Interagency Human Immunodeficiency Virus Study Research Articles

Racial/Ethnic Differences in Spontaneous HCV Clearance in HIV Infected and Uninfected Women

Among individuals without human immunodeficiency virus (HIV), African Americans have lower spontaneous clearance of hepatitis C virus (HCV) than Caucasians, and women have higher clearance than men. Few studies report racial/ethnic differences in acute HCV in HIV infected, or Hispanic women. We examined racial/ethnic differences in spontaneous HCV clearance in a population of HCV mono- and co-infected women. We conducted a cross sectional study of HCV seropositive women (897 HIV infected and 168 HIV uninfected) followed in the US multicenter, NIH-funded Women's Interagency HIV Study (WIHS), to determine the association of race/ethnicity with spontaneous HCV clearance, as defined by undetectable HCV RNA at study entry. Among HIV and HCV seropositive women, 18.7 % were HCV RNA negative, 60.9 % were African American, 19.3 % Hispanic and 17.7 % Caucasian. HIV infected African American women were less likely to spontaneously clear HCV than Hispanic (OR 0.59, 95 % CI 0.38-0.93, p = 0.022) or Caucasian women (OR 0.57, 95 % CI 0.36-0.93, p = 0.023). Among HIV uninfected women, African Americans had less HCV clearance than Hispanics (OR 0.18, 95 % CI 0.07-0.48, p = 0.001) or Caucasians (OR 0.26, 95 % CI 0.09-0.79, p = 0.017). There were no significant differences in HCV clearance between Hispanics and Caucasians, among either HIV infected (OR 0.97, 95 % CI 0.57-1.66, p = 0.91) or uninfected (OR 1.45, 95 % CI 0.56-3.8, p = 0.45) women. African Americans were less likely to spontaneously clear HCV than Hispanics or Caucasians, regardless of HIV status. No significant differences in spontaneous HCV clearance were observed between Caucasian and Hispanic women. Future studies incorporating IL28B genotype may further explain these observed racial/ethnic differences in spontaneous HCV clearance.

Depressive symptoms are increased in the early perimenopausal stage in ethnically diverse human immunodeficiency virus–infected and human immunodeficiency virus–uninfected women

The risk of clinically significant depressive symptoms increases during perimenopause. With highly active antiretroviral treatment (HAART), more human immunodeficiency virus (HIV)-infected women survive to transition through 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. Participants included 835 HIV-infected women and 335 HIV-uninfected controls from the Women's Interagency HIV Study (63% African American). The Center for Epidemiologic Studies Depression 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. Compared with premenopausal women, early perimenopausal women (OR [odds ratio], 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 HIV-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). In HIV-infected and HIV-uninfected women, the odds of elevated depressive symptoms were significantly higher during early perimenopause. Elevated depressive symptoms were associated with nonadherence to HAART, underscoring the importance of screening and treating depressive symptoms in HIV-infected women who have experienced a change in the regularity of their menstrual cycles.

Negative Predictive Value of Pap Testing

To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value. Participants in the Women's Interagency HIV Study were monitored with conventional Pap tests every 6 months. After excluding those with abnormal Pap test results before study, cervical disease, or hysterectomy, women with negative enrollment Pap test results were monitored for development of precancer within 15 or 39 months, defined as a Pap test result read as high-grade squamous intraepithelial lesion, atypical glandular cells favor neoplasia, or adenocarcinoma in situ, or a cervical biopsy read as cervical intraepithelial neoplasia 2 or worse. Correlations between one or more consecutive negative Pap test results and subsequent precancer were assessed using Cox proportional hazards models. Among 942 HIV-infected women with negative baseline Pap test results, eight (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap test results, precancer was rare, with no cases within 15 months and 10 of 539 (2%) within 39 months. No women developed precancer or cancer within 39 months after 10 consecutive negative Pap test results. Risks for precancer within 15 months after negative Pap test result included current smoking (adjusted hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.2-2.0 compared with nonsmokers), younger age (adjusted HR 1.5, 95% CI 1.1-2.1 for women aged younger than 31 years compared with older than 45 years), and lower CD4 count (adjusted HR 11.8, 95% CI 1.3-2.3 for CD4 200-500/microliter, adjusted HR 2.2, 95% CI 1.6-2.9 for CD4 less than 200/microliter, compared with CD4 more than 500/microliter). Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate. II.

Abstract 64: Microvascular Endothelial Dysfunction, Oxidative Stress and Reduced Arginine: Adma in Premenopausal Women With HIV

Cardiovascular disease (CVD) is common in persons infected with the human immunodeficiency virus (HIV) who are receiving highly active antiretroviral therapy (HAART). Since CVD generally begins with microvascular dysfunction, we tested the hypothesis that women with HIV have microvascular endothelial dysfunction. We related this to reactive oxygen species (ROS), NOS substrate: inhibitor ratio (arginine: ADMA) and inflammation. Subcutaneous microvascular arterioles (SMAs) were isolated from gluteal skin biopsies from 11 premenopausal, virally suppressed African American HIV positive women receiving HAART but without CVD risk factors and 10 healthy matched controls in the Women’s Interagency HIV Study (WHIS). Preconstricted SMAs were mounted in a Mulvany-Halpern myograph and relaxed with graded concentrations of acetylcholine (ACh). Endothelium derived relaxation (EDR), endothelium-derived relaxation factor (EDRF; NOS-dependent relaxation), endothelium derived hyperpolarizing factor (EDHF; K + -channel dependent relaxation) and endothelium derived contracting factor (EDCF; ACh-induced contraction with relaxation pathways inhibited) were related to plasma cytokines (array) and plasma arginine: ADMA ratio (measured by capillary zone electrophoresis).Compared to controls, HIV infected subjects had reduced EDRs (50±6 vs 78±3%; P< 0.01), EDRF (27±4 vs 38±3%, P< 0.05), EDHF(18±4 vs 39±4%, P< 0.05) and decreased NO activity (0.18±0.05vs 0.69±0.17ΔUnits, P< 0.05 from DAF-FM fluorescence).They had an ACh-induced EDCF (21±2vs7±3%, P< 0.01) and increased microvascular ROS (0.14±0.04 vs 0.04±0.04 Δunits; P< 0.01 from tempo-9ACfluorescence). Plasma cytokines in HIV subjects showed enhanced inflammation and plasma arginine: ADMA concentrations were reduced (178±12 vs 203±13 μmol/ μmol; P< 0.005). In conclusion, pre-menopausal women receiving HAART with virally suppressed HIV who were free of CVD risk factors developed defective microvascular EDRF and EDHF with reduced NO and NOS substrate: inhibitor ratio. They had inflammation and their microvessels developed a new ACh-induced EDCF and enhanced ROS. These profound microvascular disturbances in apparently healthy young women may herald the development of premature CVD.

Lower liver-related death in African-American women with human immunodeficiency virus/hepatitis C virus coinfection, compared to Caucasian and Hispanic women

Among individuals with and without concurrent human immunodeficiency virus (HIV), racial/ethnic differences in the natural history of hepatitis C virus (HCV) have been described. African Americans have lower spontaneous HCV clearance than Caucasians, yet slower rates of liver fibrosis once chronically infected. It is not clear how these differences in the natural history of hepatitis C affect mortality, in either HIV-positive or -negative individuals. We conducted a cohort study of HIV/HCV coinfected women followed in the multicenter Women's Interagency HIV Study to determine the association of self-reported race/ethnicity with all-cause and liver-related mortality. Survival analyses were performed using Cox's proportional hazards models. The eligible cohort (n = 794) included 140 Caucasians, 159 Hispanics, and 495 African Americans. There were 438 deaths and 49 liver-related deaths during a median follow-up of 8.9 years and maximum follow-up of 16 years. African-American coinfected women had significantly lower liver-related mortality, compared to Caucasian (hazard ratio [HR], 0.41; 95% confidence interval [CI]: 0.19-0.88; P = 0.022) and Hispanic coinfected women (HR, 0.38; 95% CI: 0.19-0.76; P = 0.006). All-cause mortality was similar between racial/ethnic groups (HRs for all comparisons: 0.82-1.03; log-rank test: P = 0.8). African-American coinfected women were much less likely to die from liver disease, as compared to Caucasians and Hispanics, independent of other causes of death. Future studies are needed to investigate the reasons for this marked racial/ethnic discrepancy in liver-related mortality.

Risk of cervical precancer and cancer among HIV-infected women with normal cervical cytology and no evidence of oncogenic HPV infection.

US cervical cancer screening guidelines for human immunodeficiency virus (HIV)-uninfected women 30 years or older have recently been revised, increasing the suggested interval between Papanicolaou (Pap) tests from 3 years to 5 years among those with normal cervical cytology (Pap test) results who test negative for oncogenic human papillomavirus (HPV). Whether a 3-year or 5-year screening interval could be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown. To determine the risk of cervical precancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as 2 separate end points, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test result and were negative for oncogenic HPV. Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional US cohort of the Women's Interagency HIV Study, between October 1, 2001, and September 30, 2002, with follow-up through April 30, 2011. Semiannual visits at 6 clinical sites included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using polymerase chain reaction. The primary analysis was truncated at 5 years of follow-up. Five-year cumulative incidence of cervical precancer and cancer. No oncogenic HPV was detected in 369 (88% [95% CI, 84%-91%]) HIV-infected women and 255 (91% [95% CI, 88%-94%]) HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women, 2 cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500 cells/μL or greater. Histologic data were obtained from 4 of the 6 clinical sites. There were 6 cases of CIN-2+ in 145 HIV-uninfected women (cumulative incidence, 5% [95% CI, 1%-8%]) and 9 cases in 219 HIV-infected women (cumulative incidence, 5% [95% CI, 2%-8%]). This included 1 case of CIN-2+ in 44 oncogenic HPV-negative HIV-infected women with CD4 cell count less than 350 cells/μL (cumulative incidence, 2% [95% CI, 0%-7%]), 1 case in 47 women with CD4 cell count of 350 to 499 cells/μL (cumulative incidence, 2% [95% CI, 0%-7%]), and 7 cases in 128 women with CD4 cell count of 500 cells/μL or greater (cumulative incidence, 6% [95% CI, 2%-10%]). One HIV-infected and 1 HIV-uninfected woman had CIN-3, but none had cancer. The 5-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.

Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection

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). 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. 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. Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.

Pharmacist counseling in a cohort of women with HIV and women at risk for HIV

Background and methodsAchieving 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.ResultsOf 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.ConclusionPharmacist 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.

Association among Vitamin D, Oral Candidiasis, and Calprotectinemia in HIV

Vitamin D deficiency is associated with negative health outcomes, including infections. Vitamin D modulates inflammation and down-regulates the expression of calprotectin, a molecule which influences neutrophil functions and which has been linked to oral candidiasis (OC), the most prevalent oral lesion in human immunodeficiency virus (HIV). We hypothesized a positive association between vitamin D deficiency and OC, and that this effect was partially modulated by calprotectinemia. Plasma calprotectin and serum 25 (OH) vitamin D levels were measured in stored samples from 84 HIV-seropositive Chicago women enrolled in the Oral Substudy of the Women’s Interagency HIV Study (WIHS). OC and vitamin D deficiency were diagnosed in, respectively, 14 (16.7%) and 46 (54.8%) of those studied. Vitamin D deficiency was positively associated with OC (p = 0.011) and with higher calprotectinemia (p = 0.019) in univariate analysis. After adjustment for CD4, HIV viral load, HIV treatment, and tobacco and heroin/methadone use, vitamin D deficiency remained a significant predictor of OC (OR 5.66; 95% confidence interval 1.01-31.71). This association weakened after adjustment for calprotectinemia, supporting a role for calprotectinemia as a moderator of this effect. These findings support studies to examine the effect of vitamin D status on calprotectinemia, neutrophil functions, and opportunistic mucosal infections in HIV.

Management of Patients Coinfected With HCV and HIV: A Close Look at the Role for Direct-Acting Antivirals

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Cytomegalovirus Immunoglobulin G Antibody Is Associated With Subclinical Carotid Artery Disease Among HIV-Infected Women

Cytomegalovirus (CMV) infection has been implicated in immune activation and accelerated progression of immunodeficiency from human immunodeficiency virus (HIV) coinfection. We hypothesized that CMV is associated with vascular disease in HIV-infected adults. In the Women's Interagency HIV Study, we studied 601 HIV-infected and 90 HIV-uninfected participants. We assessed the association of CMV immunoglobulin G (IgG) level with carotid artery intima-media thickness, carotid artery distensibility, Young's elastic modulus, and blood pressures. Multivariable models adjusted for age, race/ethnicity, smoking, diabetes, and body mass index. Mean CMV IgG levels were higher in HIV-infected women compared with HIV-uninfected women (P < .01). Among HIV-infected women, higher CMV IgG level was associated with decreased carotid artery distensibility (P < .01) and increased Young's modulus (P = .02). Higher CMV IgG antibody level was associated with increased prevalence of carotid artery lesions among HIV-infected women who achieved HIV suppression on antiretroviral therapy, but not among viremic or untreated HIV-infected women. Adjustment for Epstein-Barr virus antibody levels and C-reactive protein levels had no effect on the associations between CMV IgG levels and vascular parameters. Cytomegalovirus antibody titers are increased in HIV-infected women and associated with subclinical cardiovascular disease. Host responses to CMV may be abnormal in HIV infection and associated with clinical disease.

Association of Polymorphisms of the Mu Opioid Receptor Gene with the Severity of HIV Infection and Response to HIV Treatment

Mu opioid receptor (OPRM1) ligands may alter expression of chemokines and chemokine receptors involved in penetration of human immunodeficiency virus (HIV) type 1 into the cell. We suggest that OPRM1 variants may affect the pathophysiology of HIV infection. DNA samples from 1031 eligible African Americans, Hispanics, and whites from the Women's Interagency HIV Study (WIHS) who were alive as of April 2006 were analyzed. We performed regression analysis of association of 18 OPRM1 variants with a change of viral load and CD4 cell count during 2 periods: between admission to WIHS and the start of highly active antiretroviral therapy (HAART) (interval X) and between the start of HAART and the most recent WIHS visit (interval Y), and examined the association of these variants with HIV status. Regardless of genotype, a significant decrease in viral load during interval X was found for each ethnicity. Whites with allele G of the functional polymorphism 118A > G (reference sequence rs1799971) showed a smaller decrease in viral load; those bearing minor alleles IVS1 + 1050A, IVS1 + 14123A, and IVS2 + 31A showed a larger decrease in viral load over interval X (0.01 < P < .05). Hispanics with the same alleles showed a greater increase in CD4 cell count over interval Y (0.01 < P < .05). We found an association between OPRM1 variants and HIV status in African Americans and whites. OPRM1 polymorphisms may alter the severity of HIV infection before and after HAART.

Effect of Human Immunodeficiency Virus Infection on the Prevalence and Incidence of Vaginal Intraepithelial Neoplasia

To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia (VAIN) in human immunodeficiency virus (HIV)-seropositive women. 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. End points included abnormal Pap test results after hysterectomy and VAIN regardless of hysterectomy. Over a median of 5.6 years of follow-up, vaginal Pap test results were abnormal at 1,076 (29%; 95% confidence interval [CI] 25-33%) of 3,700 visits among HIV-seropositive compared with 31 (4%; 95% CI 2-8%) of 763 visits among HIV-seronegative women (P<.001). Abnormal Pap test results included 641 atypical squamous cells of undetermined significance, 425 low-grade squamous intraepithelial lesions, and 10 high-grade squamous intraepithelial lesions in HIV-seropositive women and 28 atypical squamous cells of undetermined significance and three low-grade squamous intraepithelial lesions in HIV-seronegative women. The incidence of abnormal Pap test results after hysterectomy was 14 per 100 person-years among HIV-seropositive and two per 100 person-years among HIV-seronegative women (P<.001) and remained stable across time. The 5-year clearance rate of abnormal Pap test results was 34 per 100 person-years for HIV-seropositive and 116 per 100 person-years for HIV-seronegative women (P<.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 VAIN 2 or worse was 0.2 and 0.01 per 100 person-years for HIV-seropositive and HIV-seronegative women (P=.001). Two HIV-seropositive women developed stage II cancers with remission after radiotherapy. Vaginal Pap test results are often abnormal in HIV-seropositive women. Although more common than in HIV-seronegative women, VAIN 2 or worse and especially vaginal cancers are infrequent.

Do HIV-Positive Women with Prior Hysterectomies Require Pap Testing?

Immunocompetent women who have undergone hysterectomies for benign disease can forgo further Pap testing. Whether this practice can be extended to women with human immunodeficiency virus (HIV) infection was investigated among women with prior hysterectomies enrolled in the Women's Interagency HIV Study and followed for a …

Risk Factors for Oral HPV Infection among a High Prevalence Population of HIV-Positive and At-Risk HIV-Negative Adults

Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals. This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis. Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6-2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each P(trend) < 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (P(trend) < 0.001) and higher number of lifetime sexual partners (P(trend) = 0.03) were strong risk factors. Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV. Immunosuppression may contribute to increased persistence or progression of oral HPV infection.

Atazanavir Concentration in Hair Is the Strongest Predictor of Outcomes on Antiretroviral Therapy

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. 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). 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]). 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.

T Cell Activation and Senescence Predict Subclinical Carotid Artery Disease in HIV-Infected Women

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

Immune Dysregulation and Vascular Risk in HIV-Infected Patients: Implications for Clinical Care

Epidemiological data from a number of cohorts suggest increased cardiovascular disease rates among human immunodeficiency virus (HIV)–infected, compared with non-HIV-infected, patients [1, 2]. Consistent with these observations, recent data from carefully conducted studies suggest increased atherosclerotic indices, including increased carotid intima-media thickness (IMT) [3] and coronary atherosclerotic plaque burden in HIV-infected patients [4]. Elevated rates of traditional cardiovascular disease (CVD) risk factors contribute to increased risk, and individual antiretroviral medications are likely to play a role [5]. In addition, emerging evidence suggests that HIVrelated inflammatory and immunologic factors also contribute substantially to cardiovascular disease among HIVinfected patients. Interest in inflammatory and immune-mediated mechanisms for HIV-related CVD was fueled, in part, by an unanticipated result from the SMART study, which randomized patients to a viral suppression or a drug conservation group, with treatment interruption occurring at prespecified CD4 cell counts [6]. The hypothesis of SMART was that drug conservation would minimize the toxicity of antiretroviral therapy (ART) and reduce cardiovascular and other secondary events. In contrast to the hypothesized result, the study showed increased CVD rates in the drug conservation group compared with the viral suppression group [6, 7]. These data suggest the intriguing possibility that more consistent and prolonged ART is associated with less cardiovascular disease, suggesting a benefit of treatment that outweighs cumulative toxicity. Subsequent analyses demonstrated elevated rates of several inflammatory markers in the drug conservation/treatment interruption group [8], and further investigations have revealed associations between elevated inflammatory markers and all-cause mortality in patients with HIV infection [8, 9]. More recently, several cohort studies have shown a lower CD4 cell count to be associated with increased rates of surrogate markers of atherosclerosis or of CVD event rates [10–13], adjusting for traditional CVD risk factors. Of note, recent studies have also suggested that CVD risk remains elevated for virologically suppressed HIVinfected patients. A study evaluating carotid IMT (cIMT) found that HIV controllers—patients with plasma HIV RNA levels of ,75 copies/mL in the absence of ART—had higher cIMT, a marker of preclinical atherosclerosis, compared with HIV-negative patients. These findings suggest that factors intrinsic to controlled HIV infection or its accompanying low-level viremia may confer increased CVD risk [14]. Kaplan et al [15] offer further insight into factors that might drive this increased CVD risk in this issue of the Journal. Using data from the Women’s Interagency HIV Study (WIHS), the study investigates whether CD4 and CD8 T cell activation (defined by coexpression of CD38 and HLA-DR) and senescence (defined by absence of CD28 and presence of CD57) are associated with subclinical carotid artery disease among HIV-infected patients. As anticipated, HIV-infected women exhibited a significantly higher frequency of activated CD4 and CD8 T cells and of immunosenescent CD8 T cells, compared with HIV-negative women; there was also a trend toward increased levels of immunosenescent CD4 T cells. Of note, levels of immune activation and senescence were higher comparing treated and virologically suppressed Received 8 October 2010; accepted 8 November 2010. Potential conflicts of interest: S.K.G. has received research funding from Theratechnologies and Bristol-Myers Squibb and has served as consultant for Theratechnologies and EMDSerono. Reprints or correspondence: Dr Steven K. Grinspoon, Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit St, Longfellow 207, Boston, MA 02114 (sgrinspoon@partners.org). The Journal of Infectious Diseases 2011;1–3 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals .permissions@oup.com 1537-6613/2011/00-0001$15.00 DOI: 10.1093/infdis/jiq084

A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women

Previous studies of the association of the C17T polymorphism of the mu opiate receptor gene with substance dependence compared cases with substance dependence to controls and usually found no significant association. However, the studies were limited by small sample size-no study had more than 12 subjects with the TT genotype, a genotype that is rare in white and Asian subjects. Moreover, drug use is not dichotomous but follows a spectrum from non-use to modest, intermittent use, to use several times daily. We asked whether the Kreek-McHugh-Schluger-Kellogg (KMSK) scales for alcohol, cocaine, opiates and tobacco that quantify substance use during the time of a subject's maximal use might be more sensitive measures than dichotomous outcomes. We administered the KMSK scales and completed C17T genotyping on 1009 human immunodeficiency virus (HIV)-infected and 469 HIV-uninfected women in The Women's Interagency HIV Study, an ongoing study of HIV in women. Forty-two of the 697 African American, 1 of the 182 Hispanic and none of the 161 white women had the TT genotype. KMSK cocaine, alcohol and tobacco scores were significantly higher in the African American women with the TT genotype (P = 0.008, 0.0001, and 0.006, respectively), but opiate scores were not. Ordinal regression models controlling for HIV serostatus, age, education, and income had odds ratios for the TT genotype for predicting alcohol, tobacco, cocaine and opiates scores of 2.1 (P = 0.02), 2.4 (P = 0.0004), 2.0 (P = 0.03) and 1.9 (P = 0.07). We conclude that the TT genotype of OPRM1 may increase the risk of substance use and abuse.

Relationship between complementary/alternative treatment use and illicit drug use among a cohort of women with, or at risk for, HIV infection.

Two of the most pressing public health challenges in the United States are treating human immunodeficiency virus (HIV) infection and illegal substance use. High rates of complementary and alternative medicine (CAM) use have been reported by individuals who suffer from both of these diseases. The goal of this study was to examine the relationship between CAM use and illegal substance use in a cohort of women with HIV or at risk for HIV disease. Based on previous research, it was hypothesized that CAM use may decrease substance use. This was a longitudinal cohort study. The subjects comprised Women in the Women's Interagency HIV Study. The role of CAM use in illegal substance use was examined. Due to the hierarchical structure of the dataset, logistic regression analysis adjusting for repeated measurements (generalized estimating equation model) was carried out to assess associations of CAM use and illicit drug use. There were 2176 women included in the analysis. After excluding for marijuana use, CAM use was associated with less drug use (odds ratio 0.82; 95% confidence interval: 0.73, 0.90). The results supported our hypothesis that CAM users are more health conscious and thus less likely to use illicit drugs. Future studies should target both specific drugs and CAM modalities to help finalize this association.