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1.  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
2.  Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine 
AIDS (London, England)  2012;26(16):2097-2106.
Objective
CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.
Design
The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.
Methods
Five putative functional polymorphisms were tested for associations with virologic suppression within one year after NNRTI initiation in women naïve to antiretroviral agents (n=91). Principal components (PCs) were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.
Results
Rs3745274 was significantly associated with virologic suppression (OR=3.61, 95% CI 1.16-11.22, p trend=0.03); the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66-infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for PCs (p trend=0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.
Conclusion
The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted given the potential clinical importance of this finding.
doi:10.1097/QAD.0b013e3283593602
PMCID: PMC3940150  PMID: 22951632
CYP2B6; population substructure; women; NNRTIs; confounding
3.  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
4.  Risk of exposure to HIV differs according to catechol-o-methyltransferase Val158Met genotype 
AIDS (London, England)  2013;27(11):1779-1782.
The Met allele of the catechol-o-methyltransferase (COMT) Val158Met polymorphism is associated with increased cortical dopamine and risk behaviors including illicit drug use and unprotected sex. Therefore, we examined whether or not the distribution of the Val158Met genotype differed between HIV-infected and HIV-uninfected women. We conducted an Armitage-Cochran Test and logistic regression to compare genotype frequencies between 1,848 HIV-infected and 612 HIV-uninfected women from the Women’s Interagency HIV Study (WIHS). The likelihood of carrying one or two Met alleles was greater in HIV-infected women (61%) compared to HIV-uninfected women (54%), Z = −3.60, p < 0.001. We report the novel finding of an association between the Val158Met genotype and HIV serostatus that may be mediated through the impact of dopamine function on propensity for risk-taking.
doi:10.1097/QAD.0b013e328361c6a1
PMCID: PMC3897122  PMID: 23807274
5.  The insulin-like growth factor axis and risk of liver disease in hepatitis C virus/HIV-co-infected women 
AIDS (London, England)  2008;22(4):527-531.
Objective
Insulin-like growth factor (IGF) I stimulates the proliferation of hepatic stellate cells (HSC), the primary source of extracellular matrix accumulation in liver fibrosis. In contrast, insulin-like growth factor binding protein (IGFBP) 3, the most abundant IGFBP in circulation, negatively modulates HSC mitogenesis. To investigate the role of the IGF axis in hepatitis C virus (HCV)-related liver disease among high-risk patients, we prospectively evaluated HCV-viremic/HIV-positive women.
Design
A cohort investigation.
Methods
Total IGF-I and IGFBP-3 were measured in baseline serum specimens obtained from 472 HCV-viremic/HIV-positive subjects enrolled in the Women's Inter-agency HIV Study, a large multi-institutional cohort. The aspartate aminotransferase to platelet ratio index (APRI), a marker of liver fibrosis, was assessed annually.
Results
Normal APRI levels (< 1.0) at baseline were detected in 374 of the 472 HCV-viremic/HIV-positive subjects tested, of whom 302 had complete liver function test data and were studied. IGF-I was positively associated [adjusted odds ratio comparing the highest and lowest quartiles (AORq4–q1), 5.83; 95% confidence interval (CI) 1.17–29.1; Ptrend = 0.03], and IGFBP-3 was inversely associated (AORq4–q1, 0.13; 95% CI 0.02–0.76; Ptrend = 0.04), with subsequent (incident) detection of an elevated APRI level(> 1.5), after adjustment for the CD4 T-cell count, alcohol consumption, and other risk factors.
Conclusion
High IGF-I may be associated with increased risk and high IGFBP-3 with reduced risk of liver disease among HCV-viremic/HIV-positive women.
doi:10.1097/QAD.0b013e3282f22cdf
PMCID: PMC3507535  PMID: 18301066
aspartate aminotransferase to platelet ratio index; APRI; hepatitis C virus (HCV); HIV; IGFBP-3; IGF; liver disease
6.  The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of US women 
AIDS (London, England)  2011;25(15):1823-1832.
Objective
HIV causes inflammation that can be at least partially corrected by HAART. To determine the qualitative and quantitative nature of cytokine perturbation, we compared cytokine patterns in three HIV clinical groups including HAART responders (HAART), untreated HIV non-controllers (NC), and HIV-uninfected (NEG).
Methods
Multiplex assays were used to measure 32 cytokines in a cross-sectional study of participants in the Women's Interagency HIV Study (WIHS). Participants from 3 groups were included: HAART (n=17), NC (n=14), and HIV NEG (n=17).
Results
Several cytokines and chemokines showed significant differences between NC and NEG participants, including elevated IP-10 and TNF-α and decreased IL-12(p40), IL-15, and FGF-2 in NC participants. Biomarker levels among HAART women more closely resembled the NEG, with the exception of TNF-α and FGF-2. Secondary analyses of the combined HAART and NC groups revealed that IP-10 showed a strong, positive correlation with viral load and negative correlation with CD4+ T cell counts. The growth factors VEGF, EGF, and FGF-2 all showed a positive correlation with increased CD4+ T cell counts.
Conclusion
Untreated, progressive HIV infection was associated with decreased serum levels of cytokines important in T cell homeostasis (IL-15) and T cell phenotype determination (IL-12), and increased levels of innate inflammatory mediators such as IP-10 and TNF-α. HAART was associated with cytokine profiles that more closely resembled those of HIV uninfected women. The distinctive pattern of cytokine levels in the 3 study groups may provide insights into HIV pathogenesis, and responses to therapy.
doi:10.1097/QAD.0b013e3283489d1f
PMCID: PMC3314300  PMID: 21572306
HIV; CD4+ T cells; cytokines; chemokines; HAART
7.  Protease Inhibitor Levels in Hair Samples Strongly Predict Virologic Responses to HIV Treatment 
AIDS (London, England)  2009;23(4):471-478.
Objective
Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. Currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months and may provide a novel method for predicting therapeutic responses.
Design/methods
The Women's Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly-prescribed protease inhibitors (PIs) - lopinavir (LPV) and atazanavir (ATV) - in small hair samples. We examined the association between hair PI levels and initial virologic responses to therapy in multivariate logistic regression models.
Results
ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new PI-based regimen. For participants initiating LPV/RTV, the odds ratio (OR) for virologic suppression was 39.8 (95%CI 2.8–564) for those with LPV hair levels in the top tertile (>1.9ng/mg) compared to the bottom (≤0.41ng/mg) when controlling for self-reported adherence, age, race, starting viral load and CD4, and prior PI experience. For women starting ATV, the adjusted OR for virologic success was 7.7 (95%CI 2.0-29.7) for those with hair concentrations in the top tertile (>3.4ng/mg) compared to the lowest (≤1.2ng/mg).
Conclusions
PI levels in small hair samples were the strongest independent predictor of virologic success in a diverse group of HIV-infected adults. This noninvasive method for determining ARV exposure may have particular relevance for the epidemic in resource-poor settings due to the ease of collecting and storing hair.
doi:10.1097/QAD.0b013e328325a4a9
PMCID: PMC2654235  PMID: 19165084
Hair levels; therapeutic drug monitoring; antiretroviral exposure; virologic response; protease inhibitors; atazanavir; lopinavir; WIHS cohort
8.  Low CD4+ T cell count as a major atherosclerosis risk factor in HIV-infected women and men 
AIDS (London, England)  2008;22(13):1615-1624.
Objective
To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical carotid artery atherosclerosis.
Design
Cross-sectional study nested within a prospective cohort study
Methods
Among participants in the Women's Interagency HIV Study (1,331 HIV-infected women, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study (600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness (CIMT) using B-mode ultrasound. We estimated adjusted mean CIMT differences and prevalence ratios (PRs) for carotid lesions associated with HIV-related disease and treatments, with multivariate adjustment to control for possible confounding variables.
Results
Among HIV-infected individuals, a low CD4+ T cell count was independently associated with an increased prevalence of carotid lesions. Compared to the reference group of HIV-uninfected individuals, the adjusted PR for lesions among HIV-infected individuals with CD4+ T-cell count <200 cells/mm3 was 2.00 (95% confidence interval 1.22, 3.28) in women and 1.74 (95% confidence interval 1.04, 2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis.
Conclusions
Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men.
doi:10.1097/QAD.0b013e328300581d
PMCID: PMC2624572  PMID: 18670221
9.  Association of self-reported race with AIDS death in continuous HAART users in a cohort of HIV-infected women in the United States 
AIDS (London, England)  2013;27(15):2413-2423.
Objective:
To assess the association of race with clinical outcomes in HIV-positive women on continuous HAART.
Design:
Prospective study that enrolled women from 1994 to 1995 and 2001 to 2002.
Setting:
Women's Interagency HIV Study, a community-based cohort in five US cities.
Participants:
One thousand, four hundred and seventy-one HIV-positive continuous HAART users.
Main outcome measures:
Times to AIDS and non-AIDS death and incident AIDS-defining illness (ADI) after HAART initiation.
Results:
In adjusted analyses, black vs. white women had higher rates of AIDS death [adjusted hazard ratio (aHR) 2.14, 95% confidence interval (CI) 1.30, 3.50; P = 0.003] and incident ADI (aHR 1.58, 95% CI 1.08, 2.32; P = 0.02), but not non-AIDS death (aHR 0.91, 95% CI 0.59, 1.39; P = 0.65). Cumulative AIDS death incidence at 10 years was 17.3 and 8.3% for black and white women, respectively. Other significant independent pre-HAART predictors of AIDS death included peak viral load (aHR 1.70 per log10, 95% CI 1.34, 2.16; P < 0.001), nadir CD4+ cell count (aHR 0.65 per 100 cells/μl, 95% CI 0.56, 0.76; P < 0.001), depressive symptoms by Center for Epidemiology Studies Depression score at least 16 (aHR 2.10, 95% CI 1.51, 2.92; P < 0.001), hepatitis C virus infection (aHR 1.57, 95% CI 1.02, 2.40; P = 0.04), and HIV acquisition via transfusion (aHR 2.33, 95% CI 1.21, 4.49; P = 0.01). In models with time-updated HAART adherence, association of race with AIDS death remained statistically significant (aHR 3.09, 95% CI 1.38, 6.93; P = 0.006).
Conclusion:
In continuous HAART-using women, black women more rapidly died from AIDS or experienced incident ADI than their white counterparts after adjusting for confounders. Future studies examining behavioral and biologic factors in these women may further the understanding of HAART prognosis.
doi:10.1097/01.aids.0000432537.92958.73
PMCID: PMC3815041  PMID: 24037210
AIDS; HAART; HIV; race; survival; women

Results 1-9 (9)