highly predictive of age at final menstrual period in HIV-infected women. Measuring antimüllerian hormone in HIV-infected women may enable clinicians to predict risk of early menopause, and potentially implement individualized treatment plans to prevent menopause-related comorbidities and to aid in interpretation of symptoms.

Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women.

BACKGROUND: Little is known about fertility choices and pregnancy outcome rates among HIV-infected women in the current combination antiretroviral treatment era. OBJECTIVE: We sought to describe trends and factors associated with live-birth and abortion rates among HIV-positive and high-risk HIV-negative women enrolled in the Women's Interagency HIV Study in the United States. STUDY DESIGN: We analyzed longitudinal data collected from Oct. 1, 1994, through Sept. 30, 2012, through the Women's Interagency HIV Study. Age-adjusted rates per 100 person-years live births and induced abortions were calculated by HIV serostatus over 4 time periods. Poisson mixed effects models containing variables associated with live births and abortions in bivariable analyses (P < .05) generated adjusted incidence rate ratios and 95% confidence intervals. RESULTS: There were 1356 pregnancies among 2414 women. Among HIV-positive women, age-adjusted rates of live birth increased from 1994 through 1997 to 2006 through 2012 (2.85-7.27/100 person-years, P trend < .0001). Age-adjusted rates of abortion in HIV-positive women remained stable over these time periods (4.03-4.29/100 person-years, P trend = .09). Significantly lower live-birth rates occurred among HIV-positive compared to HIV-negative women in 1994 through 1997 and 1997 through 2001, however rates were similar during 2002 through 2005 and 2006 through 2012. Higher CD4+ T cells/mm3 (≥350 adjusted incidence rate ratio, 1.39 [95% CI 1.03-1.89] vs <350) were significantly associated with increased live-birth rates, while combination antiretroviral treatment use (adjusted incidence rate ratio, 1.35 [95% CI 0.99-1.83]) was marginally associated with increased live-birth rates. Younger age, having a prior abortion, condom use, and increased parity were associated with increased abortion rates among both HIV-positive and HIV-negative women. CD4+ T-cell count, combination antiretroviral treatment use, and viral load were not associated with abortion rates. CONCLUSION: Unlike earlier periods (pre-2001) when live-birth rates were lower among HIV-positive women, rates are now similar to HIV-negative women, potentially due to improved health status and combination antiretroviral treatment. Abortion rates remain unchanged, illuminating a need to improve contraceptive services.

Menstrual cycle phase and single tablet antiretroviral medication adherence in women with HIV.

Suboptimal adherence to antiretroviral (ARV) therapy among HIV-infected individuals is associated with increased risk of progression to AIDS and the development of HIV resistance to ARV medications. To examine whether the luteal phase of the menstrual cycle is independently associated with suboptimal adherence to single tablet regimen (STR) ARV medication, data were analyzed from a multicenter cohort study of HIV-infected women who reported regular menstrual cycles and were taking an STR. In a cross-sectional analysis, suboptimal adherence to an STR among women in their follicular phase was compared with suboptimal adherence among women in their luteal phase. In two-way crossover analyses, whereby the same woman was assessed for STR medication adherence in both her follicular and luteal phases, the estimated exact conditional odds of non-adherence to an STR was measured. In adjusted logistic regression analysis of the cross-sectional data (N=327), women with ≤12 years of education were more than three times more likely to have suboptimal adherence (OR=3.6, p=.04) compared to those with >12 years of education. Additionally, women with Center for Epidemiological Studies Depression Scale (CES-D) scores ≥23 were 2.5-times more likely to have suboptimal adherence (OR=2.6, p=.02) compared to those with CES-D scores <23. In conditional logistic regression analyses of the crossover data (N=184), having childcare responsibilities was associated with greater odds of ≤95% adherence. Menstrual cycle phase was not associated with STR adherence in either the cross-sectional or crossover analyses. The lack of association between phase of the menstrual cycle and adherence to an STR in HIV-infected women means attention can be given to other more important risk factors for suboptimal adherence, such as depression, level of education, and childcare responsibilities.

Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause.

Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent. In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations. We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups. Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale. They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements. Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition. Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels. Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory. Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women. Hormone concentrations were not significantly related to mood. Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition. Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study.

Macrophage inflammatory markers are associated with subclinical carotid artery disease in women with human immunodeficiency virus or hepatitis C virus infection.

OBJECTIVE: Infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) may be associated with atherosclerosis and vascular disease. Macrophages are a major component of atherosclerotic plaque, and classically activated (M1) macrophages contribute to plaque instability. Our goal was to identify plasma biomarkers that reflect macrophage inflammation and are associated with subclinical atherosclerosis. APPROACH AND RESULTS: We tested whether M1 macrophages produce galectin-3-binding protein in vitro. Then, we measured galectin-3-binding protein and the soluble macrophage biomarkers soluble cluster of differentiation (CD) 163 and soluble CD14 in 264 participants in the Women's Interagency HIV Study. Women were positive for HIV, HCV, both, or neither (66 in each group, matched for age, race/ethnicity, and smoking status). Carotid artery disease was assessed by ultrasound measurement of right distal common carotid artery intima-media thickness, distensibility, and presence of atherosclerotic lesions (intima-media thickness >1.5 mm). Plasma galectin-3-binding protein was higher in HCV+ than HCV- women (P<0.01) but did not differ by HIV status. The 3 inflammatory macrophage markers were significantly correlated with each other and negatively correlated with CD4+ counts in HIV-infected women. We defined a macrophage score as 1, 2, or 3 biomarkers elevated above the median. In models adjusted for traditional risk factors, higher macrophage scores were significantly associated with increased atherosclerotic lesions and lower carotid distensibility. Receiver-operator curve analysis of lesions revealed that the markers added predictive value beyond traditional risk factors and C-reactive protein. CONCLUSIONS: The macrophage inflammatory markers galectin-3-binding protein, soluble CD163, and soluble CD14 are significantly associated with carotid artery disease in the setting of HIV and HCV infection.

The Effects of Viral Load Burden on Pregnancy Loss among HIV-Infected Women in the United States.

BACKGROUND: To evaluate the effects of HIV viral load, measured cross-sectionally and cumulatively, on the risk of miscarriage or stillbirth (pregnancy loss) among HIV-infected women enrolled in the Women's Interagency HIV Study between 1994 and 2013. METHODS: We assessed three exposures: most recent viral load measure before the pregnancy ended, log10 copy-years viremia from initiation of antiretroviral therapy (ART) to conception, and log10 copy-years viremia in the two years before conception. RESULTS: The risk of pregnancy loss for those with log10 viral load >4.00 before pregnancy ended was 1.59 (95% confidence interval (CI): 0.99, 2.56) times as high as the risk for women whose log10 viral load was ≤1.60. There was not a meaningful impact of log10 copy-years viremia since ART or log10 copy-years viremia in the two years before conception on pregnancy loss (adjusted risk ratios (aRRs): 0.80 (95% CI: 0.69, 0.92) and 1.00 (95% CI: 0.90, 1.11), resp.). CONCLUSIONS: Cumulative viral load burden does not appear to be an informative measure for pregnancy loss risk, but the extent of HIV replication during pregnancy, as represented by plasma HIV RNA viral load, predicted loss versus live birth in this ethnically diverse cohort of HIV-infected US women.

Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women.

CONTEXT: The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). OBJECTIVE: Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. DESIGN: Randomized controlled trial stratified by time-since-menopause. SETTING: Academic institution. PARTICIPANTS: Healthy postmenopausal women. INTERVENTION: Oral E2 with/without sequential vaginal progesterone. MAIN OUTCOME MEASURES: Standard lipids and 21 LPs quantitated by ion mobility every 6 months. RESULTS: Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. CONCLUSION: HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

Feasibility and acceptability of sexually transmitted infection screening during antenatal care of women in Dhaka, Bangladesh.

BACKGROUND: Sexually transmitted infections (STIs) are a major public health concern worldwide. Untreated STIs may have serious sequelae, particularly in pregnant women. The objective of this study was to assess the feasibility and acceptability of screening and treating common STIs in women during pregnancy in Bangladesh. METHODS: Women were enrolled from four maternity clinics/hospitals serving the lower-middle class population in Dhaka, Bangladesh. The participants were interviewed, and vaginal swab samples were collected by clinical staff. Specimens were tested for Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis and high-risk Human Papilloma Viruses (HPVs) using GeneXpert (Cepheid, Sunnyvale, California). Women were informed of their test results and were provided treatment for curable infections. A test of cure was performed. RESULTS: Out of 1157 pregnant women approached, 1000 (86.4%) participated. Ninety-one percent women learned of their test results on the same day of testing. Out of the 996 valid results, 7 (0.7%) tested positive for Chlamydia trachomatis and 1 (0.1%) for Trichomonas vaginalis. There were no gonorrhoea cases. Out of the 971 women with valid results for high-risk HPVs, 46 (4.7%) tested positive. CONCLUSIONS: Screening women for STIs during antenatal care was highly feasible and well-accepted in Bangladesh. While the prevalence of common curable STIs was very low, hrHPV infection prevalence was moderately high. Our findings support period monitoring of STIs and continued prevention efforts for cervical cancer in Bangladesh.

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.

The association of self-perception of body fat changes and quality of life in the Women's Interagency HIV Study.

Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1671 HAART-using HIV-seropositive women (mean age 40±8 years; 54% African-American, 24% reporting <95% HAART adherence) from the Women's Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however, peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites was associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects.

Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study.

BACKGROUND: Herpes zoster (HZ) is common among HIV-infected individuals, but the impacts of highly active antiretroviral therapy (HAART) and HAART adherence on HZ risk have not been well studied. METHODS: The effects of HAART and HAART adherence on HZ incidence were evaluated by comparing HIV-infected women on HAART (HAART use group) with the HIV-infected women remaining HAART naïve (HAART naïve group) in the Women's Interagency HIV Study (WIHS). A 1:1 matching with propensity score for predicting HAART initiation was conducted to balance background covariates at index visit, including HIV disease stage. Kaplan-Meier method was used to compare the risk of HZ development between the matched pairs. Cox proportional hazard models were used to assess the effects of HAART and HAART adherence on HZ incidence. RESULTS: Through propensity score matching, 389 pairs of participants were identified and they contributed 3,909 person years after matching. The background covariates were similar between the matched pairs at the index visit. The participants had a mean age around 39 years old, and about 61% of them were Black and 22% were Latina. No significant difference in HZ risk was observed between the HAART use group and the HAART naïve group during the first year of follow-up in any analyses. In the univariate analysis, the HAART use group had marginally lower HZ risk (Hazard Ratio (HR): 0.72; 95% Confidence Interval (CI): 0.48-1.1) over the entire follow-up period. However, women with a HAART adherence level of ≥95% had significantly lower HZ risk (HR: 0.54; 95% CI: 0.31, 0.94) compared to the HAART naïve women. The association remained significant after adjusting for quality of life score and acyclovir use, but it attenuated and was no longer statistically significant after adjusting for an intermediate variable, either CD4+ T cell counts or HIV viral load. CONCLUSIONS: Among adult women, we observed a significant preventive effect of long-term HAART use on HZ incidence when a HAART adherence level of ≥95% was attained, and this effect was mediated through reduction of HIV viral load and improvement of CD4+ T cell counts.

The association of hysterectomy with or without ovarian conservation with subclinical atherosclerosis progression in healthy postmenopausal women.

OBJECTIVE: While the deleterious associations of surgical menopause after bilateral oophorectomy with cardiovascular disease are documented, less is specifically known concerning subclinical atherosclerosis progression. METHODS: We used data from 590 healthy postmenopausal women randomized to hormone therapy or placebo in the Early versus Late Intervention Trial with Estradiol (ELITE), which was conducted from July 2005 to February 2013. Subclinical atherosclerosis progression was measured as annual rate of change in carotid artery intima-media thickness (CIMT) over a median 4.8 years. Mixed-effects linear models assessed the association of hysterectomy and bilateral oophorectomy compared with natural menopause with CIMT progression adjusted for age and treatment assignment. We also tested modifying associations by age at or years since oophorectomy or hysterectomy. RESULTS: Among 590 postmenopausal women, 79 (13.4%) underwent hysterectomy with bilateral oophorectomy and 35 (5.9%) underwent hysterectomy with ovarian conservation, a median of 14.3 years before trial randomization. Compared with natural menopause, women who underwent hysterectomy with and without bilateral oophorectomy had higher fasting plasma triglycerides while women who underwent bilateral oophorectomy had lower plasma testosterone. The CIMT progression rate in bilaterally oophorectomized women was 2.2 µm/y greater than natural menopause ( P = 0.08); specifically, compared with natural menopause, the associations were significantly greater in postmenopausal women who were older than 50 years at the time of bilateral oophorectomy ( P = 0.014) and in postmenopausal women who underwent bilateral oophorectomy more than 15 years before randomization ( P = 0.015). Moreover, the CIMT progression rate in hysterectomized women with ovarian conservation was 4.6 µm/y greater than natural menopause ( P = 0.015); in particular, compared with natural menopause, the association was significantly greater in postmenopausal women who underwent hysterectomy with ovarian conservation more than 15 years before randomization ( P = 0.018). CONCLUSIONS: Hysterectomy with bilateral oophorectomy and ovarian conservation were associated with greater subclinical atherosclerosis progression relative to natural menopause. The associations were stronger for later age and longer time since oophorectomy/hysterectomy. Further research should continue to examine long-term atherosclerosis outcomes related to oophorectomy/hysterectomy.

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.

T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women.

BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults. METHODS: T cell phenotyping and carotid ultrasound were assessed among 115 HIV-infected women and 43 age- and race/ethnicity-matched HIV-uninfected controls participating in the Women's Interagency HIV Study. Multivariate analyses were used to assess the association of T cell activation (CD38(+)HLA-DR(+)) and senescence (CD28(-)CD57(+)) with subclinical carotid artery disease. RESULTS: Compared with HIV-uninfected women, frequencies of CD4(+)CD38(+)HLA-DR(+), CD8(+)CD38(+)HLA-DR(+), and CD8(+)CD28(-)CD57(+) T cells were higher among HIV-infected women, including those who achieved viral suppression while receiving antiretroviral treatment. Among HIV-infected women, adjusted for age, antiretroviral medications, and viral load, higher frequencies of activated CD4(+) and CD8(+) T cells and immunosenescent CD8(+) T cells were associated with increased prevalence of carotid artery lesions (prevalence ratio(lesions) associated with activated CD4(+) T cells, 1.6 per SD [95% confidence interval {CI}, 1.1-2.2]; P = .02; prevalence ratio(lesions) associated with activated CD8(+) T cells, 2.0 per SD [95% CI, 1.2-3.3]; P < .01; prevalence ratio(lesions) associated with senescent CD8(+) T cells, 1.9 per SD [95% CI, 1.1-3.1]; P = .01). CONCLUSIONS: HIV-associated T cell changes are associated with subclinical carotid artery abnormalities, which may be observed even among those patients achieving viral suppression with effective antiretroviral therapy.

Concentrations of endogenous sex steroid hormones and SHBG in healthy postmenopausal women.

Studies reporting age-specific reference ranges of endogenous sex steroid hormones in postmenopausal women are relatively scarce. If levels differ by age, dosing and treatment regimens should vary among postmenopausal women accordingly. Our objective was to establish reference ranges for sex steroid hormones and sex hormone binding globulin (SHBG) by age group and overall, and to investigate their association with demographic characteristics. Serum samples were obtained from 1207 healthy postmenopausal women aged 41-92, not using hormone therapy, at the baseline visit of 3 clinical trials. Estrone (E1), estradiol (E2), and total testosterone (T) were measured by radioimmunoassay with preceding purification steps; SHBG was measured by direct chemiluminescent immunoassay. Free T (FT) was calculated. Women were categorized by 5-year age groups. There was little change in the mean estrogen levels among the different age groups (E2: 9-12 pg/mL; E1: 33-35 pg/mL). Mean total T levels increased gradually with age from 19.9-26.2 ng/dL, but FT mean levels were relatively constant (3.7-4.6 pg/mL). Mean SHBG levels increased with age from 43-68 nmol/L. A generalized linear model tested the association of each demographic characteristic with the hormones and SHBG. A significant association was derived. Our study provides valuable insight into the profiles of serum sex steroid hormones and SHBG in different healthy postmenopausal women aged 41-92 years.