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1.  Smoking Cessation and Recidivism in the Women's Interagency Human Immunodeficiency Virus Study 
Background
Smoking increases the risk of morbidity and mortality and is particularly harmful to HIV-infected people.
Purpose
To explore smoking trends and longitudinal factors associated with smoking cessation and recidivism among participants in the Women's Interagency HIV Study.
Methods
From 1994 through 2011, 2,961 HIV-infected and 981 HIV-uninfected women were enrolled and underwent semi-annual interviews and specimen collection. Smoking prevalence was evaluated annually and risk factors associated with time to smoking cessation and recidivism were analyzed in 2013 using survival models.
Results
The annual cigarette smoking prevalence declined from 57% in 1995 to 39% in 2011 (p-trend<0.0001). Among smokers, factors significantly associated with a longer time to smoking cessation included less education, alcohol use, having health insurance, >10-year smoking duration, self-reported poor health rating, and having hypertension. Pregnancy in the past 6 months was associated with a shorter time to cessation. Among HIV-infected women, additional risk factors for longer time to cessation included lower household income, use of crack/cocaine/heroin, CD4 cell count ≤200, and highly active antiretroviral therapy (HAART) use. Predictors of smoking recidivism included marijuana use, enrollment in 1994–1996, and not living in one's own place. Among HIV-infected women, enrollment in 2001-2002 and crack/cocaine/heroin use were associated with a shorter time to recidivism, whereas older age and HAART use were associated with a longer time to recidivism.
Conclusions
Despite declining rates of cigarette smoking, integrated interventions are needed to help women with and at risk for HIV infection to quit smoking and sustain cessation.
doi:10.1016/j.amepre.2014.02.010
PMCID: PMC4065848  PMID: 24746376
2.  Taking It One Day at a Time: African American Women Aging with HIV and Co-Morbidities 
AIDS Patient Care and STDs  2014;28(7):372-380.
Abstract
Self-managing HIV/AIDS presents challenges for anyone infected. These challenges may be further complicated for older HIV-infected African American women who acquired the disease at younger ages and now have co-morbidities. Little is known regarding how women's age identity, social responsibilities, co-morbidities, and romantic relationship status influence their HIV self-management. Five focus groups were conducted in Washington DC, with HIV-positive African American women aged 52–65. Topics included HIV and co-morbidity self-management, social support needs, medication adherence, and future plans for old age. A constant comparison approach was applied during data analysis. Co-morbidities, including diabetes and hypertension, were perceived to be more difficult to self-manage than HIV. This difficulty was not attributed to aging but to daily struggles such as lack of income and/or health insurance, an inflexible work schedule, and loneliness. Social responsibilities, including caring for family, positively impacted participants' ability to self-manage HIV by serving as motivation to stay healthy in order to continue to help family members. In contrast, inflexible work schedules negatively impacted women's ability to sustain medication adherence. Overall, this study demonstrates that HIV and co-morbidity self-management are inextricably linked. We can no longer afford to view engagement in HIV care as a single-disease issue and hope to attain optimal health and well-being in our HIV-affected populations. Optimal HIV self-management must be framed within a larger context that simultaneously addresses HIV and co-morbidities, while considering how social and cultural factors uniquely intersect to influence older African American women's self-management strategies.
doi:10.1089/apc.2014.0024
PMCID: PMC4074760  PMID: 24933093
3.  Urinary Biomarkers of Kidney Injury Are Associated with All-Cause Mortality in the Women’s Interagency HIV Study (WIHS) 
HIV medicine  2013;15(5):291-300.
Objectives
Chronic kidney disease (CKD) is common in HIV; CKD is associated with mortality. Urinary markers of tubular injury have been associated with future kidney disease risk, but associations with mortality are unknown.
Methods
We evaluated the association of urinary interleukin-18(IL-18), liver fatty acid binding protein(L-FABP), kidney injury molecule-1(KIM-1), neutrophil gelatinase-associated lipocalin(NGAL), albumin-to-creatinine ratio(ACR) with 10-year, all-cause death in 908 HIV-infected women. Kidney function was estimated using cystatin C (eGFRcys).
Results
There were 201 deaths during 9,269 person-years of follow-up. After demographic adjustment, compared to the lowest tertile, highest tertiles of IL-18 (HR 2.54,95%CI 1.75–3.68), KIM-1 (2.04,1.44–2.89), NGAL(1.50,1.05–2.14), and ACR(1.63,1.13–2.36) were associated with higher mortality. After multivariable adjustment including eGFRcys, only the highest tertiles of IL-18, (1.88,1.29–2.74) and ACR (1.46,1.01–2.12) remained independently associated with mortality. Findings with KIM-1 were borderline (1.41, 0.99–2.02). We found a J-shaped association between L-FABP and mortality. Compared to persons in the lowest tertile, HR for middle tertile of L-FABP was 0.67 (0.46–0.98) after adjustment. Findings were stronger when IL-18, ACR and L-FABP were simultaneously included in models.
Conclusions
Among HIV-infected women, some urinary markers of tubular injury are associated with mortality risk, independently of eGFRcys and ACR. These markers represent potential tools to identify early kidney injury in persons with HIV.
doi:10.1111/hiv.12113
PMCID: PMC3975680  PMID: 24313986
HIV; IL-18; KIM-1; L-FABP; NGAL; urinary biomarkers
4.  Psychosocial Correlates of Gender-Based Violence Among HIV-Infected and HIV-Uninfected Women in Three US Cities 
AIDS Patient Care and STDs  2014;28(5):260-267.
Abstract
Gender-based violence (GBV) is common among women with and at risk for HIV, yet little is known about the GBV associated psychological factors that could be modifiable through behavioral interventions. The current study examined the associations between some of these psychological factors (i.e., hopelessness, consideration of future consequences, self esteem), mental health symptoms, substance abuse, and GBV among a sample of 736 HIV-infected and sociodemographically similar uninfected participants in the Women's Interagency HIV Study (WIHS). Results indicated high rates of lifetime GBV among the sample (58%), as well as high rates of childhood sexual abuse (CSA) (22.2%). HIV-infected women were more likely to be hopeless and to experience lower consideration of future consequences as compared to uninfected women. Multivariable analysis indicated that current non-injection drug use and a history of injection drug use were the main correlates of GBV and CSA, even when other psychosocial variables were included in analytic models. Being born outside of the US reduced the likelihood of GBV and CSA. Future research directions and intervention implications are discussed.
doi:10.1089/apc.2013.0342
PMCID: PMC4011431  PMID: 24724987
5.  Macrophage inflammatory markers are associated with subclinical carotid artery disease in women with HIV or HCV infection 
Objective
Infection with hepatitis C (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 (Gal-3BP) in-vitro. Then we measured Gal-3BP and the soluble macrophage biomarkers sCD163 and sCD14 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 (cIMT), distensibility, and presence of atherosclerotic lesions (IMT>1.5 mm). Plasma Gal-3BP was higher in HCV+ than HCV− women (p<0.01), but did not differ by HIV status. The three 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 Gal-3BP, sCD163 and sCD14 are significantly associated with carotid artery disease in the setting of HIV and HCV infection.
doi:10.1161/ATVBAHA.113.303153
PMCID: PMC4067091  PMID: 24651679
atherosclerosis; women; AIDS; immune system; risk factors
6.  Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms 
Oncotarget  2015;6(11):9045-9060.
Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.
PMCID: PMC4496201  PMID: 25826087
podoplanin; cancer; cell migration; receptor; lectin
7.  Determination of HIV-1 coreceptor tropism using proviral DNA in women before and after viral suppression 
Background
An HIV-1 tropism test is recommended prior to CCR5 antagonist administration to exclude patients harboring non-R5 virus from treatment with this class of antiretrovirals. HIV-1 tropism determination based on proviral DNA (pvDNA) may be useful in individuals with plasma viral RNA suppression. We developed a genotypic tropism assay for pvDNA and assessed its performance in a retrospective analysis of samples collected longitudinally.
Results
We randomly selected paired plasma/PBMC samples from the Women’s Interagency HIV Study with plasma viral load ≥5,000 cp/mL at time 1 (T1), undetectable viral load maintained for ≥1 year and CD4+ >200 cells/μL at time 2 (T2). pvDNA was isolated from cryopreserved PBMCs. Sequences were analyzed in triplicate from 49/50 women, with tropism assigned using the geno2pheno (g2p) algorithm. The median time between T1 and T2 was 4.1 years. CXCR4-using virus was detected in 24% of the RNA samples and 33% of the pvDNA samples at T1, compared to 37% of the pvDNA samples at T2. Concordance between plasma RNA and pvDNA tropism was 88% at T1 and 80% at T2. The g2p scores for RNA (T1) vs DNA (T1, T2) were strongly correlated (Spearman rho: 0.85 (T1); 0.78 (T2)). In women with evidence of tropism switch at T2 (either R5 to non-R5 or non-R5 to R5), there was a correlation between change in tropism and time. Mean pvDNA viral load decreased by 0.4 log10 copies/106 cells between T1 and T2 (p < 0.0001), but this decrease was not significantly associated with tropism status.
Conclusions
We demonstrated that pvDNA tropism in women with HIV-1 suppression is concordant with prior RNA tropism results, even after a median time of >4 years. pvDNA tropism testing may be useful to determine eligibility of patients with viral suppression to switch to a CCR5-antagonist based regimen as well as for research purposes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12981-015-0055-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12981-015-0055-x
PMCID: PMC4403710  PMID: 25897314
HIV; Tropism; pvDNA
8.  INCREASE IN SINGLE-TABLET REGIMEN USE AND ASSOCIATED IMPROVEMENTS IN ADHERENCE-RELATED OUTCOMES IN HIV-INFECTED WOMEN 
Introduction
The use of single-tablet ART regimens and its implications on adherence among HIV-infected women have not been well-described.
Methods
Participants were enrolled in the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006–2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen, using a case-crossover design.
Results
15,523 person-visits, representing 1,727 women (53% black, 29% Hispanic, 25% IDU, median age 47), were included. Use of single-tablet regimens among ART users increased from 7% in 2006 to 27% in 2013; adherence increased from 78% to 85% during the same period (both p<0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted RR 1.05, 95% CI 1.03–1.08) and virologic suppression (RR 1.06, 95% CI 1.01–1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers.
Conclusion
Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits.
doi:10.1097/QAI.0000000000000082
PMCID: PMC3999284  PMID: 24326606
adherence; antiretroviral therapy; HIV; time factors; United States; viral load; women
9.  Hearing Loss among HIV-Seropositive and HIV-Seronegative Men and Women 
IMPORTANCE
Hearing sensitivity among adults has quality of life implications as individuals become older. There are limited data on hearing loss among aging HIV+ adults.
OBJECTIVES
1) To evaluate pure-tone hearing thresholds among HIV+ and HIV- adults with similar demographic characteristics. 2) To determine if HIV disease variables and antiretroviral therapy (ART) are associated with pure-tone threshold levels.
DESIGN, SETTING, AND PARTICIPANTS
262 men (117 HIV+) from the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study (MACS) and 134 women (105 HIV+) from the Washington, DC site of the Women's Interagency HIV Study (WIHS) participated. Pure-tone air-conduction thresholds were collected in a sound-treated room at octave frequencies from 250 through 8000 Hz, along with interoctave frequencies of 750, 3000, and 6000 Hz.
INTERVENTION(S)
None.
MAIN OUTCOME AND MEASURES
In each ear, a low-frequency pure-tone average (LPTA) was calculated using air-conduction thresholds at 250, 500, 1000, and 2000 Hz and a high-frequency PTA (HPTA) was calculated using air-conduction thresholds at 3000, 4000, 6000, and 8000 Hz. Linear mixed regression models tested the effect of HIV on hearing after adjusting for age, sex, race, and noise exposure history. Differential HIV effects for LPTA and HPTA and better/worse ear were also examined. CD4+ and CD8+ T-cell counts, log10 plasma HIV RNA concentrations, ever having had an AIDS-defining condition, and cumulative time on ART were included in the models for HIV+ participants only.
RESULTS
HPTA and LPTA were significantly higher (18% and 12%, respectively), for HIV+ participants compared to HIV- participants for the better ear. The direction of the effect was consistent across both the better and worse ear. There were no significant associations between HIV disease variables or treatment variables and LPTA or HPTA.
CONCLUSIONS AND RELEVANCE
HIV+ adults had significantly poorer lower and higher frequency hearing compared to HIV- adults. High frequency hearing loss is consistent with an accelerated aging (presbycusis); hearing loss in the low frequency range among middle-aged individuals is an unexpected finding. Since some vowels and consonants have predominantly low frequency acoustic energy, poorer hearing in lower frequencies may lead to increased communication difficulties in HIV+ individuals.
doi:10.1001/jamaoto.2014.3302
PMCID: PMC4369193  PMID: 25541676
Hearing loss; Human immunodeficiency virus (HIV); Antiretroviral therapy (ART); Multicenter AIDS Cohort Study (MACS); Women's Interagency HIV Study (WIHS)
10.  HIV RNA Levels in Plasma and Cervical Vaginal Lavage Fluid in Elite Controllers and HAART Recipients 
AIDS (London, England)  2014;28(5):739-743.
Objectives
The introduction of highly active antiretroviral therapy (HAART) leads to control of HIV replication to <50 copies/ml, similar to levels in “elite controllers”. Low-level viral replication may be one of the contributing factors to persistent immune activation/inflammation in HAART treated individuals. There are still gaps in our knowledge whether low level replication persists in systemic versus mucosal sites.
Design and Methods
Subjects for this study were recruited from the Women’s Interagency HIV Study. We evaluated 33 “elite controllers” who naturally controlled HIV replication and 33 matched HAART-suppressed recipients. This study employed a sensitive target-capture transcription-mediated-amplification assay to compare low-level virus concentrations in plasma and cervical-vaginal lavage (CVL) samples from HIV+ HAART recipients and “elite controllers”.
Results
The median (IQR) plasma viral load S/Co for “elite controllers” was 10.5 (3.9, 21.1) which was significantly (p<0.001) higher than the S/Co for HAART recipients (2.0 (1, 4.9])). The majority of CVL samples from both groups had undetectable HIV RNA and the proportion of CVL samples with a cutoff >1.0 was not different between “elite controllers” and HAART-suppressed recipients.
Conclusions
This study demonstrated persistent low-level HIV replication in “elite controllers”, suggesting potential value of HAART treatment for these individuals. Absent or very low levels of HIV RNA in CVL indicate very low risk of secondary sexual transmission for both groups.
doi:10.1097/QAD.0000000000000150
PMCID: PMC4160049  PMID: 24326356
11.  Assessment of Habitat Representation across a Network of Marine Protected Areas with Implications for the Spatial Design of Monitoring 
PLoS ONE  2015;10(3):e0116200.
Networks of marine protected areas (MPAs) are being adopted globally to protect ecosystems and supplement fisheries management. The state of California recently implemented a coast-wide network of MPAs, a statewide seafloor mapping program, and ecological characterizations of species and ecosystems targeted for protection by the network. The main goals of this study were to use these data to evaluate how well seafloor features, as proxies for habitats, are represented and replicated across an MPA network and how well ecological surveys representatively sampled fish habitats inside MPAs and adjacent reference sites. Seafloor data were classified into broad substrate categories (rock and sediment) and finer scale geomorphic classifications standard to marine classification schemes using surface analyses (slope, ruggedness, etc.) done on the digital elevation model derived from multibeam bathymetry data. These classifications were then used to evaluate the representation and replication of seafloor structure within the MPAs and across the ecological surveys. Both the broad substrate categories and the finer scale geomorphic features were proportionately represented for many of the classes with deviations of 1-6% and 0-7%, respectively. Within MPAs, however, representation of seafloor features differed markedly from original estimates, with differences ranging up to 28%. Seafloor structure in the biological monitoring design had mismatches between sampling in the MPAs and their corresponding reference sites and some seafloor structure classes were missed entirely. The geomorphic variables derived from multibeam bathymetry data for these analyses are known determinants of the distribution and abundance of marine species and for coastal marine biodiversity. Thus, analyses like those performed in this study can be a valuable initial method of evaluating and predicting the conservation value of MPAs across a regional network.
doi:10.1371/journal.pone.0116200
PMCID: PMC4356544  PMID: 25760858
12.  Common Clinical Conditions – Age, Low BMI, Ritonavir Use, Mild Renal Impairment - Affect Tenofovir Pharmacokinetics in a Large Cohort of HIV-Infected Women 
AIDS (London, England)  2014;28(1):59-66.
Objective
Tenofovir is used commonly in HIV treatment and prevention settings, but factors that correlate with tenofovir exposure in real-world setting are unknown.
Design
Intensive pharmacokinetic (PK) studies of tenofovir in a large, diverse cohort of HIV-infected women over 24-hours at steady-state were performed and factors that influenced exposure (assessed by areas-under-the-time-concentration curves, AUCs) identified
Methods
HIV-infected women (n=101) on tenofovir-based therapy underwent intensive 24-hour PK sampling. Data on race/ethnicity, age, exogenous steroid use, menstrual cycle phase, concomitant medications, recreational drugs and/or tobacco, hepatic and renal function, weight and body mass index (BMI) were collected. Multivariable models using forward stepwise selection identified factors associated with effects on AUC. Glomerular filtration rates (GFR) prior to starting tenofovir were estimated by the CKD-EPI equation using both creatinine and cystatin-C measures
Results
The median (range) of tenofovir AUCs was 3350 (1031–13,911) ng x h/mL. Higher AUCs were associated with concomitant ritonavir use (1.33-fold increase, p 0.002), increasing age (1.21-fold increase per decade, p=0.0007) and decreasing BMI (1.04-fold increase per 10% decrease in BMI). When GFR was calculated using cystatin-C measures, mild renal insufficiency prior to tenofovir initiation was associated with higher subsequent exposure (1.35-fold increase when pre-tenofovir GFR <70mL/min, p=0.0075).
Conclusions
Concomitant ritonavir use, increasing age, decreasing BMI and lower GFR prior to tenofovir initiation as estimated by cystatin C were all associated with elevated tenofovir exposure in a diverse cohort of HIV-infected women. Clinicians treating HIV-infected women should be aware of common clinical conditions that affect tenofovir exposure when prescribing this medication.
doi:10.1097/QAD.0000000000000033
PMCID: PMC3956315  PMID: 24275255
Tenofovir; pharmacokinetics; HIV-infected women; diverse populations; GFR; cystatin C
13.  Understanding the disparity: Predictors of virologic failure in women using highly active antiretroviral therapy vary by race and/or ethnicity 
Journal of acquired immune deficiency syndromes (1999)  2013;64(3):10.1097/QAI.0b013e3182a095e9.
Background
Stark racial/ethnic disparities in health outcomes exist among those living with HIV in the United States. One of three primary goals of the National HIV/AIDS Strategy is to reduce HIV-related disparities and health inequities.
Methods
Using data from HIV-infected women participating in the Women’s Interagency HIV Study from April 2006 to March 2011, we measured virologic failure (HIV RNA >200 copies/mL) following suppression (HIV RNA <80 copies/mL) on HAART. We identified predictors of virologic failure using discrete-time survival analysis and calculated racial/ethnic-specific population attributable fractions (PAFs).
Results
Of 887 eligible women, 408 (46%) experienced virologic failure during the study period. Hispanic and White women had significantly lower hazards of virologic failure than African-American women (Hispanic hazard ratio, HR=0.8, 95% confidence interval [0.6, 0.9]; White HR=0.7 [0.5, 0.9]). The population attributable fraction of virologic failure associated with low income was higher in Hispanic (aHR=2.2 [0.7, 6.5], PAF=49%) and African-American women (aHR=1.8 [1.1, 3.2], PAF=38%) than among White women (aHR=1.4 [0.6, 3.4], PAF=16%). Lack of health insurance compared to public health insurance was associated with virologic failure only among Hispanic (aHR=2.0 [0.9, 4.6], PAF=22%) and White women (aHR=1.9 [0.7, 5.1], PAF=13%). By contrast, depressive symptoms were associated with virologic failure only among African-American women (aHR=1.6 [1.2, 2.2], PAF=17%).
Conclusions
In this population of treated HIV-infected women, virologic failure was common, and correlates of virologic failure varied by race/ethnicity. Strategies to reduce disparities in HIV treatment outcomes by race/ethnicity should address racial/ethnic-specific barriers including depression and low income to sustain virologic suppression.
doi:10.1097/QAI.0b013e3182a095e9
PMCID: PMC3816935  PMID: 23797695
disparities; race/ethnicity; virologic failure; HAART; HIV; women
14.  Single Nucleotide Polymorphisms in TrkB and Risk for Depression: Findings from the Women’s Interagency HIV Study 
Individuals infected with human immunodeficiency virus type 1 (HIV) are more likely than non-infected individuals to develop depression. HIV lowers brain-derived neurotrophic factor (BDNF), a neurotrophic factor whose receptors play a crucial role in the pathophysiology of depression. Therefore, we examined whether a single-nucleotide polymorphism (SNP) in the BDNF gene (rs56164415) and related receptors TrkB (rs1212171) and p75NTR (rs2072446) were associated with depression in HIV infected individuals. 1365 HIV positive and 371 HIV negative female subjects were included. The distribution of alleles was analyzed independently in African-Americans (non-Hispanic) and Caucasians (non-Hispanic). We have found that the absence of depressive symptoms in HIV positive subjects is associated with a genetic variation of the TrkB but not BDNF or p75NTR genes. This mutation explains 0.8% and 4.4% of the variability for the absence of depression in African-Americans and Caucasians, respectively.
doi:10.1097/QAI.0b013e3182a468e9
PMCID: PMC3780967  PMID: 24047966
association studies; BDNF; HIV-1; p75NTR; rs1212171; rs2072446
15.  Microvascular Endothelial Dysfunction and Enhanced Thromboxane and Endothelial Contractility in Patients with HIV 
1.1. Background
The prevalence of cardiovascular disease is increased with human immunodeficiency virus (HIV) infection, but the mechanism is unclear. We hypothesized that HIV increases microvascular reactive oxygen species, thereby impairing endothelial function and enhancing contractility.
1.2. Method
Subcutaneous microarterioles were isolated from gluteal skin biopsies in premenopausal, African American, HIV positive women receiving effective anti-retroviral therapy, but without cardiovascular risk factors except for increased body mass index (n=10) and healthy matched controls (n=10). The arterioles were mounted on myographs, preconstricted and relaxed with acetylcholine for: endothelium-dependent relaxation, endothelium-dependent relaxation factor (nitric oxide synthase-dependent relaxation), endothelium-dependent hyperpolarizing factor (potassium-channel dependent relaxation) and endothelium-independent relaxation (nitroprusside). Contractions were tested to endothelium-dependent contracting factor (acetylcholine contraction with blocked relaxation); phenylephrine, U-46,619 and endothelin-1. Plasma L-arginine and asymmetric dimethylarginine were measured by high performance capillary electrophoresis.
1.3. Results
The micro-arterioles from HIV positive women had significantly (% change in tension; P<0.05) reduced acetylcholine relaxation (-51 ± 6 vs. -78 ± 3%), endothelium-dependent relaxation factor (-28 ± 4 vs. -39 ± 3%), endothelium-dependent hyperpolarizing factor (-17 ± 4 vs. -37 ± 4%) and decreased nitric oxide activity (0.16 ± 0.03 vs. 0.70 ± 0.16 Δ unit) but unchanged nitroprusside relaxation. They had significantly enhanced endothelium-dependent contracting factor (+21 ± 6 vs. +7 ± 2%) and contractions to U-46,619 (+164 ± 10 vs. +117 ± 11%) and endothelin-1(+151 ± 12 vs. +97 ± 9%), but not to phenylephrine. There was enhanced reactive oxygen species with acetylcholine (0.11 ± 0.02 vs. 0.05 ± 0.01 Δ unit; P<0.05) and endothelin-1 (0.31 ± 0.06 vs. 0.10 ± 0.02 Δ unit; P<0.05). Plasma L-arginine: assymetric dimethyl arginine rates was reduced (173 ± 12 vs. 231 ± 6 μmol·μmol-1, P<0.05).
1.4. Conclusion
Premenopausal HIV positive womenhad microvascular oxidative stress with severe endothelial dysfunction and reduced nitric oxide and arginine: assymetric dimethylarginine ratio but enhanced endothelial, thromboxane and endothelin contractions. These microvascular changes may herald later cardiovascular disease.
doi:10.4172/2155-6113.1000267
PMCID: PMC4066983  PMID: 24967147
Cardiovascuar disease (CVD); Endothelial dysfunction; Nitric oxide (NO); Endothelium-dependent relaxing factor (EDRF); Reactive oxygen species (ROS); Asymmetric dimethylarginine (ADMA); Thromboxane-prostanoid receptors (TP-Rs); Endothelin-1 (ET-1)
16.  Vitamin D and Insulin Resistance in Non-Diabetic Women's Interagency HIV Study Participants 
AIDS Patient Care and STDs  2013;27(6):320-325.
Abstract
We explored the relationship between vitamin D levels and insulin resistance (IR) among 1082 nondiabetic (754 HIV-infected) women enrolled in the Women's Interagency HIV study (WIHS), a large and well-established cohort of HIV infected and uninfected women in the US. Vitamin D levels 20–29 ng/mL were considered insufficient and <20 ng/mL deficient. IR was estimated using the homeostasis model assessment (HOMA) and a clinically significant cut-off ≥2.6 was used for HOMA-IR. In the unadjusted analysis, women who were vitamin D insufficient or deficient were 1.62 (95% CI: 1.01–2.61, p=0.05) and 1.70 (95% CI: 1.11–2.60, p=0.02) times more likely to have HOMA values≥2.6 compared to women with sufficient vitamin D. The association did not remain significant after adjustment for factors associated with IR. Among the 754 HIV-infected women, current PI use (OR 1.61, 95% CI: 1.13–2.28, p=0.008) remained independently associated with HOMA ≥2.6 while vitamin D insufficiency (OR 1.80, 95% CI: 0.99–3.27, p=0.05) was marginally associated with HOMA ≥2.6 after adjustment. Ethnicity, body mass index, smoking status, and hepatitis C status were independently associated with insulin resistance in HIV-infected and uninfected women. We found a marginally significant association between vitamin D insufficiency and insulin resistance among nondiabetic HIV-infected WIHS women.
doi:10.1089/apc.2012.0400
PMCID: PMC3671624  PMID: 23675750
17.  Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV Study 
AIDS (London, England)  2013;27(9):1516-1519.
Summary
Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.
doi:10.1097/QAD.0b013e32835fd8a9
PMCID: PMC3909663  PMID: 23435295
lipids; HAART; HIV infection; inflammation
18.  The Use of Nanotrap Particles Technology in Capturing HIV-1 Virions and Viral Proteins from Infected Cells 
PLoS ONE  2014;9(5):e96778.
HIV-1 infection results in a chronic but incurable illness since long-term HAART can keep the virus to an undetectable level. However, discontinuation of therapy rapidly increases viral burden. Moreover, patients under HAART frequently develop various metabolic disorders and HIV-associated neuronal disease. Today, the main challenge of HIV-1 research is the elimination of the residual virus in infected individuals. The current HIV-1 diagnostics are largely comprised of serological and nucleic acid based technologies. Our goal is to integrate the nanotrap technology into a standard research tool that will allow sensitive detection of HIV-1 infection. This study demonstrates that majority of HIV-1 virions in culture supernatants and Tat/Nef proteins spiked in culture medium can be captured by nanotrap particles. To determine the binding affinities of different baits, we incubated target molecules with nanotrap particles at room temperature. After short sequestration, materials were either eluted or remained attached to nanotrap particles prior to analysis. The unique affinity baits of nanotrap particles preferentially bound HIV-1 materials while excluded albumin. A high level capture of Tat or Tat peptide by NT082 and NT084 particles was measured by western blot (WB). Intracellular Nef protein was captured by NT080, while membrane-associated Nef was captured by NT086 and also detected by WB. Selective capture of HIV-1 particles by NT073 and NT086 was measured by reverse transcriptase assay, while capture of infectious HIV-1 by these nanoparticles was demonstrated by functional transactivation in TZM-bl cells. We also demonstrated specific capture of HIV-1 particles and exosomes-containing TAR-RNA in patients' serum by NT086 and NT082 particles, respectively, using specific qRT-PCR. Collectively, our data indicate that certain types of nanotrap particles selectively capture specific HIV-1 molecules, and we propose to use this technology as a platform to enhance HIV-1 detection by concentrating viral proteins and infectious virions from infected samples.
doi:10.1371/journal.pone.0096778
PMCID: PMC4018389  PMID: 24820173
19.  HIV and Recent Illicit Drug Use Interact to Affect Verbal Memory in Women 
Objective
HIV infection and illicit drug use are each associated with diminished cognitive performance. This study examined the separate and interactive effects of HIV and recent illicit drug use on verbal memory, processing speed and executive function in the multicenter Women's Interagency HIV Study (WIHS).
Methods
Participants included 952 HIV-infected and 443 HIV-uninfected women (mean age=42.8, 64% African-American). Outcome measures included the Hopkins Verbal Learning Test - Revised (HVLT-R) and the Stroop test. Three drug use groups were compared: recent illicit drug users (cocaine or heroin use in past 6 months, n=140), former users (lifetime cocaine or heroin use but not in past 6 months, n=651), and non-users (no lifetime use of cocaine or heroin, n=604).
Results
The typical pattern of recent drug use was daily or weekly smoking of crack cocaine. HIV infection and recent illicit drug use were each associated with worse verbal learning and memory (p's<.05). Importantly, there was an interaction between HIV serostatus and recent illicit drug use such that recent illicit drug use (compared to non-use) negatively impacted verbal learning and memory only in HIV-infected women (p's <0.01). There was no interaction between HIV serostatus and illicit drug use on processing speed or executive function on the Stroop test.
Conclusion
The interaction between HIV serostatus and recent illicit drug use on verbal learning and memory suggests a potential synergistic neurotoxicity that may affect the neural circuitry underlying performance on these tasks.
doi:10.1097/QAI.0b013e318289565c
PMCID: PMC3628722  PMID: 23392462
20.  Mucosal associated invariant T cells: Don't forget your vitamins 
Cell Research  2012;23(4):460-462.
T lymphocytes express clonal receptors, called T cell receptors (TCRs), which specifically recognize antigens presented in combination with major histocompatibility molecules (MHC). To date, T cell antigens can be broadly categorized into two classes: peptides and lipids. A recent paper published in Nature by Kjer-Nielsen and colleagues reveals that a unique population of T lymphocytes expresses TCRs that recognize a completely new and unexpected class of antigens, vitamin metabolites.
doi:10.1038/cr.2012.168
PMCID: PMC3616427  PMID: 23208418
21.  Tenofovir use and urinary biomarkers among HIV-infected women in the Women's Interagency HIV Study (WIHS) 
Background
Tenofovir has been associated with renal tubular injury. Biomarkers that signal early tubular dysfunction are needed because creatinine rise lags behind tenofovir-associated kidney dysfunction. We examined several urinary biomarkers to determine if rises accompanying tenofovir initiation preceded creatinine changes.
Methods
Three urinary biomarkers of tubular impairment- neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl- β -D-glucosaminidase (NAG), and β-2-microglobulin (β2MG)-were measured across three time points (one pre-tenofovir visit and two post tenofovir visits) in one hundred and thirty two HIV-positive women from the Women's Interagency HIV Study (WIHS). Women initiating HAART containing tenofovir were propensity score matched to women initiating HAART without tenofovir and women not on HAART.
Results
There were no differences between groups for NGAL or NAG but β2MG was 19 times more likely to be elevated among tenofovir users at the 2nd post tenofovir visit compared to non-TDF users at the pre-tenofovir visit (p<0.01). History of proteinuria was associated with elevated NGAL (p <0.01). Factors associated with elevated NAG were GFR<60 ml/min, history of proteinuria, hepatitis C (p<0.01 for all) and diabetes mellitus (p=0.05). Factors associated with increased odds of elevated β2MG were HIV RNA>100,000 copies/ml, hepatitis C, boosted protease inhibitor (PI) use, and GFR<60 ml/min (p≤0.01 for all).
Conclusions
β2MG levels are elevated in women on tenofovir indicating probable early renal dysfunction. Biomarker elevation is additionally associated with baseline chronic kidney disease, uncontrolled viremia, and boosted PI use. Future studies are needed to explore urinary biomarker thresholds in identifying treated HIV-infected individuals at risk for renal dysfunction.
doi:10.1097/QAI.0b013e31828175c9
PMCID: PMC3692572  PMID: 23254151
Tenofovir; urinary biomarkers; HIV infected women
22.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
Background
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1) are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
Methods
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1, and ACR in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women’s Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
Results
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (p<0.0001), 12% for KIM-1 (p=0.081), and 47% for ACR (p<0.0001). Higher HIV RNA level (15% per 10-fold increase, p<0.0001), lower CD4 count (8% per doubling, p=0.0025), HCV infection (30%, p=0.00018), and lower HDL (5% per 10 mg/dL, p=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%, p<0.0001) and diabetes (47%, p=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase, p=0.0004) was also associated with higher ACR.
Conclusions
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
doi:10.3851/IMP2677
PMCID: PMC3933452  PMID: 23970313
23.  Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach 
AIDS (London, England)  2013;27(9):1473-1481.
Objective
CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown.
Design
A total of 564 AIDS-free women in the Women's Interagency HIV Study were followed over 6.1 years (median) after T-cell activation assessment. A cluster analysis approach was used to evaluate the concurrent activation patterns of CD4 and CD8 T cells at the beginning of follow-up in relation to AIDS progression.
Methods
Percentages of CD4 and CD8 T cells with HLA-DR± and CD38± were assessed by flowcytometry. Eight immunologic variables (four on each CD4+ and CD8+: DR± and CD38±) were assessed to yield a 4-cluster solution on samples obtained before clinical endpoints. Proportional hazards survival regression estimated relative risks for AIDS progression by cluster membership.
Results
Compared with the other three clusters, outstanding activation features of each distinct cluster of women were: Cluster 1: higher CD8+CD38– DR– (average = 41% of total CD8 T-cell pool), CD4+CD38– DR– (average = 53% of total CD4 T-cell pool), and CD8+CD38– DR+ (28%); Cluster 2: higher CD8+CD38+DR– (44%) and CD4+CD38+DR– (58%); Cluster 3: higher CD8+CD38+DR+ (49%) and CD4+ CD38+DR– (48%); Cluster 4: higher CD8+CD38+DR+ (49%), CD4+CD38+DR+ (36%) and CD4+CD38– DR+ (19%). Compared with cluster 1, women in cluster 4 had two-fold increased risk of AIDS progression (Hazard ratio = 2.13; 95% confidence interval = 1.30–3.50) adjusted for CD4 cell count, HIV RNA, and other confounders.
Conclusion
A profile including CD4 and CD8 T-cell activation provided insight into HIV pathogenesis indicating concurrent hyperactivation of CD4 and CD8 T cells is associated with AIDS progression.
doi:10.1097/QAD.0b013e3283601bad
PMCID: PMC3949252  PMID: 23945505
AIDS; cluster analysis; immune activation
24.  The Impact of Interactions with Providers on Stroke Caregivers’ Needs 
Purpose
Preparation for caregiving is improved through engaged interactions between stroke family caregivers and healthcare providers throughout the care trajectory. We explored caregivers’ perceptions about interactions with providers in rehabilitation, and how these experiences affected caregiver preparation.
Design
Seventeen caregivers, included in this grounded theory study, were interviewed during a rehabilitation stay and post-discharge. Data were analyzed using dimensional and comparative analysis.
Findings
Caregivers described interactions with providers on a continuum from collaborative to disconnected, and a range of strategies to enhance interactions.
Conclusions
Caregivers want to be actively engaged with providers during inpatient rehabilitation and collaborative interactions enhance preparedness and care satisfaction.
Relevance
Family members should be assessed for caregiving capacity and interactions between providers and caregivers should be individualized to specific needs. Providers must also be aware that many caregivers are not active information seekers. They must engage caregivers who may not even know what questions to ask.
doi:10.1002/rnj.69
PMCID: PMC3742102  PMID: 23529947
stroke; caregiving; family-centered care; interaction; qualitative research
25.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Background
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Design
Retrospective cohort analysis.
Methods
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
Results
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Conclusion
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
doi:10.1097/QAD.0b013e328362e874
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women

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