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1.  Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts 
Background
Several lung diseases are increasingly recognized as comorbidities with HIV; however, few data exist related to the spectrum of respiratory symptoms, diagnostic testing, and diagnoses in the current HIV era. The objective of the study is to determine the impact of HIV on prevalence and incidence of respiratory disease in the current era of effective antiretroviral treatment.
Methods
A pulmonary-specific questionnaire was administered yearly for three years to participants in the Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS). Adjusted prevalence ratios for respiratory symptoms, testing, or diagnoses and adjusted incidence rate ratios for diagnoses in HIV-infected compared to HIV-uninfected participants were determined. Risk factors for outcomes in HIV-infected individuals were modeled.
Results
Baseline pulmonary questionnaires were completed by 907 HIV-infected and 989 HIV-uninfected participants in the MACS cohort and by 1405 HIV-infected and 571 HIV-uninfected participants in the WIHS cohort. In MACS, dyspnea, cough, wheezing, sleep apnea, and incident chronic obstructive pulmonary disease (COPD) were more common in HIV-infected participants. In WIHS, wheezing and sleep apnea were more common in HIV-infected participants. Smoking (MACS and WIHS) and greater body mass index (WIHS) were associated with more respiratory symptoms and diagnoses. While sputum studies, bronchoscopies, and chest computed tomography scans were more likely to be performed in HIV-infected participants, pulmonary function tests were no more common in HIV-infected individuals. Respiratory symptoms in HIV-infected individuals were associated with history of pneumonia, cardiovascular disease, or use of HAART. A diagnosis of asthma or COPD was associated with previous pneumonia.
Conclusions
In these two cohorts, HIV is an independent risk factor for several respiratory symptoms and pulmonary diseases including COPD and sleep apnea. Despite a higher prevalence of chronic respiratory symptoms, testing for non-infectious respiratory diseases may be underutilized in the HIV-infected population.
doi:10.1186/1471-2466-14-75
PMCID: PMC4021087  PMID: 24884738
AIDS; HIV; Pulmonary disease; Chronic obstructive; Respiratory tract diseases; Sleep apnea syndromes
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.  Relation of HLA Class I and II Supertypes with Spontaneous Clearance of Hepatitis C Virus 
Genes and immunity  2013;14(5):330-335.
Human leukocyte antigen (HLA) genotype has been associated with probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; p=0.004) was associated with HCV persistence while DR8 (PR=1.8; p=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became non-significant in analysis that included supertypes while B*57:03 (PR=1.9; p=0.008) and DRB1*07:01 (PR=1.7; p=0.005) retained significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.
doi:10.1038/gene.2013.25
PMCID: PMC3723800  PMID: 23636221
hepatitis C virus; HLA; human leukocyte antigen; supertype
4.  Effect of Human Immunodeficiency Virus Infection on the Prevalence and Incidence of Vaginal Intraepithelial Neoplasia 
Obstetrics and Gynecology  2012;119(3):582-589.
Objective
To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia in human immunodeficiency virus (HIV)-seropositive women.
Methods
Pap tests were done semiannually for 335 HIV-seropositive and 75 HIV-seronegative women with prior hysterectomy in the prospective Women’s Interagency HIV Study cohort. Endpoints included abnormal Pap tests after hysterectomy and vaginal intraepithelial neoplasia regardless of hysterectomy.
Results
Over a median of 5.6 years of follow-up, vaginal Pap tests were abnormal at 1,076 (29%, 95% C.I. 25%, 33%) of 3,700 visits among HIV seropositive vs. 31 (4%, 95% C.I. 2%, 8%) of 763 visits among seronegative women (P < 0.001). Abnormal Pap tests included 641 atypical squamous cells of undetermined significance (ASC-US), 425 low-grade squamous intraepithelial lesions (LSIL), and 10 high-grade squamous intraepithelial lesions in HIV-seropositive women, and 28 ASC-US and three LSIL in HIV-seronegative women. The incidence of abnormal Pap tests after hysterectomy was 14/100 person-years among HIV-seropositive and 2/100 person-years among HIV-seronegative women (P < 0.001) and remained stable across time. The 5-year clearance rate of abnormal Pap tests was 34/100 person-years for HIV-seropositive and 116/100 person-years for HIV-seronegative women (P < 0.001). In multivariate regression models, women with lower CD4 counts were more likely to have and less likely to clear abnormal cytology when it occurred. The incidence of vaginal intraepithelial neoplasia 2+ was 0.2 and 0.01 per 100 person-years for HIV-seropositive and HIV-seronegative women (P = 0.001). Two HIV-seropositive women developed Stage II cancers, with remission after radiotherapy.
Conclusion
Vaginal Pap tests are often abnormal in HIV-seropositive women. Though more common than in HIV-seronegative women, vaginal intraepithelial neoplasia 2+ and especially vaginal cancers are infrequent.
doi:10.1097/AOG.0b013e318244ee3d
PMCID: PMC3285255  PMID: 22353957
5.  A Single-Nucleotide Polymorphism in CYP2B6 Leads to >3-Fold Increases in Efavirenz Concentrations in Plasma and Hair Among HIV-Infected Women 
The Journal of Infectious Diseases  2012;206(9):1453-1461.
Background. Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)–infected women.
Methods. We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors.
Results. Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure.
Conclusions. This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.
doi:10.1093/infdis/jis508
PMCID: PMC3466997  PMID: 22927450
6.  Depressive Symptoms are Increased in the Early Perimenopausal Stage in Ethnically Diverse HIV+ and HIV− Women 
Menopause (New York, N.Y.)  2012;19(11):1215-1223.
Objective
The risk of clinically significant depressive symptoms increases during the perimenopause. With highly active antiretroviral treatment (HAART), more HIV-infected women survive to transition through the menopause. In a cross-sectional analysis, we evaluated the association of menopausal stage and vasomotor symptoms with depressive symptoms in an ethnically diverse, cohort of women with a high prevalence of HIV.
Methods
Participants included 835 HIV-infected women and 335 HIV-uninfected controls from the Women’s Interagency HIV Study (WIHS; 63% African-American). The Center for Epidemiological Studies Depression (CES-D) scale was used to screen for elevated depressive symptoms. Menopausal stages were defined according to standard definitions. Logistic regression analysis was used to identify predictors of elevated depressive symptoms.
Results
Compared to premenopausal women, early perimenopausal (OR 1.74, 95%CI 1.17–2.60), but not late perimenopausal or postmenopausal women were more likely to show elevated depressive symptoms in adjusted analyses. The odds were similar in HIV-infected and HIV-uninfected women. Persistent vasomotor symptoms also predicted elevated depressive symptoms in HIV-infected and uninfected women (OR 1.45, 95%CI 1.02–2.06). In HIV-infected women, menopausal stage interacted with antiretroviral use (p=0.02); the likelihood of elevated depressive symptoms in early perimenopause compared with premenopause was especially high in HAART-untreated women (OR 3.87, 95%CI 1.57–9.55).
Conclusions
In HIV+ and HIV− women, the odds of elevated depressive symptoms were significantly higher during the early perimenopause. Elevated depressive symptoms were associated with nonadherence to HAART, underscoring the importance of screening and treating depressive symptoms in HIV+ women who have experienced a change in the regularity of their menstrual cycles.
doi:10.1097/gme.0b013e318255434d
PMCID: PMC3483358  PMID: 22872013
HIV; Depression; Menopause; Perimenopause; African American; Vasomotor
7.  Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection 
The Journal of Infectious Diseases  2012;206(5):780-789.
Background.Inflammation persists in treated human immunodeficiency virus (HIV) infection and may contribute to an increased risk for non–AIDS-related pathologies. We investigated the correlation of cytokine responses with changes in CD4 T-cell levels and coinfection with hepatitis C virus (HCV) during highly active antiretroviral treatment (HAART).
Methods.A total of 383 participants in the Women's Interagency HIV Study (212 with HIV monoinfection, 56 with HCV monoinfection, and 115 with HIV/HCV coinfection) were studied. HIV-infected women had <1000 HIV RNA copies/mL, 99.7% had >200 CD4 T cells/μL; 98% were receiving HAART at baseline. Changes in CD4 T-cell count between baseline and 2–4 years later were calculated. Peripheral blood mononuclear cells (PBMCs) obtained at baseline were used to measure interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) responses to Toll-like receptor (TLR) 3 and TLR4 stimulation.
Results.Undetectable HIV RNA (<80 copies/mL) at baseline and secretion of IL-10 by PBMCs were positively associated with gains in CD4 T-cell counts at follow-up. Inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) were also produced in TLR-stimulated cultures, but only IL-10 was significantly associated with sustained increases in CD4 T-cell levels. This association was significant only in women with HIV monoinfection, indicating that HCV coinfection is an important factor limiting gains in CD4 T-cell counts, possibly by contributing to unbalanced persistent inflammation.
Conclusions.Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.
doi:10.1093/infdis/jis380
PMCID: PMC3491747  PMID: 22693231
8.  Variations in Serum Mullerian Inhibiting Substance Between White, Black and Hispanic Women 
Fertility and sterility  2008;92(5):1674-1678.
Objective
To compare serum mullerian inhibiting substance (MIS) levels between white, black and Hispanic women to determine if ovarian aging occurs at a different time course for women of different racial groups.
Design
Longitudinal study of serum MIS levels in women of different race/ethnicity over two different time points.
Setting
Women’s Interagency HIV Study, a multicenter prospective cohort study.
Patient(s)
Serum samples obtained from 809 participants (122 white, 462 black and 225 Hispanic women).
Intervention(s)
Comparison of serum MIS between women of different race/ethnicity at two time points (median age 37.5 years and 43.3 years).
Main Outcome Measure(s)
Variation in MIS by race/ethnicity over time, controlling for age, BMI, HIV status and smoking.
Result(s)
Compared to white women, average MIS values were lower among black (25.2% lower, p=0.037) and Hispanic (24.6% lower, p=0.063) women, adjusting for age, BMI, smoking and HIV status.
Conclusion
There is an independent effect of race/ethnicity on the age-related decline in MIS over time.
doi:10.1016/j.fertnstert.2008.08.110
PMCID: PMC3037722  PMID: 18930217
Mullerian inhibiting substance; antiMullerian hormone; ovarian reserve; race; ethnicity
9.  Influence of gender on receipt of guideline-based antiretroviral therapy in the era of HAART 
AIDS Care  2011;24(1):20-29.
United States HIV treatment guidelines delineate preferred antiretroviral regimens (ART) and discourage use of subpotent, toxic, or adversely interacting combinations. It is unclear how often patients receive guideline concordant ART and what factors are correlated with receiving guideline-inconsistent ART. The objective of this study was to assess ART reported by participants of the Women's Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS) to determine whether gender is associated with receipt of guideline-inconsistent ART. ART reported by WIHS and MACS participants from 1/1/2001 – 12/31/2007 was assessed for concordance with HIV guidelines. Logistic regression with generalized estimating equations estimated the crude and adjusted odds ratios and 95% confidence intervals associated with guideline-inconsistent regimens. Of 2937 participants, 463 subjects (WIHS n=263; MACS n=200) reported guideline-inconsistent ART during the study period. Age greater than 50 years (aOR = 2.22, 95% CI 1.14, 4.33) and HIV-1 RNA (aOR=1.17, 95% CI 1.08, 1.25) but not participant gender (aOR= 1.21, 95% CI 0.88, 1.65) were associated with guideline-inconsistent ART. The prevalence of guideline inconsistent ART peaked in 2004, however there was not a statistically significant increase or decrease over time. Guideline inconsistent ART was not related to gender, but was often used by older patients, and patients with higher viral loads. Monitoring ART quality based on concordance with expert guidelines could improve treatment outcomes in a substantial number of patients.
doi:10.1080/09540121.2011.592814
PMCID: PMC3222784  PMID: 21732716
antiretroviral; gender; guideline; concordance; treatment disparities
10.  Microanalysis of the antiretroviral nevirapine in human hair from HIV-infected patients by liquid chromatography-tandem mass spectrometry 
Analytical and bioanalytical chemistry  2011;401(6):1923-1933.
Sufficient drug exposure is crucial for maintaining durable responses to HIV treatments. However, monitoring drug exposure using single blood samples only provides short-term information and is highly subject to intra-individual pharmacokinetic variation. Drugs can accumulate in hair over a long period of time, so hair drug levels can provide drug exposure information over prolonged periods. We now report on a specific, sensitive and reproducible LC-MS/MS method for measuring nevirapine (NVP), a widely used antiretroviral drug, levels in human hair using even a single short strand of hair. Hair samples are cut into small segments and drug is extracted in methanol/trifluoroacetic acid (v/v, 9:1) shaken at 37°C in a water bath overnight, followed by liquid-liquid extraction under alkaline conditions. The extracted samples are then separated on a BDS-C18 column with mobile phase composed as 50% acetonitrile containing 0.15% acetic acid and 4 mM ammonium acetate with an isocratic elution for a total run time of 3 min. and detected by triple quadrupole electrospray multiple reaction mode at precursor/product ion at 267.0>225.9 m/z. Deuterated nevirapine-d5 was used as internal standard. This method was validated from 0.25 to 100 ng/mg using 2 mg hair samples. The accuracies for spiked NVP hair control samples were 98–106% with coefficients of variation (CV) less than 10%. The CV for incurred hair control samples was less than 7%. The extraction efficiency for incurred control hair samples was estimated at more than 95% by repeated extractions. This method has been successfully applied to analyze more than 1000 hair samples from participants in a large ongoing cohort study of HIV-infected participants. We also showed that nevirapine in human hair can easily be detected in a single short strand of hair. This method will allow us to identify drug non-adherence using even a single strand of hair.
doi:10.1007/s00216-011-5278-7
PMCID: PMC3477620  PMID: 21847531
Antiretroviral drug; Nevirapine; Hair; LC-MS/MS; TDM; Adherence
11.  LOWER LEVELS OF INTERLEUKIN-12 PRECEDE THE DEVELOPMENT OF TUBERCULOSIS AMONG HIV-INFECTED WOMEN 
Cytokine  2011;56(2):325-331.
Tuberculosis (TB) is the worldwide leading cause of death among HIV-infected individuals, accounting for more than half of AIDS-related deaths. A high risk of tuberculosis (TB) has been shown in early stages of the HIV disease, even in the presence of normal CD4+ cell counts. Moreover, the factors that determine protective immunity vs. susceptibility to M. tuberculosis cannot be fully explained by simple changes in IFNγ levels or a shift from Th1 to Th2 cytokines. This work investigated the relationship between cytokine expression profiles in peripheral blood mononuclear cells (PBMC) and susceptibility to M. tuberculosis in ten HIV+ women who went on to develop TB. RNA transcripts for IL-4, IL-4δ2, IL-10, IL-12(p35), IL-13, IL-17A, IFNγ and TNFα were measured by real-time quantitative PCR in unstimulated or TB peptide antigen-stimulated PBMCs from ten HIV+ women with positive tuberculin skin tests (TST) and compared with HIV-seropositive and seronegative women without previous TB and negative TST. Stimulated PBMC cultures showed significantly lower expression of IL-12p35 (p=0.004) and IL-10 (p=0.026) in the HIV+TB+ group six to twelve months before onset of TB compared to HIV+TB− women. Unstimulated PBMC from HIV+TB+ women also had lower expression of Th2 cytokines [IL-4 (p=0.056) and IL-13 (p=0.050)] compared to HIV+TB− women. These results suggest that lower IL-12 production by PBMC in response to TB antigens and lower levels of both Th1 and Th2 cytokines by PBMC correlate with future development of TB in HIV-infected women and may be responsible for their increased susceptibility.
doi:10.1016/j.cyto.2011.08.018
PMCID: PMC3466167  PMID: 21880503
Interferon-γ(IFNγ); Interleukin-4 (IL-4); Interleukin-12 (IL-12); Human Immunodeficiency Virus (HIV); Tuberculosis (TB)
12.  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
13.  Seroincidence of 2009 H1N1 infection in HIV-infected and HIV-uninfected women prior to vaccine availability 
AIDS (London, England)  2011;25(9):1229-1232.
The 2009 H1N1 pandemic was a unique opportunity to investigate differences in influenza infection using serology by HIV status. Using serial serum specimens collected from 1 April to 30 September 2009 and the prior 2 years from Women’s Interagency HIV study participants, there was no difference in serologic evidence of 2009 H1N1 infection among HIV-infected women with a CD4 cell count at least 350 cells/µl compared with HIV-uninfected women. Owing to evidence showing a greater risk of influenza-related complications, HIV-infected individuals should continue to be a priority group for vaccination.
doi:10.1097/QAD.0b013e3283471cf2
PMCID: PMC3442364  PMID: 21505313
14.  Pharmacist counseling in a cohort of women with HIV and women at risk for HIV 
Background and methods
Achieving high adherence to antiretroviral therapy for human immunodeficiency virus (HIV) is challenging due to various system-related, medication-related, and patient-related factors. Community pharmacists can help patients resolve many medication-related issues that lead to poor adherence. The purpose of this cross-sectional survey nested within the Women’s Interagency HIV Study was to describe characteristics of women who had received pharmacist medication counseling within the previous 6 months. The secondary objective was to determine whether HIV-positive women who received pharmacist counseling had better treatment outcomes, including self-reported adherence, CD4+ cell counts, and HIV-1 viral loads.
Results
Of the 783 eligible participants in the Women’s Interagency HIV Study who completed the survey, only 30% of participants reported receiving pharmacist counseling within the last 6 months. Factors independently associated with counseling included increased age (odds ratio [OR] 1.28; 95% confidence interval [CI] 1.07–1.55), depression (OR 1.75; 95% CI 1.25–2.45), and use of multiple pharmacies (OR 1.65; 95% CI 1.15–2.37). Patients with higher educational attainment were less likely to report pharmacist counseling (OR 0.68; 95% CI 0.48–0.98), while HIV status did not play a statistically significant role. HIV-positive participants who received pharmacist counseling were more likely to have optimal adherence (OR 1.23; 95% CI 0.70–2.18) and increased CD4+ cell counts (+43 cells/mm3, 95% CI 17.7–104.3) compared with those who had not received counseling, though these estimates did not achieve statistical significance.
Conclusion
Pharmacist medication counseling rates are suboptimal in HIV-positive and at-risk women. Pharmacist counseling is an underutilized resource which may contribute to improved adherence and CD4+ counts, though prospective studies should be conducted to explore this effect further.
doi:10.2147/PPA.S30797
PMCID: PMC3393123  PMID: 22791983
human immunodeficiency virus; acquired immunodeficiency syndrome; antiretroviral therapy; community pharmacy; pharmacy practice; women’s health
15.  The Relation of HLA Genotype to Hepatitis C Viral Load and Markers of Liver Fibrosis in HIV-Infected and HIV-Uninfected Women 
The Journal of Infectious Diseases  2011;203(12):1807-1814.
Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.
Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.
Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).
Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
doi:10.1093/infdis/jir192
PMCID: PMC3100515  PMID: 21606539
16.  Atazanavir Concentration in Hair Is the Strongest Predictor of Outcomes on Antiretroviral Therapy 
In a longitudinal study of outcomes on atazanavir-based therapy in a large cohort of HIV-infected women, hair levels of atazanavir were the strongest independent predictor of virologic suppression. Hair antiretroviral concentrations may serve as a useful tool in HIV care.
Background. Adequate exposure to antiretrovirals is important to maintain durable responses, but methods to assess exposure (eg, querying adherence and single plasma drug level measurements) are limited. Hair concentrations of antiretrovirals can integrate adherence and pharmacokinetics into a single assay.
Methods. Small hair samples were collected from participants in the Women's Interagency HIV Study (WIHS), a large cohort of human immunodeficiency virus (HIV)-infected (and at-risk noninfected) women. From 2003 through 2008, we analyzed atazanavir hair concentrations longitudinally for women reporting receipt of atazanavir-based therapy. Multivariate random effects logistic regression models for repeated measures were used to estimate the association of hair drug levels with the primary outcome of virologic suppression (HIV RNA level, <80 copies/mL).
Results. 424 WIHS participants (51% African-American, 31% Hispanic) contributed 1443 person-visits to the analysis. After adjusting for age, race, treatment experience, pretreatment viral load, CD4 count and AIDS status, and self-reported adherence, hair levels were the strongest predictor of suppression. Categorized hair antiretroviral levels revealed a monotonic relationship to suppression; women with atazanavir levels in the highest quintile had odds ratios (ORs) of 59.8 (95% confidence ratio, 29.0–123.2) for virologic suppression. Hair atazanavir concentrations were even more strongly associated with resuppression of viral loads in subgroups in which there had been previous lapses in adherence (OR, 210.2 [95% CI, 46.0–961.1]), low hair levels (OR, 132.8 [95% CI, 26.5–666.0]), or detectable viremia (OR, 400.7 [95% CI, 52.3–3069.7]).
Conclusions. Antiretroviral hair levels surpassed any other predictor of virologic outcomes to HIV treatment in a large cohort. Low antiretroviral exposure in hair may trigger interventions prior to failure or herald virologic failure in settings where measurement of viral loads is unavailable. Monitoring hair antiretroviral concentrations may be useful for prolonging regimen durability.
doi:10.1093/cid/cir131
PMCID: PMC3079399  PMID: 21507924
17.  The impact of HIV clinical pharmacists on HIV treatment outcomes: a systematic review 
Objective
Due to the rapid proliferation of human immunodeficiency virus (HIV) treatment options, there is a need for health care providers with knowledge of antiretroviral therapy intricacies. In a HIV multidisciplinary care team, the HIV pharmacist is well-equipped to provide this expertise. We conducted a systematic review to assess the impact of HIV pharmacists on HIV clinical outcomes.
Methods
We searched six electronic databases from January 1, 1980 to June 1, 2011 and included all quantitative studies that examined pharmacist’s roles in the clinical care of HIV-positive adults. Primary outcomes were antiretroviral adherence, viral load, and CD4+ cell count and secondary outcomes included health care utilization parameters, antiretroviral modifications, and other descriptive variables.
Results
Thirty-two publications were included. Despite methodological limitation, the involvement of HIV pharmacists was associated with statistically significant adherence improvements and positive impact on viral suppression in the majority of studies.
Conclusion
This systematic review provides evidence of the beneficial impact of HIV pharmacists on HIV treatment outcomes and offers suggestions for future research.
doi:10.2147/PPA.S30244
PMCID: PMC3333818  PMID: 22536064
pharmacist; HIV/AIDS; clinical; adherence; impact
18.  CC Chemokine Receptor 5 Genotype and Susceptibility to Transmission of Human Immunodeficiency Virus Type 1 in Women 
The Journal of Infectious Diseases  2003;187(4):569-575.
The human gene for CC chemokine receptor 5, a coreceptor for human immunodeficiency virus type 1 (HIV-1), affects susceptibility to infection. Most studies of predominantly male cohorts found that individuals carrying a homozygous deleted form of the gene, Δ32, were protected against transmission, but protection did not extend to Δ32 heterozygotes. The role played by this mutation in HIV-1 transmission to women was studied in 2605 participants in the Women's Interagency HIV Study. The Δ32 gene frequency was 0.026 for HIV-1–seropositive women and 0.040 for HIV-1–seronegative women, and statistical analyses showed that Δ32 heterozygotes were significantly less likely to be infected (odds ratio, 0.63 [95% confidence interval, 0.44–0.90]). The CCR5 Δ32 heterozygous genotype may confer partial protection against HIV-1 infection in women. Because Δ32 is rare in Africans and Asians, it seems plausible that differential genetic susceptibility, in addition to social and behavioral factors, may contribute to the rapid heterosexual spread of HIV-1 in Africa and Asia.
doi:10.1086/367995
PMCID: PMC3319124  PMID: 12599073
19.  Human Leukocyte Antigen Genotype and Risk of HIV Disease Progression before and after Initiation of Antiretroviral Therapy▿‡ 
Journal of Virology  2011;85(20):10826-10833.
While the human leukocyte antigen (HLA) genotype has been associated with the rate of HIV disease progression in untreated patients, little is known regarding these relationships in patients using highly active antiretroviral therapy (HAART). The limited data reported to date identified few HLA-HIV disease associations in patients using HAART and even occasional associations that were opposite of those found in untreated patients. We conducted high-resolution HLA class I and II genotyping in a random sample (n = 860) of HIV-seropositive women enrolled in a long-term cohort initiated in 1994. HLA-HIV disease associations before and after initiation of HAART were examined using multivariate analyses. In untreated HIV-seropositive patients, we observed many of the predicted associations, consistent with prior studies. For example, HLA-B*57 (β = −0.7; 95% confidence interval [CI] = −0.9 to −0.5; P = 5 × 10−11) and Bw4 (β = −0.2; 95% CI = −0.4 to −0.1; P = 0.009) were inversely associated with baseline HIV viral load, and B*57 was associated with a low risk of rapid CD4+ decline (odds ratio [OR] = 0.2; 95% CI = 0.1 to 0.6; P = 0.002). Conversely, in treated patients, the odds of a virological response to HAART were lower for B*57:01 (OR = 0.2; 95% CI = 0.0 to 0.9; P = 0.03), and Bw4 (OR = 0.4; 95% CI = 0.1 to 1.0; P = 0.04) was associated with low odds of an immunological response. The associations of HLA genotype with HIV disease are different and sometimes even opposite in treated and untreated patients.
doi:10.1128/JVI.00804-11
PMCID: PMC3187522  PMID: 21849458
20.  Immune Responses to HIV in the Female Reproductive Tract, Immunologic Parallels with the Gastrointestinal Tract, and Research Implications 
The female reproductive tract is a major site of mucosa-associated lymphoid tissue and susceptibility to HIV infection, yet the tissue site(s) of infection and the impact of HIV infection on this important mucosal tissue remain poorly understood. CD4+ T-cells and other cell types expressing the major coreceptors for HIV, CCR5 and CXCR4, are abundant in both the lower reproductive tract (endocervix and vagina) and the upper tract (endocervix and uterus), and are highly susceptible to infection. Antiviral defenses in the female reproductive tract are mediated by a variety of soluble factors, and by mucosal effector cells that differ phenotypically from their counterparts in blood. The immunologic characteristics of the female reproductive tract parallel those of the gut, where major HIV-related immunologic injury occurs. The susceptibility of the female reproductive tract to HIV infection and immunopathogenesis suggests important new avenues for further research.
doi:10.1111/j.1600-0897.2010.00948.x
PMCID: PMC3063101  PMID: 21223420
HIV; CTL; NK cells; MALT; gastrointestinal tract
22.  CCR2 Genotype and Disease Progression in a Treated Population of HIV Type 1–Infected Women 
Both antiretroviral therapy and the human coreceptor polymorphism CCR2-V64I slow progression of human immunodeficiency virus type 1 (HIV-1) disease. To examine the effect of V64I on disease progression in patients receiving therapy, we determined CCR2 genotypes in the Women’s Interagency HIV Study cohort. We studied 2047 HIV-1–infected women, most of whom initiated treatment during the study. No association was seen between CCR2 genotype and either disease progression or therapeutic response, suggesting that the benefits of treatment most likely overshadow the salutary effects of the V64I polymorphism.
doi:10.1086/423386
PMCID: PMC3164116  PMID: 15472820
23.  The relationship between non-injection drug use behaviors on progression to AIDS and death in a cohort of HIV seropositive women in the era of highly active antiretroviral therapy use 
Addiction (Abingdon, England)  2005;100(7):990-1002.
Aims
To evaluate the effects of longitudinal patterns and types of non-injection drug use (NIDU) on HIV progression in the highly active antiretroviral therapy (HAART) era.
Design
Women’s Interagency HIV Study (WIHS), a prospective cohort study conducted at six US sites.
Methods
Data were collected semi-annually from 1994 to 2002 on 1046 HIV+ women. Multivariate Cox proportional hazards modeling was used to estimate relative hazards for developing AIDS and for death by pattern and type of NIDU.
Findings
During follow-up, 285 AIDS events and 287 deaths, of which 177 were AIDS-related, were reported. At baseline, consistent and former NIDU was associated with CD4+ counts of < 200 cells/μl (43% and 46%, respectively) and viral load > 40 000 copies/ml (53% and 55%, respectively). Consistent NIDU reported less HAART use (53%) compared with other NIDU patterns. Stimulant use was associated with CD4+ cell counts of < 200 cells/μl (53%) and lower HAART initiation (63%) compared with other NIDU types. In multivariate analyses, progression to AIDS was significantly higher among consistent (RH = 2.52), inconsistent (RH = 1.63) and former (RH = 1.56) users compared with never users; and for stimulant (RH = 2.04) and polydrug (RH = 1.65) users compared with non-users. Progression to all-cause death was higher only among former users (RH = 1.48) compared with never users in multivariate analysis. NIDU behaviors were not associated with progression to AIDS-related death.
Conclusions
In this study, pattern and type of NIDU were associated with HIV progression to AIDS and all-cause mortality. These differences were associated with lower HAART utilization among consistent NIDU and use of stimulants, and poor baseline immunological and virological status among former users.
doi:10.1111/j.1360-0443.2005.01098.x
PMCID: PMC3128378  PMID: 15955015
Acquired immunodeficiency syndrome; highly active anti-retroviral therapy; human immunodeficiency virus; mortality; non-injection drug use
24.  Cervical Shedding of HIV-1 RNA Among Women With Low Levels of Viremia While Receiving Highly Active Antiretroviral Therapy 
Background
Among women with low o r undetectable quantities of HIV-1 RNA in plasma, factors associated with genital HIV-1 RNA shedding, including choice of treatment regimen, are poorly characterized.
Methods
We measured HIV-1 RNA in cervical swab specimens obtained from participants in the Women’s Interagency HIV Study who had concurrent plasma viral RNA levels <500 copies/mL, and we assessed factors associated with genital HIV shedding. The study was powered to determine the relative effects of antiretroviral protease inhibitors (PIs) versus nonnucleoside reverse transcriptase inhibitors (NNRTIs) on viral RNA shedding.
Results
Overall, 44 (15%) of 290 women had detectable HIV-1 RNA in cervical specimens. In the final multivariate model, shedding was independently associated with NNRTI (vs. PI) use (odds ratio [OR], 95% confidence interval [CI]: 2.24, 1.13 to 4.45) and illicit drug use (OR, 95% CI: 2.41, 0.96 to 5.69).
Conclusions
This is the largest study to define risks for genital HIV-1 RNA shedding in women with low/undetectable plasma virus. Shedding in this population was common, and NNRTI-based highly active antiretroviral therapy (HAART) (vs. PI-based HAART) was associated with genital HIV shedding. Further study is required to determine the impact of these findings on transmission of HIV from mother to child or to sexual partners.
doi:10.1097/01.qai.0000248352.18007.1f
PMCID: PMC3126662  PMID: 17106279
compartmentalization; genital; HIV; nonnucleoside reverse transcriptase inhibitor; protease inhibitor; undetectable; viral replication; women
25.  Increased Circulating Interleukin-7 Levels in HIV-1–Infected Women 
Summary
Sex-based differences in CD4 T-cell (CD4) counts are well recognized, but the basis for these differences has not been identified. Conceivably, homeostatic factors may play a role in this process by regulating T-cell maintenance and repletion. Interleukin (IL)-7 is essential for normal T-cell production and homeostasis. We hypothesized that differences in IL-7 might contribute to sex-based differences in CD4 counts. Circulating IL-7 levels were analyzed in 299 HIV-1–infected women and men. Regression analysis estimated that IL-7 levels were 40% higher in women than in men (P = 0.0032) after controlling for CD4 count, age, and race. Given the important role of IL-7 in T-cell development and homeostasis, these findings suggest that higher IL-7 levels may contribute to higher CD4 counts in women.
PMCID: PMC3119025  PMID: 16284535
interleukin-7; sexual dimorphism; CD4-positive T cells; cytokines; sex differences

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