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1.  Antiretroviral Therapy Modifies the Genetic Effect of Known Type 2 Diabetes-Associated Risk Variants in the Women’s Interagency HIV Study 
AIDS (London, England)  2014;28(12):1815-1823.
Objective
Type 2 diabetes (DM) incidence is increased in HIV-infected persons. We examined the associations of DM with known DM-risk alleles from the general population in the context of HIV infection and explored effect modification by combination antiretroviral treatment (cART).
Methods
The Women’s Interagency HIV Study (WIHS) is a prospective cohort of HIV-infected women. Seventeen European-derived DM-risk polymorphisms were genotyped in eligible WIHS participants. Analyses were run separately for non-African-Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident DM) and African-Americans (n=591, 49 with incident DM). Cox proportional hazards models were fit to estimate hazard ratios (HRs) for DM overall and within strata of cART.
Results
In non-African-Americans, heterogeneity across cART regimen was observed for 9 of 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with DM risk among women taking 2 NRTIs+NNRTI. Five polymorphisms were statistically significantly associated with DM among women treated with ≥2 NRTIs + ≥1 PI and one polymorphism was associated with DM among those treated with ≥3 NRTIs ± NNRTI. The HR per risk allele for IGF2BP2 rs1470579 was 2.67 (95% CI 1.67–4.31) for women taking cART with ≥2 NRTIs+≥1 PI and 2.45 (95% CI 1.08–5.53) in women taking ≥3 NRTIs±NNRTI (phet=2.50×10−3). No such associations were observed in African-Americans.
Conclusions
Genetic susceptibility to DM, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/PI components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these DM-risk variants.
doi:10.1097/QAD.0000000000000366
PMCID: PMC4269472  PMID: 24932614
type 2 diabetes; genetics; HIV; women; antiretroviral therapy
2.  Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer 
Objective
Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.
Design/Methods
In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.
Results
Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.
Conclusion
These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis.
doi:10.1097/QAI.0000000000000157
PMCID: PMC4267467  PMID: 24694931
Genital tract HIV viral load; cervical neoplasia; HPV natural history
3.  Trends in and correlates of CD4+ cell count at antiretroviral therapy initiation after changes in national ART guidelines in Rwanda 
AIDS (London, England)  2015;29(1):67-76.
Background
Initiation of antiretroviral therapy (ART) in the advanced stages of HIV infection remains a major challenge in sub-Saharan Africa. This study was conducted to better understand barriers and enablers to timely ART initiation in Rwanda where ART coverage is high and national ART eligibility guidelines first expanded in 2007–2008.
Methods
Using data on 6326 patients (≥15 years) at five Rwandan clinics, we assessed trends and correlates of CD4+ cell count at ART initiation and the proportion initiating ART with advanced HIV disease (CD4+ <200 cells/µl or WHO stage IV).
Results
Out of 6326 patients, 4486 enrolling in HIV care initiated ART with median CD4+ cell count of 211 cells/µl [interquartile range: 131–300]. Median CD4+ cell counts at ART initiation increased from 183 cells/µl in 2007 to 293 cells/µl in 2011–2012, and the proportion with advanced HIV disease decreased from 66.2 to 29.4%. Factors associated with a higher odds of advanced HIV disease at ART initiation were male sex [adjusted odds ratios (AOR) = 1.7; 95% confidence interval (CI): 1.3–2.1] and older age (AOR46–55+ vs. <25 = 2.3; 95% CI: 1.2–4.3). Among those initiating ART more than 1 year after enrollment in care, those who had a gap in care of 12 or more months prior to ART initiation had higher odds of advanced HIV disease (AOR = 5.2; 95% CI: 1.2–21.1).
Conclusion
Marked improvements in the median CD4+ cell count at ART initiation and proportion initiating ART with advanced HIV disease were observed following the expansion of ART eligibility criteria in Rwanda. However, sex disparities in late treatment initiation persisted through 2011–2012, and appeared to be driven by later diagnosis and/or delayed linkage to care among men.
doi:10.1097/QAD.0000000000000520
PMCID: PMC4487360  PMID: 25562492
antiretroviral therapy national guidelines; CD4+; determinants; HIV treatment; Rwanda
4.  Effect of HIV Infection on Body Composition and Fat Distribution in Rwandan Women 
Objective
To assess the association of HIV infection with body weight and composition in Rwandan women.
Design
Body weight and composition, the latter determined by bioelectrical impedance analysis (BIA) and by anthropometry, were compared in 620 HIV-positive and 211 HIV-negative participants. Associations of HIV with body composition were assessed, and t tests compared the groups.
Results
HIV-positive women were younger (−7.0 years, P < .001) and shorter (− 2.1 cm, P < .001). Mean body weight, body mass index (BMI), total body fat, and waist-to-hip ratio (WHR) were similar. Mean fat-free mass was 2.5% greater in HIV-negative participants, and 19% of HIV-positive group had BMI <18.5 kg/m2 versus 26% of the HIV-negative group (P < .05). CD4 counts and body composition were not associated.
Conclusions
Malnutrition was common in this cohort of Rwandan women. However, HIV infection was not associated with nutritional status. Factors other than malnutrition may influence quality-of-life outcomes in HIV-infected Rwandan women. Initiatives to improve nutritional status should be population-wide and not restricted to the HIV-infected population.
doi:10.1177/1545109710366472
PMCID: PMC4460979  PMID: 20530472
HIV; malnutrition; body composition; Rwanda; women; fat distribution
5.  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
6.  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
7.  HIV Malaria Co-Infection Is Associated with Atypical Memory B Cell Expansion and a Reduced Antibody Response to a Broad Array of Plasmodium falciparum Antigens in Rwandan Adults 
PLoS ONE  2015;10(4):e0124412.
HIV infected individuals in malaria endemic areas experience more frequent and severe malaria episodes compared to non HIV infected. This clinical observation has been linked to a deficiency in antibody responses to Plasmodium falciparum antigens; however, prior studies have only focused on the antibody response to <0.5% of P. falciparum proteins. To obtain a broader and less-biased view of the effect of HIV on antibody responses to malaria we compared antibody profiles of HIV positive (HIV+) and negative (HIV-) Rwandan adults with symptomatic malaria using a microarray containing 824 P. falciparum proteins. We also investigated the cellular basis of the antibody response in the two groups by analyzing B and T cell subsets by flow cytometry. Although HIV malaria co-infected individuals generated antibodies to a large number of P. falciparum antigens, including potential vaccine candidates, the breadth and magnitude of their response was reduced compared to HIV- individuals. HIV malaria co-infection was also associated with a higher percentage of atypical memory B cells (MBC) (CD19+CD10-CD21-CD27-) compared to malaria infection alone. Among HIV+ individuals the CD4+ T cell count and HIV viral load only partially explained variability in the breadth of P. falciparum-specific antibody responses. Taken together, these data indicate that HIV malaria co-infection is associated with an expansion of atypical MBCs and a diminished antibody response to a diverse array of P. falciparum antigens, thus offering mechanistic insight into the higher risk of malaria in HIV+ individuals.
doi:10.1371/journal.pone.0124412
PMCID: PMC4415913  PMID: 25928218
8.  Longitudinal Anthropometric Patterns Among HIV-infected and –uninfected Women 
Introduction
Previous studies suggest that indicators of central adiposity such as waist-to-hip ratio (WHR) and waist circumference may be altered by HIV infection, antiretroviral (ARV) treatment or both.
Methods
Waist and hip circumference and body mass index (BMI) were measured among participants of the Women’s Interagency HIV Study (WIHS) semiannually from 1999 to 2004. Generalized linear models evaluated longitudinal patterns of these measures and associations with demographic and clinical characteristics.
Results
WHR was significantly larger while BMI, waist and hip circumference were significantly smaller at almost all eleven semiannual visits among 942 HIV-infected compared to 266 HIV-uninfected women. Among HIV-uninfected women, mean waist and hip circumference and BMI increased over the 5 year study period (waist: +4.1 cm or 4.4%, hip: +3.76 cm or 3.5% and BMI +2.43 kg/m2 or 8.2%), while WHR remained stable. Among the HIV-infected women, waist and hip circumference, BMI and WHR did not significantly change.
Independent predictors of smaller BMI among HIV-infected women included White race, HCV seropositivity, current smoking, higher viral load and lower CD4. Independent predictors of larger WHR among HIV-infected women included age, White and Other non-African-American race, higher CD4 and PI use. Use of a HAART regimen was not an independent predictor of either BMI or WHR..
Conclusions
HIV-infected women had higher WHR compared to HIV-uninfected women, despite lower BMI, waist and hip measurements. BMI, waist and hip circumference increased over 5 years among the HIV-uninfected women, but remained stable in the HIV-infected women. Among HIV-infected women, PI use was associated with larger WHR, although HAART use itself was not appreciably associated with either BMI or WHR.
doi:10.1097/QAI.0b013e318162f597
PMCID: PMC4406344  PMID: 18197125
anthropometrics; HIV; women; waist-to-hip ratio
9.  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
10.  Insulin Resistance Change and Antiretroviral Therapy Exposure in HIV-Infected and Uninfected Rwandan Women: A Longitudinal Analysis 
PLoS ONE  2015;10(4):e0123936.
Background
We longitudinally assessed predictors of insulin resistance (IR) change among HIV-uninfected and HIV-infected (ART-initiators and ART-non-initiators) Rwandan women.
Methodology
HIV-infected (HIV+) and uninfected (HIV-) women provided demographic and clinical measures: age, body mass index (BMI) in Kg/(height in meters)2, Fat-Mass (FMI) and Fat-Free-Mass (FFMI) index, fasting serum glucose and insulin. Homeostasis Model Assessment (HOMA) was calculated to estimate IR change over time in log10 transformed HOMA measured at study enrollment or prior to ART initiation in 3 groups: HIV- (n = 194), HIV+ ART-non-initiators (n=95) and HIV+ ART-initiators (n=371). ANCOVA linear regression models of change in log10-HOMA were fit with all models included the first log10 HOMA as a predictor.
Results
Mean±SD log10-HOMA was -0.18±0.39 at the 1st and -0.21±0.41 at the 2nd measure, with mean change of 0.03±0.44. In the final model (all women) BMI at 1st HOMA measure (0.014; 95% CI=0.006-0.021 per kg/m2; p<0.001) and change in BMI from 1st to 2nd measure (0.024; 95% CI=0.013-0.035 per kg/m2; p<0.001) predicted HOMA change. When restricted to subjects with FMI measures, FMI at 1st HOMA measure (0.020; 95% CI=0.010-0.030 per kg/m2; p<0.001) and change in FMI from 1st to 2nd measure (0.032; 95% CI=0.020-0.043 per kg/m2; p<0.0001) predicted change in HOMA. While ART use did not predict change in log10-HOMA, untreated HIV+ women had a significant decline in IR over time. Use or duration of AZT, d4T and EFV was not associated with HOMA change in HIV+ women.
Conclusions
Baseline BMI and change in BMI, and in particular fat mass and change in fat mass predicted insulin resistance change over ~3 years in HIV-infected and uninfected Rwandan women. Exposure to specific ART (d4T, AZT, EFV) did not predict insulin resistance change in ART-treated HIV-infected Rwandan women.
doi:10.1371/journal.pone.0123936
PMCID: PMC4400132  PMID: 25880634
11.  Disparities in the Quality of HIV Care When Using US Department of Health and Human Services Indicators 
Althoff, Keri N. | Rebeiro, Peter | Brooks, John T. | Buchacz, Kate | Gebo, Kelly | Martin, Jeffrey | Hogg, Robert | Thorne, Jennifer E. | Klein, Marina | Gill, M. John | Sterling, Timothy R. | Yehia, Baligh | Silverberg, Michael J. | Crane, Heidi | Justice, Amy C. | Gange, Stephen J. | Moore, Richard | Kitahata, Mari M. | Horberg, Michael A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Kenneth H. | Hogg, Robert S. | Richard Harrigan, P. | Montaner, Julio SG | Cescon, Angela | Samji, Hasina | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Moore, Richard D. | Carey, John T. | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann N. | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M.John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | Althoff, Keri N. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Morton, Liz | McReynolds, Justin | Lober, William B. | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
doi:10.1093/cid/ciu044
PMCID: PMC3967825  PMID: 24463281
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression
12.  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
13.  RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women’s Interagency HIV Study (WIHS) 
Atherosclerosis  2014;233(2):666-672.
Background
Single nucleotide polymorphisms (SNPs) in the Ryanodine receptor 3 (RYR3) gene are associated with common carotid intima media thickness (CCA cIMT) in HIV-infected men. We evaluated SNPs in the RYR3 gene among HIV-infected women participating in Women’s Interagency HIV Study (WIHS).
Methods
CCA cIMT was measured using B-mode ultrasound and the 838 SNPs in the RYR3 gene region were genotyped using the Illumina HumanOmni2.5-quad beadchip. The CCA cIMT genetic association was assessed using linear regression analyses among 1213 women and also separately among White (n=139), Black (n=720) and Hispanic (n=354) women after adjusting for confounders. A summary measure of pooled association was estimated using a meta-analytic approach by combining the effect estimates from the three races. Haploblocks were inferred using Gabriel’s method and haplotype association analyses were conducted among the three races separately.
Results
SNP rs62012610 was associated with CCA cIMT among the Hispanics (p=4.41× 10−5), rs11856930 among Whites (p=5.62× 10−4), and rs2572204 among Blacks (p=2.45× 10−3). Meta-analysis revealed several associations of SNPs in the same direction and of similar magnitude, particularly among Blacks and Hispanics. Additionally, several haplotypes within three haploblocks containing SNPs previously related with CCA cIMT were also associated in Whites and Hispanics.
Discussion
Consistent with previous research among HIV-infected men, SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex, and warrants future studies to better understand regional SNP function.
doi:10.1016/j.atherosclerosis.2014.01.035
PMCID: PMC3965606  PMID: 24561552
RYR3; single nucleotide polymorphisms; HIV infection; CCA; cIMT; subclinical atherosclerosis
14.  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
15.  Prevalence of shingles and its association with PTSD among HIV-infected women in Rwanda 
BMJ Open  2015;5(3):e005506.
Objective
To examine the prevalence of reported shingles in the last 6 months and its association with post-traumatic stress disorder (PTSD), depression and severity of HIV disease in Rwandan women with HIV.
Settings
This cross-sectional study was conducted as part of the Rwanda Women's Interassociation Study and Assessment (RWISA), an observational cohort study designed to assess the impact of HIV and residual factors from experiencing rape in the 1994 genocide in Rwandan women. Participants were recruited through grassroots women's associations of people living with HIV infection and clinical care sites for HIV infection. Most participants (58.5%, n=405/692) had PTSD.
Participants
This cross-sectional analysis was conducted in 710 HIV-infected women enrolled in RWISA. Inclusion criteria were: age >15 years, informed consent, HIV test, ability to complete the interview in the local language, travel to and from the research site and participate in a baseline outpatient visit, and being naive to antiretroviral therapy at enrolment.
Primary and secondary outcome measures
The outcome of interest was self-reported shingles in the past 6 months. The exposure was PTSD defined using the cross-culturally validated Harvard Trauma Questionnaire.
Results
Overall prevalence of reported shingles in the past 6 months was 12.5% (n=89/710). There was an inverse relationship between shingles prevalence and immunological status: 7.6%, 12.3% and 16.7% of women with CD4 >350, 200–350 and <200 cells/µL, respectively, reported singles (p=0.01). In multivariate analysis, PTSD (aOR 1.7; 95% CI 1.02 to 2.89) and low CD4 (aOR 2.4; 95% CI 1.23 to 4.81) were independently associated with reported shingles in the past 6 months.
Conclusions
Our study found a significant independent relationship between PTSD and reported shingles, suggesting that PTSD may be associated with immune compromise that can result in herpes zoster reactivation. Further study is needed. It also confirmed previous findings of a strong relationship between shingles and greater immunosuppression in women with HIV infection.
doi:10.1136/bmjopen-2014-005506
PMCID: PMC4360726  PMID: 25748413
HIV/AIDS; Shingles; PTSD; Depression
16.  Echolucency of the Carotid Artery Intima‐Media Complex and Intima‐Media Thickness Have Different Cardiovascular Risk Factor Relationships: The Women's Interagency HIV Study 
Background
Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging.
Methods and Results
We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group.
Conclusions
Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.
doi:10.1161/JAHA.114.001405
PMCID: PMC4345869  PMID: 25699995
carotid arteries; epidemiology; immune system; risk factors; ultrasonics
17.  Cleavage/Alteration of Interleukin-8 by Matrix Metalloproteinase-9 in the Female Lower Genital Tract 
PLoS ONE  2015;10(1):e0116911.
Objective
Interleukin-8 (IL-8, CXCL8) plays important roles in immune responses at mucosal sites including in the lower genital tract. Since several types of bacteria produce proteases that cleave IL-8 and many types of bacteria can be present in lower genital tract microbiota, we assessed genital fluids for IL-8 cleavage/alteration.
Study Design
Genital fluids collected by lavage from 200 women (23 HIV-seronegative and 177 HIV-seropositive) were tested for IL-8 cleavage/alteration by ELISA.
Results
IL-8 cleaving/altering activity was observed in fluids from both HIV-positive (28%) and HIV-negative women (35%). There was no clear relationship between the activity and the types of bacteria present in the lower genital tract as determined by high-throughput sequencing of the 16S rRNA gene. Protease inhibitors specific for matrix metalloproteinases (MMPs) reduced the activity and a multiplex assay that detects both inactive and active MMPs showed the presence of multiple MMPs, including MMP-1, -3, -7, -8, -9, -10 and -12 in genital secretions from many of the women. The IL-8-cleaving/altering activity significantly correlated with active MMP-9 as well as with cleavage of a substrate that is acted on by several active MMPs.
Conclusions
These studies show that multiple MMPs are present in the genital tract of women and strongly suggest that MMP-9 in genital secretions can cleave IL-8 at this mucosal site. These studies suggest that MMP-mediated cleavage of IL-8 can modulate inflammatory responses in the lower genital tract.
doi:10.1371/journal.pone.0116911
PMCID: PMC4303271  PMID: 25611319
18.  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
19.  Comparison of Antibodies That Mediate HIV Type 1 gp120 Antibody-Dependent Cell-Mediated Cytotoxicity in Asymptomatic HIV Type 1-Positive Men and Women 
Abstract
Recent studies suggest that HIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies contribute to protective immunity against HIV. An important characteristic of future HIV vaccines will, therefore, be the ability to stimulate production of these antibodies in both men and women. Early studies suggest that men may have a better ADCC antibody response against HIV than women. Our objective was to determine whether men and women differ with respect to their ADCC response to HIV-1 gp120. HIV-positive, asymptomatic untreated men and women were matched for race, age, CD4+ T cell number, HIV-1 viral load, and treatment and HIV-1 gp120 ADCC antibody titers were compared. A standard 51Cr-release assay was used to determine HIV-1 gp120 ADCC antibody titers in HIV-1-seropositive individuals from the Multicenter AIDS Cohort Study (MACS; n=32) and the Women's Interagency HIV Study (WIHS; n=32). Both sexes had high ADCC titers against HIV-1 gp120: 34.4% (n=11) and 40.6% (n=13) of men and women, respectively, had titers of 10,000; 62.5% (n=20) and 56.3% (n=18) had titers of 100,000. Groups did not differ in percent specific release (% SR), lytic units (LU), correlations of titer to viral load, or titer to CD4+ T cells in men or women. Both groups also had similar cross-clade ADCC antibody responses (p>0.5 for % SR and LU). Comparable groups of asymptomatic HIV-1-infected men and women had comparable HIV-1 gp120 ADCC antibodies. Both sexes had significant cross-clade reactivity. Differences between men and women may become evident as disease progresses; this should be evaluated at later stages of HIV-1 infection.
doi:10.1089/aid.2012.0377
PMCID: PMC3887406  PMID: 23972002
20.  Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study 
Journal of neurovirology  2013;19(6):574-585.
Objective
To explore the relationship of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with cognition in women with (HIV+) and without HIV (HIV-) infection.
Design/Methods
1690 participants (1196 HIV+, 494 HIV-) in the Women's Interagency HIV Study (WIHS) with data available on anthropometric measures comprise the analytical sample. Cross-sectional analyses using linear regression models estimated the relationship between anthropometric variables and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score, CD4 count, insulin resistance, drug use, and race/ethnicity.
Results
Among HIV+ women, BMI < 18.5 kg/m2 was associated with poorer cognitive performance evidenced by longer Trails A and Trails B and shorter SDMT completion times. An obese BMI (30 kg/m2 or higher) was related to better performance on Trails B and worse performance on the Stroop Interference test. Among HIV- women, an obese BMI was related to worse performance on the Stroop – Color naming test. Few and inconsistent associations were observed between WC, WHR and cognition.
Conclusion
Among women at mid-life with chronic (at least 10 years) HIV infection, common anthropometric measures, primarily BMI, were differentially related to cognitive test performance by cognitive domain. Higher levels of BMI were associated with better cognitive function. In this era of antiretroviral therapies, restoration of health evidenced as higher BMI due to effective antiretroviral therapies, may improve cognitive function in middle-aged HIV infected women.
doi:10.1007/s13365-013-0219-1
PMCID: PMC3957488  PMID: 24338243
Cognition; HIV; Women; Overweight; Obesity; Middle-Aged
21.  Prevalence and risk factors for High-Risk Human Papillomavirus (hrHPV) infection among HIV-infected and Uninfected Rwandan women: implications for hrHPV-based screening in Rwanda 
Background
New World Health Organization guidelines recommend high-risk human papillomavirus (hrHPV) screen-and-treat strategies for cervical cancer prevention. We describe risk of, and risk factors for, testing hrHPV positive in a pilot study of hrHPV screen-and-treat conducted in Rwanda.
Methods
A total of 2,964 women, 1,289 HIV-infected (HIV [+]) and 1,675 HIV-uninfected (HIV [-]), aged 30-60 years and living in Rwanda were enrolled in 2010. Cervical specimens were collected and tested by careHPV, a DNA test for a pool of 14 hrHPV types. Prevalence with binomial 95% confidence intervals (95% CI) and determinants of testing hrHPV positive were calculated.
Results
hrHPV prevalence was higher in HIV [+] (31.8%, 95% CI = 29.2-34.4%) than HIV [-] women (8.2%, 95% CI = 6.7-9.8%; P < 0.0001). Among HIV [+] women, there was a significant trend (ptrend <0.001) of higher hrHPV prevalence with lower CD4 cell count, with the highest hrHPV prevalence among those with <200 CD4 cell counts (45.5%, 95% CI = 34.8-56.4%). In multivariate analysis of HIV [+] women, testing hrHPV positive was positively associated CD4 count of <200 cells/μL, history of 3 or more sexual partners, and history of using hormonal contraception, and negatively associated with older age. In HIV [-] women, testing hrHPV positive was negatively associated only with older age groups of 45-49 and 50-60 years and surprisingly was not associated with lifetime number of sexual partners.
Conclusion
hrHPV prevalence is high in HIV [+], especially in women with the lowest CD4 cell counts, which may have implications for utilizing hrHPV-based screening strategies such as screen-and-treat in these high-risk subgroups.
doi:10.1186/1750-9378-9-40
PMCID: PMC4413542  PMID: 25926864
HPV; HIV; Cervical cancer; Screening
22.  Serum biomarkers of immune activation and subsequent risk of non-Hodgkin B cell lymphoma among HIV-infected women 
Background
There is increasing evidence that chronic immune activation predisposes to non-Hodgkin’s lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the U.S. who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined.
Methods
We conducted a nested case-control study within the Women’s Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3–5 years, 1–3 years, and 0–1 year prior to AIDS-NHL diagnosis (n=22). Three to six HIV-infected controls, without AIDS-NHL, were matched to each case on age, race, CD4+ T cell count, and study follow-up time (n=78). Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models.
Results
Elevated levels of sCD27 (OR=7.21, 95% CI=2.62–19.88), sCD30 (OR=2.64, 95% CI=1.24–5.64), and CXCL13 (OR=2.56, 95% CI=1.32–4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a 2-to 4-fold increased risk of AIDS-NHL in certain subgroups, while elevated IL6 was associated with a 2-fold increased risk in the 0–1 year time-window, only.
Conclusion
These findings support the hypothesis that chronic B cell activation contributes to the development of AIDS-NHL in women.
Impact
sCD23, sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL.
doi:10.1158/1055-9965.EPI-13-0614
PMCID: PMC3833437  PMID: 24045923
lymphoma; B cell; cytokines; AIDS; immune activation
23.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
doi:10.1093/infdis/jit373
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
24.  CCR2 on CD14+CD16+ monocytes is a biomarker of HIV-associated neurocognitive disorders 
Objective:
To evaluate C-C chemokine receptor type 2 (CCR2) on monocyte subsets as a prognostic peripheral blood biomarker of HIV-associated neurocognitive disorders (HAND).
Methods:
We characterized monocyte populations in HIV-infected individuals with and without HAND from 2 cohorts and assessed their transmigration across an in vitro model of the human blood-brain barrier (BBB). We examined CCR2 expression among the monocyte populations as a prognostic/predictive biomarker of HAND and its functional consequences in facilitating monocyte diapedesis.
Results:
We determined that CCR2 was significantly increased on CD14+CD16+ monocytes in individuals with HAND compared to infected people with normal cognition. CCR2 remained elevated irrespective of the severity of cognitive impairment, combined antiretroviral therapy status, viral load, and current or nadir CD4 T-cell count. There was no association between CCR2 on other monocyte populations and HAND. There was a functional consequence to the increase in CCR2, as CD14+CD16+ monocytes from individuals with HAND transmigrated across our model of the human BBB in significantly higher numbers in response to its ligand chemokine (C-C) motif ligand 2 (CCL2) compared to the cell migration that occurred in people with no cognitive deficits. It should be noted that our study had the limitation of a smaller sample size of unimpaired individuals. In contrast, there was no difference in the transmigration of other monocyte subsets across the BBB in response to CCL2 in seropositive individuals with or without HAND.
Conclusions:
Our findings indicate CCR2 on CD14+CD16+ monocytes is a novel peripheral blood biomarker of HAND.
doi:10.1212/NXI.0000000000000036
PMCID: PMC4204222  PMID: 25340088
25.  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

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