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Respiratory dysfunction is common with HIV infection, but few studies have directly assessed whether HIV remains an independent risk factor for pulmonary function abnormalities in the antiretroviral therapy era. Additionally, few studies have focused on pulmonary outcomes in HIV+ women. We tested associations between risk factors for respiratory dysfunction and pulmonary outcomes in 63 HIV+ and 36 HIV-uninfected women enrolled in the Women's Interagency HIV Study. Diffusing capacity (DLCO) was significantly lower in HIV+ women (65.5% predicted vs. 72.7% predicted, P = 0.01), and self-reported dyspnea in HIV+ participants was associated with both DLCOimpairment and airflow obstruction. Providers should be aware that DLCOimpairment is common in HIV infection, and that either DLCOimpairment or airflow obstruction may cause respiratory symptoms in this population. Copyright © 2013 by Lippincott Williams & Wilkins.

Summary Objective African potato ( Hypoxis obtusa) is commonly used in Sub-Saharan Africa as a complementary herbal remedy for HIV-infected patients. It is unknown whether or not co-administration of African potato alters the pharmacokinetics of protease inhibitor antiretrovirals. The objective of this study was to investigate the impact of the African potato on the steady-state pharmacokinetics of ritonavir-boosted lopinavir (LPV/r). Methods Sixteen adult volunteers were administered LPV/r 400/100mg twice a day for 14 days, followed by concomitant administration with African potato given once daily for 7 days. Lopinavir plasma exposure as estimated by the area under the concentration–time curve over the 12-h dosing interval (AUC 0–12h , AUCτ) was determined on day 14 and again on day 21. Lopinavir in plasma was analyzed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Steady-state AUCτ and the maximum concentration following dose administration (C max ) were determined using non-compartmental methods using WinNonlin Professional version 5.2.1. Statistical analyses were performed using Stata version 12.1. Results Co-administration of African potato was not associated with any change in lopinavir AUCτ, C max , or C trough . Conclusions African potato when taken concomitantly with LPV/r is well-tolerated and not associated with clinically significant changes in lopinavir pharmacokinetics.

HIV-infected women may experience prolonged amenorrhea, suggesting altered gonadotropin and sex hormone levels. However, the impact of these endocrine disruptions on atherosclerosis has not been evaluated in women living with, or at risk for, HIV infection. We investigated the association of sex hormone and gonadotropin concentrations with subclinical atherosclerosis in HIV-infected and -uninfected premenopausal women in the Women's Interagency HIV Study.Using B-mode ultrasound, the common carotid artery intima-media thickness and distensibility were measured once. Cycle-specific FSH, total estradiol (E2), and inhibin-B concentrations were measured in 584 (414 HIV infected, 170 HIV uninfected) women. Random concentrations of total T, dehydroepiandrosterone sulphate, and SHBG were measured in 1094 (771 HIV infected, 323 HIV uninfected) women. The endocrine analytes were measured at or before the ultrasound visit. Sex hormones, FSH, and SHBG concentrations were compared between HIV-infected and -uninfected women using nonparametric testing. Linear regression models were used to evaluate the association of sex hormones, FSH, and SHBG with carotid artery intima-media thickness and distensibility adjusted for confounders. Separate analyses were conducted by HIV status.Compared with HIV-uninfected women, E2, T, and dehydroepiandrosterone sulphate concentrations were significantly lower and SHBG was higher in HIV-infected women. Adjusted for the confounders, T was significantly positively associated with distensibility (β-estimate = .04, P = .0005) among HIV-infected women, and the magnitude of association did not differ by CD4 cell count. E2 was significantly positively associated with distensibility among HIV-infected women with CD4 count less than 350 cells/μL.HIV-infected women had reduced estrogen and androgen compared with HIV-uninfected premenopausal women. T deficiency is linked with carotid artery stiffness, regardless of immune suppression, whereas E2 deficiency is linked with carotid stiffness among immunocompromised HIV-infected premenopausal women. Further research is warranted to understand the impact of endocrine dysregulation on the accelerated cardiovascular disease risk in HIV-infected women.

Correlates of bacterial vaginosis (BV) are poorly understood, especially in HIV infection. In a cohort study, HIV-seropositive and comparison seronegative women were assessed every 6 months during 1994–2015. BV was considered present when three of four Amsel criteria were met. Behavioral characteristics were assessed using structured interviews. Multivariable logistic regression used generalized estimating equation models to determine factors associated with BV. Cumulative incidence of BV over time was assessed using the log-rank test. Among 3,730 women (964 HIV seronegative and 2,766 HIV seropositive) contributing 70,970 visits, BV was diagnosed at 2,586 (14.0%) visits by HIV-seronegative women and 6,224 (11.9%) visits by HIV-seropositive women (p

A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4+ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4+ T cells, and individually SDF-1β, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1β, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4+ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies.

Background While 16S ribosomal RNA (rRNA) sequencing has been used to characterize the lung’s bacterial microbiota in human immunodeficiency virus (HIV)-infected individuals, taxonomic studies provide limited information on bacterial function and impact on the host. Metabolic profiles can provide functional information on host-microbe interactions in the lungs. We investigated the relationship between the respiratory microbiota and metabolic profiles in the bronchoalveolar lavage fluid of HIV-infected and HIV-uninfected outpatients. Results Targeted sequencing of the 16S rRNA gene was used to analyze the bacterial community structure and liquid chromatography-high-resolution mass spectrometry was used to detect features in bronchoalveolar lavage fluid. Global integration of all metabolic features with microbial species was done using sparse partial least squares regression. Thirty-nine HIV-infected subjects and 20 HIV-uninfected controls without acute respiratory symptoms were enrolled. Twelve mass-to-charge ratio (m/z) features from C18 analysis were significantly different between HIV-infected individuals and controls (false discovery rate (FDR) = 0.2); another 79 features were identified by network analysis. Further metabolite analysis demonstrated that four features were significantly overrepresented in the bronchoalveolar lavage (BAL) fluid of HIV-infected individuals compared to HIV-uninfected, including cystine, two complex carbohydrates, and 3,5-dibromo-l-tyrosine. There were 231 m/z features significantly associated with peripheral blood CD4 cell counts identified using sparse partial least squares regression (sPLS) at a variable importance on projection (VIP) threshold of 2. Twenty-five percent of these 91 m/z features were associated with various microbial species. Bacteria from families Caulobacteraceae, Staphylococcaceae, Nocardioidaceae, and genus Streptococcus were associated with the greatest number of features. Glycerophospholipid and lineolate pathways correlated with these bacteria. Conclusions In bronchoalveolar lavage fluid, specific metabolic profiles correlated with bacterial organisms known to play a role in the pathogenesis of pneumonia in HIV-infected individuals. These findings suggest that microbial communities and their interactions with the host may have functional metabolic impact in the lung. Electronic supplementary material The online version of this article (doi:10.1186/s40168-016-0147-4) contains supplementary material, which is available to authorized users.

BACKGROUND Despite the major benefits of effective antiretroviral therapy on HIV-related survival, there is an ongoing need to help alleviate medication side effects related to antiretroviral therapy use. Initial studies suggest that marijuana use may reduce HIV-related symptoms, but medical marijuana use among HIV-infected individuals has not been well described. METHODS The authors evaluated trends in marijuana use and reported motivations for use among 2776 HIV-infected women in the Women's Interagency HIV Study between October 1994 and March 2010. Predictors of any and daily marijuana use were explored in multivariate logistic regression models clustered by person using generalized estimating equation. In 2009, participants were asked if their marijuana use was medical, "meaning prescribed by a doctor," or recreational, or both. RESULTS Over the 16 years of this study, the prevalence of current marijuana use decreased significantly from 21% to 14%. In contrast, daily marijuana use almost doubled from 3.3% to 6.1% of all women and from 18% to 51% of current marijuana users. Relaxation, appetite improvement, reduction of HIV-related symptoms, and social use were reported as common reasons for marijuana use. In 2009, most marijuana users reported either purely medicinal use (26%) or both medicinal and recreational usage (29%). Daily marijuana use was associated with higher CD4 cell count, quality of life, and older age. Demographic characteristics and risk behaviors were associated with current marijuana use overall but were not predictors of daily use. CONCLUSIONS This study suggests that both recreational and medicinal marijuana use are relatively common among HIV-infected women in the United States.

Loss of CD4 T lymphocytes is central to the pathogenesis of HIV infection. Without intervention, helper T-cell function declines, followed by broad alterations in immune responses. HIV replication is efficiently controlled in most subjects by use of highly active antiretroviral therapy (HAART), which frequently results in undetectable HIV RNA and recovery of CD4 T-cell counts. However, a substantial proportion of treated subjects appear to have a higher risk for non–AIDS-defining illnesses and a life span that is estimated to be 10 years shorter, compared with HIV-negative populations [1–5]. Low CD4 T-cell counts during HAART are associated with increased risk of cancer, liver disease, and cardiovascular disease [6–8]. Persistent activation of CD4 and CD8 T cells, detected by expression of CD38 and HLA-DR, appears to be associated with limited recovery of CD4 T-cell counts [9]; current hypotheses suggest that disease progression may be more closely associated with immune activation levels than with HIV replication levels [10–12]. The trend for a higher risk of non–AIDS-related illnesses has also been observed among participants in the Women's Interagency HIV Study (WIHS), even in the presence of virologic control and initial recovery of CD4 T-cell counts [13–16]. Interleukin 10 (IL-10) is a type II cytokine initially characterized as an inhibitor of helper T-cell subtype 1 cytokines [17]. A major immunoregulatory effect of IL-10 is inhibition of antigen presentation, acting primarily on dendritic cells and monocytes [18, 19]. IL-10 may also decrease apoptosis of B and T lymphocytes [20–22]. As a consequence, several clinical studies have investigated treatment with recombinant IL-10 for subjects with inflammatory conditions such as psoriasis, Crohn disease, or rheumatoid arthritis [23]. Toll-like receptors (TLRs) are critical components of innate immunity and play a key role in pathogen defense [24]. TLR3, the receptor for double-stranded RNA, and TLR4, the receptor for bacterial lipopolysaccharide (LPS), have recognized roles in antiviral and antibacterial immunity [25, 26]. Bacterial products leaking from the intestinal mucosa [27] and residual HIV replication [28] may contribute to chronic inflammation in treated HIV infection. We investigated the ex vivo capacity of peripheral blood mononuclear cells (PBMCs) from HIV-infected women to respond to TLR3 and TLR4 ligands, representing innate responses to pathogens of intracellular or extracellular origin, respectively. Dysregulated inflammatory cytokine responses in HIV-infected women have been reported in the WIHS [29, 30]. We observed that spontaneous release of inflammatory cytokines in vitro was demonstrable in >60% of HIV-infected women but that responses to TLR3 and TLR4 stimulation were reduced in women with HIV/hepatitis C virus (HCV) coinfection, compared with women with HIV monoinfection [29]. In contrast, IL-10 responses to TLR4 stimulation were enhanced in women with HIV monoinfection, compared with women with HIV/HCV coinfection or noninfected controls. High production of IL-10 in untreated HIV infection has been considered detrimental for virus control because of IL-10 inhibition of the antiviral activity of helper T-cell subtype 1 cytokines [31]. However, the implications of altered cytokine responses, including IL-10 production, in HAART recipients are incompletely understood. The aim of this analysis was to investigate the possible influence of cytokines produced by cells of the innate immune compartment on levels of CD4 T cells over time in treated HIV infection.

Cervicovaginal HIV level (CV-VL) influences HIV transmission. Plasma viral load (PVL) correlates with CV-VL, but discordance is frequent. We evaluated how PVL, behavioral, immunological, and local factors/conditions individually and collectively correlate with CV-VL.CV-VL was measured in the cervicovaginal lavage fluid (CVL) of 481 HIV-infected women over 976 person-visits in a longitudinal cohort study. We correlated identified factors with CV-VL at individual person-visits and detectable/undetectable PVL strata by univariate and multivariate linear regression and with shedding pattern (never, intermittent, persistent ≥3 shedding visits) in 136 women with ≥3 visits by ordinal logistic regression.Of 959 person-visits, 450 (46.9%) with available PVL were discordant, 435 (45.3%) had detectable PVL with undetectable CV-VL, and 15 (1.6%) had undetectable PVL with detectable CV-VL. Lower CV-VL correlated with highly active antiretroviral therapy (HAART) usage (P = 0.01). Higher CV-VL correlated with higher PVL (P0.001), inflammation-associated cellular changes (P = 0.03), cervical ectopy (P = 0.009), exudate (P = 0.005), and trichomoniasis (P = 0.03). In multivariate analysis of the PVL-detectable stratum, increased CV-VL correlated with the same factors and friability (P = 0.05), while with undetectable PVL, decreased CV-VL correlated with HAART use (P = 0.04). In longitudinal analysis, never (40.4%) and intermittent (44.9%) shedding were most frequent. Higher frequency shedders were more likely to have higher initial PVL [odds ratio (OR) = 2.47/log10 increase], herpes simplex virus type 2 seropositivity (OR = 3.21), and alcohol use (OR = 2.20).Although PVL correlates strongly with CV-VL, discordance is frequent. When PVL is detectable, cervicovaginal inflammatory conditions correlate with increased shedding. However, genital shedding is sporadic and not reliably predicted by associated factors. HAART, by reducing PVL, is the most reliable means of reducing cervicovaginal shedding.

OBJECTIVE To estimate the prevalence, incidence, and clearance of abnormal vaginal cytology and vaginal intraepithelial neoplasia (VAIN) 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. End points included abnormal Pap test results after hysterectomy and VAIN regardless of hysterectomy. RESULTS 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

During the last decade, the enormous impact the global HIV epidemic was having on women’s health was fully recognized. However, this recognition has not wholly extended to the domestic setting; in much of the United States, the dominant focus remains on HIV infection among men who have sex with men. The relatively low prevalence of HIV infection among U.S. women (a huge population group) versus men who have sex with men and injection drug users (much smaller groups) contributes to the perception that HIV is not a major domestic women’s health consideration.

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.

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 noncontrollers, and HIV-uninfected (NEG).Multiplex assays were used to measure 32 cytokines in a cross-sectional study of participants in the Women's Interagency HIV Study. Participants from three groups were included: HAART (n = 17), noncontrollers (n = 14), and HIV NEG (n = 17).Several cytokines and chemokines showed significant differences between noncontrollers and NEG participants, including elevated interferon gamma-induced 10 (IP-10) and tumor necrosis factor-α (TNF-α) and decreased interleukin-12(p40) [IL-12(p40)], IL-15, and fibroblast growth factor-2 (FGF-2) in noncontroller 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 noncontroller groups revealed that IP-10 showed a strong, positive correlation with viral load and negative correlation with CD4(+) T-cell counts. The growth factors vascular endothelial growth factor, epidermal growth factor, and FGF-2 all showed a positive correlation with increased CD4(+) T-cell counts.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 three study groups may provide insights into HIV pathogenesis, and responses to therapy.

United States HIV guidelines delineate preferred antiretroviral treatment (ART) and discourage use of sub-potent, 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 January 2001, to 31 December 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 > 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.

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 (b 52 .4; 95% confidence interval [CI], 2.6 to 2.3; P , .00001), as well as with low odds of FIB-4‐defined (odds ratio [OR], .5; 95% CI, .2‐.9; P 5 .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3‐1.0; P 5 .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 5 .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. The natural history of hepatitis C virus (HCV) infection is highly variable. Approximately 20%‐30% of individuals clear HCV spontaneously after acute infection, and only a subset of those with persistent HCV infection

We identified demographic, clinical and biological determinants of herpes simplex virus type 2 (HSV-2) shedding among HIV-infected participants in the Women's HIV Interagency Study (WIHS). Cervicovaginal lavage (CVL) specimens from 369 HIV-infected HSV seropositive women were tested with TaqMan polymerase chain reaction (PRC) for detection HSV-2 DNA. Seven percent of women tested positive for HSV-2 DNA in CVL. Significant correlates of the presence of HSV-2 DNA in CVL were being younger, African American or Hispanic race/ethnicity and injecting drugs in the past six months ( P < 0.05). A borderline significant trend for reduced viral shedding with higher CD4+ T cell counts was observed ( P = 0.08). All women who were never observed with any genital lesions and had consistently negative self-reported history of genital sores throughout the follow-up ( n = 29, 8%) were negative for CVL HSV-2 DNA. HSV-2 DNA quantity was significantly associated with having frequent subsequent lesion recurrences (Spearman rho = 0.48, P = 0.016; adjusted prevalence ratio [APR] = 2.5, P = 0.012). Increasing the age of the host was inversely correlated with decreased viral shedding over time. However, a subset of older women continued to shed significant amounts of virus despite passage of time. This study provides genital HSV-2 DNA titre as a quantitative and symptom- and sign-based measures as qualitative predictors of HSV-2 shedding from the lower genital tract among HIV-infected women.

Objective: Transient HIV infections have been invoked to account for the cellular immune responses detected in highly virus-exposed individuals who have remained HIV-seronegative. We tested for very low levels of HIV RNA in 524 seronegative plasma samples from 311 highly exposed women and men from three longitudinal HIV cohorts. Design: Two thousand and seventy-three transcription-mediated amplification (TMA) HIV RNA tests were performed for an average of 3.95 TMA assays per plasma sample. Quadruplicate TMA assays, analyzing a total of 2 ml of plasma, provided an estimated sensitivity of 3.5 HIV RNA copies/ml. Results: Four samples from individuals who did not seroconvert within the following 6 months were positive for HIV RNA. For one sample, human polymorphism DNA analysis indicated a sample mix-up. Borderline HIV RNA detection signals were detected for the other three positive samples but further replicate TMA testing yielded no positive results. Nested PCR assays (n = 254) for HIV proviral DNA in peripheral blood mononuclear cells (PBMCs) from these three individuals were negative. Conclusion: Transient viremia was not reproducibly detected in highly HIV-exposed seronegative men and women. If transient infections do occur, plasma HIV RNA levels may remain below the detection limits of the sensitive assay used here, be of very short duration, or viral replication may be restricted to mucosal surfaces or their draining lymphoid tissues.

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.

Background: Community pharmacies play a key role in the care of patients when dispensing antiretroviral therapy. Objective: To determine factors associated with the use of multiple dispensing pharmacies to obtain medications in a population of HIV-positive and at-risk women and to determine whether use of multiple pharmacies was associated with immunologic or virologic changes for the subset of HIV-positive women. Methods: A survey on community pharmacy use was distributed to participants in the Women's Interagency HIV Study, San Francisco site, from 2004–2007. Poisson, linear, and logistic regression methods were used to determine associations between specific patient characteristics and use of multiple dispensing pharmacies and associations between multiple pharmacy use and CD4+ cell count or viral load changes. Results: There was a trend toward an association between HIV status and use of multiple pharmacies (IRR 1.23; 95% CI 1.00 to 1.51; p = 0.05). In multivariable analyses of HIV-positive women, use of additional pharmacies (over the primary pharmacy) during the study period was not associated with statistically significant changes in CD4+ count or viral load. Conclusions: HIV-positive participants may tend to use multiple pharmacies more frequently than their HIV-negative counterparts do, though this practice does not appear to be associated with poorer immunologic or virologic outcomes. Further studies should be conducted to determine whether different patient patterns of community pharmacy use affect HIV treatment outcomes.

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.

HIV-associated immune injury is hypothesized to increase the risk of preclinical disability and frailty via inflammatory pathways. We investigated the role of CD4+ T cell depletion and clinical AIDS on preclinical disability and frailty in HIV-positive women with a history of combination antiretroviral therapy (cART) and HIV-negative women.This was a cross-sectional study nested within the Women's Interagency HIV Study (WIHS), a prospective cohort study initiated in 1994 across five U.S. cities. Questionnaires and tests were performed by 573 HIV-negative and 1206 HIV-positive women. Prevalence ratios were computed using regression models.Severe CD4+ cell depletion was an independent predictor of slowness, weakness, and frailty in HIV-positive women compared with HIV-negative women. Women with CD4+ counts100 cells/mm3 were 0.13 seconds slower to complete 4 meters (95% CI 0.06-0.21), 1.25 kg weaker (95% CI -2.31--0.19), and had 2.7 times higher prevalence of frailty (95% CI 1.46-5.01).This study is one of the largest studies to administer performance-based tests to investigate disability and frailty in HIV-positive women. HIV-positive women with intact immune systems and without a history of clinical AIDS were no different from HIV-negative women on tests of slowness, weakness, and frailty phenotype.

Objective To compare serum mullerian inhibiting substance (MIS) levels between white, black, and Hispanic women to determine whether 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 and 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 and ethnicity at two time points (median age 37.5 years and 43.3 years). Main Outcome Measure(s) Variation in MIS by race and ethnicity over time, controlling for age, body mass index, HIV status, and smoking. Result(s) Compared with white women, average MIS values were lower among black (25.2% lower) and Hispanic (24.6% lower) women, adjusting for age, body mass index, smoking, and HIV status. Conclusion(s) There is an independent effect of race and ethnicity on the age-related decline in MIS over time.

Background: Small intensive pharmacokinetic (PK) studies of medications in early-phase trials cannot identify the range of factors that influence drug exposure in heterogenous populations. We performed PK studies in large numbers of HIV-infected women on nonnucleoside reverse transcriptase inhibitors (NNRTIs) under conditions of actual use to assess patient characteristics that influence exposure and evaluated the relationship between exposure and response. Methods: Two hundred twenty-five women on NNRTI-based antiretroviral regimens from the Women's Interagency HIV Study were enrolled into 12-hour or 24-hour PK studies. Extensive demographic, laboratory, and medication covariate data were collected before and during the visit to be used in multivariate models. Total NNRTI drug exposure was estimated by area under the concentration-time curves. Results: Hepatic inflammation and renal insufficiency were independently associated with increased nevirapine exposure in multivariate analyses; crack cocaine, high fat diets, and amenorrhea were associated with decreased levels (n = 106). Higher efavirenz exposure was seen with increased transaminase, albumin levels, and orange juice consumption; tenofovir use, increased weight, being African American, and amenorrhea were associated with decreased exposure (n = 119). With every 10-fold increase in nevirapine or efavirenz exposure, participants were 3.3 and 3.6 times as likely to exhibit virologic suppression, respectively. Patients with higher drug exposure were also more likely to report side effects on therapy. Conclusions: Our study identifies and quantitates previously unrecognized factors modifying NNRTI exposure in the "real-world" setting. Comprehensive PK studies in representative populations are feasible and may ultimatley lead to dose optimization strategies in patients at risk for failure or adverse events.

To study anal intraepithelial neoplasia and its associations with anal and cervical human papillomavirus (HPV), cervical neoplasia, host immune status, and demographic and behavioral risk factors in women with and at risk for HIV infection.Point-prevalence analysis nested within a prospective study of women seen at three clinical centers of the Women's Interagency HIV Study.In 2001-2003 participants were interviewed, received a gynecological examination, anal and cervical cytology testing and, if abnormal, colposcopy-guided or anoscopy-guided biopsy of visible lesions. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV probing. Logistic regression analyses were performed, and odds ratios (ORs) estimated risks for anal intraepithelial neoplasia.Four hundred and seventy HIV-infected and 185 HIV-uninfected women were enrolled. Low-grade anal intraepithelial neoplasia was present in 12% of HIV-infected and 5% of HIV-uninfected women. High-grade anal intraepithelial neoplasia was present in 9% of HIV-infected and 1% of HIV-uninfected women. In adjusted analyses among HIV-infected women, the risk factors for low-grade anal intraepithelial neoplasia were younger age [OR = 0.59, 95% confidence interval (CI) = 0.36-0.97], history of receptive anal intercourse (OR = 3.2, 95% CI = 1.5-6.8), anal HPV (oncogenic types only OR = 11, 95% CI = 1.2-103; oncogenic and nononcogenic types OR = 11, 95% CI = 1.3-96), and cervical HPV (oncogenic and nononcogenic types OR = 3.5, 95% CI = 1.1-11). In multivariable analyses among HIV-infected women, the only significant risk factor for high-grade anal intraepithelial neoplasia was anal HPV infection (oncogenic and nononcogenic types OR = 7.6, 95% CI = 1.5-38).Even in the era of highly active antiviral therapy, the prevalence of anal intraepithelial neoplasia was 16% in HIV-infected women. After controlling for potential confounders, several risk factors for low-grade anal intraepithelial neoplasia differed from risk factors for high-grade anal intraepithelial neoplasia.

Background: HIV treatment guidelines define optimal initial antiretroviral therapy (ART). Objective: To characterize initial ART used by a cohort of HIV-infected women according to US HIV treatment guidelines and determine whether regimen characteristics predict short-term outcomes. Methods: Initial ART self-reported by Women's Interagency HIV Study (WIHS) participants. Regimens were classified as guideline consistent (GC), guideline not recommended (GNR), or unlisted. Univariate and multivariate logistic regression was used to analyze factors associated with guideline category. Results: Two hundred seventeen WIHS participants initiated ART during the study period. Fifty-three percent reported use of GC ART, 17% reported GNR ART, and 30% reported ART unlisted in guidelines. Study site, higher pretreatment CD4 cell count, lower HIV RNA level, and initiation before 2001 were associated with use of GNR regimens. GC ART users had a higher rise in CD4 cell counts and more frequent undetectable HIV-1 RNA levels 2 years after initiation compared with those GNR (P = 0.0003) or unlisted initial ART. Conclusions: A higher than expected proportion of WIHS participants reported using initial ART not recommended by HIV treatment guidelines, although this decreased over time. Use of such regimens was associated with a higher incidence of switching and poorer short-term immunologic and virologic outcomes.

Purpose: Mentoring is critical to develop and nurture early career investigators, helping them to succeed in building networks of colleagues, and is especially important for investigators focused on HIV research. We piloted a multidiscipline mentoring program targeting postdoctoral scholars and early career faculty concentrating on HIV/ AIDS research. Method: The pilot mentoring program was conducted at the Center for AIDS Research (CFAR) at the University of California San Francisco and the Gladstone Institute of Virology and Immunology. Mentees were self-referred postdoctoral scholars and early career faculty. Mentors were drawn from the senior faculty. Early career mentees were matched with senior investigators for individual meetings, a monthly workshop on topics directed by the mentees, and single-day mentoring seminars. Results: More than 30 mentees and 20 mentors have participated in the pilot project. Most mentees reported that the 1-on-1 mentoring was a satisfying experience. The most highly valued activities were those that facilitated networking among mentees, networking between mentors and mentees, and workshops that focused on grant applications and first academic appointments and promotions. Conclusions: A multidisciplinary mentoring program for postdoctoral scholars and early career faculty focused on HIV/AIDS research is valuable. Umbrella organizations, such as the CFAR, are well suited to create and provide highly valued mentoring experiences.

Objective To compare Mullerian inhibiting substance (MIS) levels in serum obtained during the early follicular phase to those obtained randomly during the menstrual cycle. To determine whether HIV infection influences early follicular MIS levels, an early marker of ovarian aging. Design A cross-sectional study. Setting Women's Interagency HIV Study, a multicenter prospective study. Patient(s) Serum samples obtained from 263 (187 HIV infected and 76 uninfected) participants of the Women's Interagency HIV Study who reported menstrual bleeding during the preceding 6 months and who were not taking exogenous hormones. Intervention(s) Early follicular (cycle days 2–5) MIS samples were compared with serum samples that had been obtained without regard to menstrual cycle phase. Comparison samples were obtained within 6 weeks before or within 3 to 6 months after the early follicular samples. Early follicular FSH, E 2 , inhibin B, and MIS levels were also compared between the HIV infected and uninfected women. Main Outcome Measure(s) Correlation between early follicular MIS and prior and subsequent samples. Comparison of serum markers of ovarian reserve between HIV positive and negative women. Result(s) The MIS values from early follicular and other random cycle phases were highly correlated with each other ( r > 0.93). In multivariate analysis, increased age and FSH level and lower inhibin B levels were associated with lower MIS level; MIS values did not vary by HIV serostatus. Conclusion(s) Without regard to cycle phase, MIS was similar during early follicular phase and highly correlated with early follicular FSH and inhibin B in women with and without HIV. Measurement of serum MIS offers a simplified method of determining ovarian reserve using specimens obtained without menstrual phase timing. Furthermore, using biologic measures of reproductive aging, we found no evidence that HIV infection influences ovarian aging.

Among women with low or undetectable quantities of HIV-1 RNA in plasma, factors associated with genital HIV-1 RNA shedding, including choice of treatment regimen, are poorly characterized.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 levels500 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.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).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.

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.

Human immunodeficiency virus (HIV) infectivity increases as receptor/coreceptor expression levels increase. We determined peripheral CD4, CCR5, and CXCR4 expression levels in HIV-uninfected women who used depot medroxyprogesterone acetate (DMPA; n = 32), the levonorgestrel-releasing intrauterine device (LNG-IUD; n = 27), oral contraceptive pills (n = 32), or no hormonal contraception (n = 33). The use of LNG-IUD increased the proportion of CD4(+) and CD8(+) T cells that expressed CCR5; increases in the magnitude of T-cell subset CCR5 expression were observed with DMPA and LNG-IUD use (P < .01 for all comparisons). LNG-IUD and, to a lesser extent, DMPA use were associated with increased peripheral T-cell CCR5 expression.

Background: We measured antibody-dependent cell mediated cytotoxicity (ADCC) activity in serum and genital fluids of heterosexually exposed women during HIV seroconversion. Methods: Plasma and cervico-vaginal lavage (CVL) fluid from 11 seroconverters (SC) were analyzed biannually from one year pre- to 6 year post-seroconversion using a 51Cr-release assay to measure HIV-1 gp120 specific ADCC. Results: No SC had significant HIV specific CVL ADCC activity before seroconversion or until 1.5 yr after seroconversion. One individual had a %Specific Release (SR) of 25.4 at 2 years, 26.7 at 3 years and 21.0 at 4 years after seroconversion in CVL. Another sample had 4.7% SR at 2 years, 5.3 at 3 years, 10.9 at 4 years, and 8.4 at 5 years after seroconversion in CVL. A third had no activity until 17% SR 5 years after seroconversion in CVL. A fourth showed activity of 36.5% SR at 6.5 years after seroconversion. Seven women had no ADCC activity in their CVL. Paired serum samples showed HIV specific ADCC activity prior to the appearance of CVL ADCC activity. Conclusions: HIV specific ADCC activity in CVL rose 2 years after seroconversion; ADCC was present in the serum prior to this time. These data suggest that genital tract ADCC activity is not present until well after acute infection.

© 2014 The Author(s). Epidemiological studies indicate that progestin-containing contraceptives increase susceptibility to HIV, although the underlying mechanisms involving the upper female reproductive tract are undefined. To determine the effects of depot medroxyprogesterone acetate (DMPA) and the levonorgestrel intrauterine system (LNG-IUS) on gene expression and physiology of human endometrial and cervical transformation zone (TZ), microarray analyses were performed on whole tissue biopsies. In endometrium, activated pathways included leukocyte chemotaxis, attachment, and inflammation in DMPA and LNG-IUS users, and individual genes included pattern recognition receptors, complement components, and other immune mediators. In cervical TZ, progestin treatment altered expression of tissue remodeling and viability but not immune function genes. Together, these results indicate that progestins influence expression of immune-related genes in endometrium relevant to local recruitment of HIV target cells with potential to increase susceptibility and underscore the importance of the upper reproductive tract when assessing the safety of contraceptive products.

OBJECTIVE To define the incidence of tuberculin skin test (TST) conversion and to evaluate the yield of annual testing in an era of declining tuberculosis incidence rate in the United States. METHODS Annual TSTs were performed on initially TST-negative women (HIV infected, 995; uninfected, 260) from October 1995 through March 2002. RESULTS A total of 4,622 repeat TSTs were performed during 5,530 person-years. The incidence of TST conversion was 0.8 case per 100 person-years for HIV-infected and 1.0 case per 100 person-years for uninfected women. Non-Hispanic blacks, women younger than 40 years of age, and HIV-infected women who had recently initiated active therapy were more likely to experience TST conversion. The incidence of conversion decreased over the course of the study from a peak of 21 cases per 937 tests in 1996 to 1 case per 179 tests in 2002 (P = 0.046 for trend). Twenty-one of 47 conversions occurred on the second TST, implying that boosting accounted for a number of conversions. CONCLUSIONS The yield of annual skin testing diminished from 1996 to 2002. Our data suggest that repeating testing after initiation of HIV therapy, regardless of CD4 cell change, is warranted. If serial testing is undertaken, initial 2-step testing should be performed to allow for accurate interpretation of subsequent tests and earlier identification of persons with latent Mycobacterium tuberculosis infection.

Objective: To determine the prevalence of infection with herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) among women with and at high risk for HIV infection, and to evaluate the effect of HAART on the recurrence of genital lesions. Methods: We evaluated the epidemiology and clinical manifestations associated with HSV-1 and HSV-2 among 1796 HIV-infected and 476 HIV-uninfected women enrolled in a multisite cohort study. Serum antibodies to HSV-1 and HSV-2 at baseline and self-reported history of genital herpes, reports of recent genital sores and presence of genital ulcers on examination, and use of HAART regimen at each study visit were analyzed. Results: Reactivity to HSV-1 only and HSV-2 only was detected in 18% and 20% of HIV-infected, and in 28% and 18% of HIV-uninfected participants respectively; 58% of HIV-infected women and 45% of HIV-uninfected women were seropositive for both HSV types. Reactivity to HSV-2 was associated with increasing age, more male sexual partners, earlier sexual debut, African-American race, Latina ethnicity, less education and lower income. HIV-uninfected women reported significantly fewer genital sores than HIV-infected women who had used HAART for at least 1 year and had optimal CD4 cell gain and viral suppression (adjusted odds ratio (OR), 0.19; 95% confidence interval (Cl), 0.13-0.28). Conclusion: Use of HAART and subsequent immune recovery does not completely eliminate the effect of HIV infection on genital lesions among women with concurrent HSV-2 infection.

Objectives: To describe the prevalence of specific protease inhibitor (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations and the relationship between the presence of these mutations and immunologic outcomes following PI/NNRTI initiation among a cohort of HIV-1-infected women. Methods: Viral genotypic resistance testing was done for 366 women enrolled in the Women's Interagency HIV Study at the visit immediately prior to 1st reported use of PI or NNRTI (baseline) and at the visit approximately 1 year after PI/NNRTI initiation. We modeled the changes in CD4 + T-cell counts and HIV RNA levels approximately 1 year after therapy initiation as a function of baseline and follow-up markers, type of antiretroviral therapy used, and resistance mutations. Results: At baseline, 52% of women showed only nucleoside reverse transcriptase inhibitor (NRTI) mutations, 38% showed no mutations, and 10% showed PI or NNRTI mutations. Only 40% of women showed viral response (HIV-1 RNA ≤ 80 copies/mL) 1 year after initiating a PI or NNRTI. Among those without a viral response, 54% developed PI or NNRTI mutations. NNRTI (among those with baseline NRTI mutations) and PI resistance mutations were associated with better CD4 + cell count changes (mean increase of 118 cells/mm 3 and 64 cells/mm 3 , respectively, as compared with viral nonresponders with no PI or NNRTI mutations). Conclusions: In this population-based cohort, virologic failure with PI or NNRTI resistance was common. Viremia with these resistance mutations was associated with preserved CD4 + T-cell count responses, providing evidence of reduced virulence or viral fitness.

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.

Background The evidence that drug treatment programs are associated with changes in sexual behavior and, thus, have prevention benefits beyond addiction is inconclusive. We examined whether entry into drug treatment was associated with subsequent alterations in sexual behavior among a group of drug-using women. Methods Data were collected semiannually via structured interviews over 8 years. Generalized estimating equations evaluated the relationship between self-reported drug treatment at each visit and sexual abstinence and consistent condom use in the subsequent 6-month period. Results In this sample ( N = 1,658; mean age, 37.3 years; 57.5% African American; 80.3% HIV positive; 49.6% crack/cocaine users), 40% reported being in a variety of drug treatment programs. Those undergoing drug treatment (vs. those not) were less likely to become sexually active (adjusted odds ratio [AOR], 0.83; 95% confidence interval [CI], 0.76–0.91); this association was unchanged when the frequency of attendance and number of different drug treatment programs were evaluated. Drug treatment was not associated with subsequent consistent condom, regardless of frequency of attendance, but involvement in at least three treatment programs was (AOR, 1.40; 95% CI, 1.00–1.97). Conclusions Additional efforts are needed to integrate effective sexual risk reduction programs into drug treatment settings; expanding access to different types of drug treatment modalities may be indicated.

Objective: To characterize changing survival patterns after development of clinical AIDS from 1984 to 2004, when different antiretroviral therapies were being introduced. Design: Cohort of homosexual men since 1984 and cohort of women since 1994. Methods: A total of 1504 men and 461 women were followed for all-cause mortality after an incident AIDS diagnosis. Relative hazards of death and relative times to death were determined in five therapy eras: no/monotherapy (July 1984–December 1989), monotherapy/combination therapy (January 1990–December 1994), HAART introduction (January 1995–June 1998), short-term stable HAART use (July 1998–June 2001), and moderate-term stable HAART use (July 2001–December 2003). Results: A total of 1057 (54%) study participants died. The time at which 25% of individuals died after an AIDS diagnosis increased significantly from 0.56 years [95% confidence interval (CI), 0.50–0.64] in the no/monotherapy era to 0.74 (95% CI, 0.67–0.82), 1.78 (95% CI, 1.29–2.44), 4.22 (95% CI, 2.94–6.05) and 5.08 years (95% CI, 2.39–10.79) in the four subsequent therapy eras, respectively. Inferences on the beneficial effects of HAART were confirmed after adjustment by age, sex, type of AIDS diagnosis and CD4 cell count at diagnosis. The pattern of the hazard of death after AIDS changed from increasing in the pre-HAART era to being lower and non-increasing in the eras of HAART. Conclusions: The sustained beneficial effect of HAART, even in individuals with clinical AIDS and extensive treatment histories, attenuates concerns about emergence of resistance but augurs that a substantial number of HIV-infected individuals may require care for very long periods.

Objectives The authors explored the frequency of dental care utilization and identified the main barriers to access to dental care among U.S. women with HIV infection and uninfected women at high risk of becoming infected. Methods The authors' prospective study included HIV-infected and uninfected women enrolled in the northern California and Chicago sites of the Women's Interagency HIV Study. A trained interviewer administered a standardized questionnaire to participants by phone. The authors explored subjects' utilization of dental care in relation to predisposing, enabling and need variables using both univariate and multivariate analyses. Results The 363 participants were predominantly black and unemployed and had a history of using injected drugs. Not using dental care was most prevalent among HIV-negative women, particularly in Chicago. Multivariate analyses revealed that the strongest predictors of nonuse of dental care included being of a race other than white, fear of dentists and perception of poor or fair oral health. Conclusion Women not infected with HIV but at high risk of developing the infection appear to have even greater unmet dental needs than do HIV-positive women. Being of a race other than white and fear of dentists are strong predictors of not using dental care. Practice Implications The Ryan White Comprehensive AIDS Resources Emergency Act facilitates dental care access for people who are HIV-positive, and is the likely explanation for the higher prevalence of dental care use in this group compared with uninfected women at high risk of becoming infected. This underscores the need for Medicaid to include dental coverage for low-income populations in all states.

We characterized factors and temporal trends associated with discontinuation of highly active antiretroviral therapy (HAART) among 936 HIV-infected women enrolled in the Women's Interagency HIV Study. A multivariate analysis of post-HAART initiation exposures found that high HIV RNA levels (relative hazard [RH] = 1.36, P < 0.001) and high depressive symptom scores (RH = 1.53, P = 0.012) were associated with HAART discontinuation. The adjusted hazard of discontinuation was higher in the 2 most recent calendar periods compared with the first (RH = 1.61, P = 0.026; RH = 1.56, P = 0.074, respectively). The increasing risk of HAART discontinuation in recent calendar periods and changes in the clinical factors associated with discontinuation reflect ongoing and dynamic shifts in the approach to HAART utilization.

Objective To estimate the effect of discontinuing antiretroviral therapy (ART) on survival, among women who initiated highly active antiretroviral therapy (HAART). Design A multicenter cohort study. Methods A total of 951 HAART-initiated women were followed for total mortality between 1995 and 2002. The relative hazard (RH) of death attributable to discontinuing all ART was estimated using an inverse probability of treatment-weighted marginal structural Cox proportional hazards model, as well as standard Cox models. Results Three hundred and forty-three out of 951 women discontinued all ART during the 3187 person-years of follow-up, and 116 died. The RH of death attributable to discontinuation was 1.97 [95% confidence interval (CI) 1.17, 3.31] from the marginal structural Cox model. A RH of 1.49 (95% CI 0.94, 2.35) was observed using the same set of covariates in a standard Cox model. Conclusion An increased risk of mortality for those HAART initiators who discontinued ART was observed using a marginal structural Cox model. This increased risk was independent of measured treatment failure, and was greatly attenuated in a standard Cox model with time-varying covariates.

The importance of reviewing and studying sex-based differences in pharmacologic parameters is demonstrated by the increasing data on gender variation in drug efficacy and toxicity profiles. Sex-based differences in the four major factors that contribute to interindividual pharmacokinetic variability—bioavailability, distribution, metabolism, and elimination—are theorized to stem from variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P450 activity, drug transporter function, and excretion activity. Sex-determined variations in pharmacodynamics have traditionally been more difficult to study, but a number of recent studies have explored these differences. This review examines the biologic basis of differences in pharmacokinetics and pharmacodynamics between the sexes and summarizes studies that have addressed these differences. As an example, sex-based variation in the efficacy and toxicity of antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is explored more thoroughly to illustrate some of the factors underlying sex-based differences in drug therapy.

To estimate the net (i.e., overall) effect of highly active antiretroviral therapy (HAART) on time to acquired immunodeficiency syndrome (AIDS) or death, the authors used inverse probability-of-treatment weighted estimation of a marginal structural model, which can appropriately adjust for time-varying confounders affected by prior treatment or exposure. Human immunodeficiency virus (HIV)-positive men and women (n = 1,498) were followed in two ongoing cohort studies between 1995 and 2002. Sixty-one percent (n = 918) of the participants initiated HAART during 6,763 person-years of follow-up, and 382 developed AIDS or died. Strong confounding by indication for HAART was apparent; the unadjusted hazard ratio for AIDS or death was 0.98. The hazard ratio from a standard time-dependent Cox model that included time-varying CD4 cell count, HIV RNA level, and other time-varying and fixed covariates as regressors was 0.81 (95% confidence interval: 0.61, 1.07). In contrast, the hazard ratio from a marginal structural survival model was 0.54 (robust 95% confidence interval: 0.38, 0.78), suggesting a clinically meaningful net benefit of HAART. Standard Cox analysis failed to detect a clear net benefit, because it does not appropriately adjust for time-dependent covariates, such as HIV RNA level and CD4 cell count, that are simultaneously confounders and intermediate variables.

Human immunodeficiency virus type 1 (HIV-1) currently infects ∼40 million people worldwide [1]. More than 95% of all new cases occur in developing countries, with heterosexual transmission being the predominant route of infection [1]. Rates of HIV-1 infection continue to increase, particularly among nonwhites and women [1]. In sub-Saharan Africa, a region that accounts for 70% of infected individuals globally, women with HIV-1 now outnumber men with HIV-1 [1]. Host differences may contribute to the rapid spread of HIV-1 in some areas of the world; specific genetic traits have been found to influence susceptibility to HIV-1 transmission and disease progression. In addition to CD4, the primary HIV-1 receptor, a functional secondary receptor is required to initiate infection. Human β-chemokine receptors serve this function, with CCR5 serving as coreceptor for macrophage-tropic strains of HIV-1 [2]. A 32-bp deletion (Δ32) in the CCR5 gene renders this receptor nonfunctional, and cells that are homozygous for this mutation are highly resistant to infection by macrophage-tropic strains of HIV-1 [3]. The mutation is most common in white populations, where the frequency of the Δ32 allele ranges from 4% to 16%; ∼20% of whites are heterozygous, and 1% are homozygous for Δ32 [4]. However, this allele is less common among US blacks and Latinas and was absent in Africans and Asian populations studied in anthropological surveys and investigations of non–HIV-related conditions [4]. Investigation of large cohorts of individuals exposed sexually or parenterally to HIV-1 found that the homozygous Δ32 mutation confers a high level of resistance to infection [5–8]. These studies, primarily composed of white men, also found that Δ32 heterozygotes exhibit delayed HIV-1 disease progression but were not protected against transmission [6–8]. However, a more recent study of high-risk HIV-1–seronegative men did demonstrate partial protection against HIV-1 infection in those with the Δ32 heterozygous genotype [9]. Because Δ32 heterozygotes of either sex express a reduced number of CCR5 receptors, compared with individuals with the wild-type genotype, the partial protection and delayed disease progression in heterozygotes may be related to the decreased number of CCR5 receptors and the resulting decreased virus load. Transmission studies involving women showed variable results; 2 studies suggested that the heterozygous state confers partial protection against HIV-1 infection [5, 10], whereas 3 other studies did not [9, 11, 12]. However, all the previous analyses had a suboptimal statistical power for assessing this question, with no more than 630 women in each study. Recently, investigators constructed a mathematical model of the dynamics of HIV-1 transmission in populations with or without the Δ32 mutation. This model predicted that the Δ32 allele would slow the heterosexual spread of the epidemic in populations where the mutation was common [13]. This prediction, coupled with the results from previous cohort studies, points out the importance of studying the role of the Δ32 deletion in HIV-1 transmission in a larger cohort of women. Studies have documented sex-specific differences in HIV-1 transmission, infection, and disease progression [10, 14–18]. Because the routes and mechanisms of HIV-1 infection may differ in significant ways between men and women, we investigated the relationship of CCR5 genotype to the likelihood of HIV-1 infection among women enrolled in the Women's Interagency HIV Study (WIHS), a large study of HIV-1 infection in women conducted in 5 US cities.

HIV infection and associated immunodeficiency are known to alter the course of human papillomavirus (HPV) infections and of associated diseases.This study investigated the association between HIV and HPV and genital warts.HPV testing and physical examinations were performed in two large prospective studies: the Women's Interagency HIV Study (WIHS) and the HIV Epidemiology Research Study (HERS). Statistical methods incorporating dependencies of longitudinal data were used to examine the relationship between HIV and HPV and genital warts.A total of 1008 HIV-seronegative and 2930 HIV-seropositive women were enrolled in the two studies. The prevalence of HPV 6 or 11 was 5.6 times higher in HIV-seropositive women in the WIHS and 3.6 times higher in the HERS. Genital wart prevalence increased by a factor of 3.2 in the WIHS and 2.7 in the HERS in HIV-seropositive women. In the WIHS, infection with HPV type 6 or 11, in comparison with no HPV infection, was associated with odds of genital wart prevalence of 5.1 (95% CI: 2.9-8.8), 8.8 (95% CI: 6.1-12.8), and 12.8 (95% CI: 8.8-18.8) in HIV-seronegative women, HIV-seropositive women withor =201 CD4 cells/microl, and HIV-seropositive women withor =200 CD4 cells/microl, respectively. In the HERS, infection with HPV type 6 or 11 was associated with odds of 2.7 (95% CI: 1.6-4.6), 4.9 (95% CI: 3.2-7.7), and 5.3 (95% CI: 3.3-8.5) in these same groups. Other HPV types showed a similar dose-response relation, but of substantially lower magnitude and statistical significance.HIV infection and immunodeficiency synergistically modified the relation between HPV 6 or 11 infection and genital wart prevalence.

Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication.

Background HIV infection has been associated with early menopausal onset, which may have adverse long-term health consequences. Antimullerian hormone, a biomarker of ovarian reserve and gonadal aging, is reduced in HIV-infected women. Objective We sought to assess the relationship of antimullerian hormone to age of menopause onset in HIV-infected women. Study Design We used antimullerian hormone levels measured in plasma in 2461 HIV-infected participants from the Women's Interagency HIV Study to model the age at final menstrual period. Multivariable normal mixture models for censored data were used to identify factors associated with age at final menstrual period. Results Higher antimullerian hormone at age 40 years was associated with later age at final menstrual period, even after multivariable adjustment for smoking, CD4 cell count, plasma HIV RNA, hepatitis C infection, and history of clinical AIDS. Each doubling of antimullerian hormone was associated with a 1.5-year increase in the age at final menstrual period. Median age at final menstrual period ranged from 45 years for those in the 10th percentile of antimullerian hormone to 52 years for those in the 90th percentile. Other factors independently associated with earlier age at final menstrual period included smoking, hepatitis C infection, higher HIV RNA levels, and history of clinical AIDS. Conclusion Antimullerian hormone is highly predictive of age at final menstrual period in HIV-infected women. Measuring antimullerian hormone in HIV-infected women may enable clinicians to predict risk of early menopause, and potentially implement individualized treatment plans to prevent menopause-related comorbidities and to aid in interpretation of symptoms.

BackgroundIndividuals with HIV infection commonly have pulmonary function abnormalities, including airflow obstruction and diffusion impairment, which may be more prevalent among recreational drug users. To date, the relationship between drug use and pulmonary function abnormalities among those with HIV remains unclear.ObjectiveTo determine associations between recreational drug use and airflow obstruction, diffusion impairment, and radiographic emphysema in men and women with HIV.MethodsCross-sectional analysis of pulmonary function and self-reported recreational drug use data from a cohort of 121 men and 63 women with HIV. Primary outcomes were the presence (yes/no) of: 1) airflow obstruction, (pre- or post-bronchodilator forced expiratory volume in 1 second/forced vital capacity1% of lung voxels