Common and Divergent Features of T Cells from Blood, Gut, and Genital Tract of Antiretroviral Therapy-Treated HIV+ Women.

T cells residing in mucosal tissues play important roles in homeostasis and defense against microbial pathogens. The gut and female reproductive tract (FRT) are both tolerogenic environments, but they differ in the kinds of foreign Ags they need to tolerate. How these different environments influence the properties of their T cells is poorly understood, but important for understanding women's health. We recruited antiretroviral therapy-suppressed women living with HIV who donated, within one visit, blood and tissue samples from the ileum, colon, rectosigmoid, endometrium, endocervix, and ectocervix. With these samples, we conducted 36-parameter cytometry by time of flight phenotyping of T cells. Although gut and FRT T cells shared features discriminating them from their blood counterparts, they also harbored features distinguishing them from one another. These included increased proportions of CD69+ T resident memory cells of the T effector memory phenotype, as well as preferential coexpression of CD69 and CD103, on the gut-derived cells. In contrast, CD69+CD103+ T resident memory CD8+ T cells from FRT, but not those from gut, preferentially expressed PD1. We further determined that a recently described population of CXCR4+ T inflammatory mucosal cells differentially expressed multiple other chemokine receptors relative to their blood counterparts. Our findings suggest that T cells resident in different tolerogenic mucosal sites take on distinct properties.

Tissue-specific differences in HIV DNA levels and mechanisms that govern HIV transcription in blood, gut, genital tract and liver in ART-treated women.

INTRODUCTION: Sex-specific differences affect multiple aspects of HIV infection, yet few studies have quantified HIV levels in tissues from women. Since an HIV functional cure will likely require a major reduction of infected cells from most tissues, we measured total and intact HIV DNA and the HIV transcription profile in blood, gut, genital tract and liver from HIV-positive antiretroviral therapy (ART) -treated women. METHODS: Peripheral blood mononuclear cells (PBMC) and biopsies from the gastrointestinal (ileum, colon, rectosigmoid +/- liver) and genital (ectocervix, endocervix and endometrium) tracts were collected from 6 ART-treated (HIV RNA < 200 copies/mL) women. HIV DNA (total and intact) and levels of read-through, initiated (total), 5'elongated, polyadenylated and multiply spliced HIV transcripts were measured by droplet digital PCR. Immunophenotyping of cells was performed using Cytometry by time of flight (CyTOF). RESULTS: We detected total HIV DNA in all tissues and intact HIV DNA in blood, ileum, colon, rectosigmoid and ectocervix. Initiated HIV transcripts per provirus were higher in PBMC and endometrium than in ileum, colon, rectosigmoid, ectocervix or endocervix, and higher in the rectum than either ileum or colon. 5'Elongated HIV transcripts per provirus were comparable in PBMC and endometrium, but higher than in gut or cervical samples. Polyadenylated and multiply spliced HIV transcripts were detected in PBMC (6/6 and 3/6 individuals respectively), but rarely in the tissues. CONCLUSIONS: These results suggest tissue-specific differences in the mechanisms that govern HIV expression, with lower HIV transcription in most tissues than blood. Therapies aimed at disrupting latency, such as latency-reversing or latency-silencing agents, will be required to penetrate into multiple tissues and target different blocks to HIV transcription.

Reproductive tract immune cells from pregnant women or those using depot medroxyprogesterone acetate show no excess susceptibility to HIV-1: Results of an ex vivo fusion assay.

INTRODUCTION: Ex vivo fusion assays offer an efficient method for studying HIV-1 entry associated with contraceptive use and pregnancy outside of cohort studies of HIV-1 incidence. METHODS: We measured ex vivo HIV-1 fusion to cervical or endometrial immune cells from three groups of women: pregnant, non-pregnant not using hormonal or intrauterine contraception, and using depot medroxyprogesterone acetate (DMPA). RESULTS AND CONCLUSIONS: There was no excess susceptibility to HIV-1 fusion of cells from pregnant women or DMPA users compared to controls. Although the number of target cells in endometrium was higher in DMPA users compared to controls, HIV-1 fusion was lower. IMPLICATIONS: In ex vivo assays, HIV-1 showed no enhanced fusion to cervical immune cells from pregnant women or DMPA users compared to controls, and lower fusion to endometrial immune cells from DMPA users. This assay is useful for studying hormonal and contraceptive effects on HIV-1 entry into reproductive tract immune cells.

Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions.

Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P4) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E2) to each progestin influenced the number of differentially expressed genes and biofunctions in P4 and MPA, while LNG and NETA signatures were more independent of E2. Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E2. Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use.

Parallel studies of mucosal immunity in the reproductive and gastrointestinal mucosa of HIV-infected women.

PROBLEM: The effects of HIV on the gastrointestinal tract (GIT), including CD4 depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are poorly understood, and most studies have focused on ectocervix and vagina without assessing the upper tract. Here, we investigated CD4+ T-cell frequency, phenotype, and HIV-specific T-cell responses in the endocervix and endometrium of HIV-infected women, comparing these tissues to the GIT. METHOD OF STUDY: Mucosal samples and blood were obtained from 18 women: four who were HIV-positive and not on cART for at least 3 years prior to sampling, including two natural controllers (viral load [VL] undetectable and CD4 >350); nine women on cART with low to undetectable VL; and five HIV-uninfected women. Mucosal samples included terminal ileum, sigmoid colon, endocervical cytobrush, endocervical curettage, and endometrial biopsy. T-cell frequency, phenotypes, and HIV-specific T-cell responses were analyzed by multiparameter flow cytometry. RESULTS: T-cell activation, measured by CD38/HLA-DR co-expression, remained significantly elevated in endometrium following cART, but was lower in gastrointestinal tissues. HIV-specific CD8+ T-cell responses were detected in ileum, colon, and endometrial tissues of women both on and off cART, and were of higher magnitude on those not on cART. CONCLUSION: Our findings reveal differences in CD4+ T-cell frequencies, immune activation, and HIV-specific T-cell responses between the gastrointestinal and reproductive tracts, and highlight differences between HIV controllers and women on cART.

Genetic and clinical predictors of CD4 lymphocyte recovery during suppressive antiretroviral therapy: Whole exome sequencing and antiretroviral therapy response phenotypes.

Increase of peripheral blood CD4 lymphocyte counts is a key goal of combined antiretroviral therapy (cART); most, but not all, recipients respond adequately and promptly. A small number of studies have examined specific genetic factors associated with the extent of CD4 recovery. We report a genome-wide examination of factors that predict CD4 recovery in HIV-infected women. We identified women in in a cohort study who were on cART with viral load below 400 copies, and drew racially and ethnically matched samples of those with good CD4 response over 2 years or poor response. We analyzed the exomes of those women employing next generation sequencing for genes associated with CD4 recovery after controlling for non-genetic factors identified through forward stepwise selection as important. We studied 48 women with good CD4 recovery and 42 with poor CD4 recovery during virologically-suppressive cART. Stepwise logistic regression selected only age as a statistically significant (p<0.05) non-genetic predictor of response type (each additional year of age reduced the odds of good recovery by 11% (OR = 0.89, CI = 0.84-0.96, p = 0.0009). After adjustment for age and genomic estimates of race and ethnicity, 41 genes harbored variations associated with CD4 recovery group (p≤0.001); 5 of these have been previously reported to be associated with HIV infection, 4 genes would likely influence CD4 homeostasis, and 13 genes either had known functions or were members of product families that had functions for which interactions with HIV or effects on lymphocyte homeostasis were biologically plausible. Greater age was the strongest acquired factor that predicted poor CD4 cell recovery. Sequence variations spanning 41 genes were independently predictive of CD4 recovery. Many of these genes have functions that impact the cell cycle, apoptosis, lymphocyte migration, or have known interactions with HIV. These findings may help inform new hypotheses related to responses to HIV therapy and CD4 lymphocyte homeostasis.

Effects of the levonorgestrel-containing intrauterine device, copper intrauterine device, and levonorgestrel-containing oral contraceptive on susceptibility of immune cells from cervix, endometrium and blood to HIV-1 fusion measured ex vivo.

Globally, HIV/AIDS is a leading cause of morbidity worldwide among reproductive-aged cisgender women, highlighting the importance of understanding effects of contraceptives on HIV-1 risk. Some observational studies suggest there may be an increased risk of HIV-1 acquisition among women using the long-acting injectable progestin contraceptive, depo-medroxyprogesterone acetate. The potential mechanism of this susceptibility is unclear. There are few data on the role of the upper female reproductive tract in HIV-1 transmission, and the mechanisms of HIV-1 infection are likely to differ in the upper compared to the lower reproductive tract due to differences in tissue composition and variable effects of sex steroids on mucosal immune cell distribution and activity. In this study, we measured the susceptibility of mucosal immune cells from the upper female reproductive tract to HIV-1 entry using the virion-based HIV-1 fusion assay in samples from healthy female volunteers. We studied 37 infectious molecular clones for their ability to fuse to cells from endometrial biopsies in three participants and found that subtype (B or C) and origin of the virus (transmitted founder or chronic control) had little influence on HIV-1 fusion susceptibility. We studied the effect of contraceptives on HIV-1 susceptibility of immune cells from the cervix, endometrium and peripheral blood by comparing fusion susceptibility in four groups: users of the copper intrauterine device (IUD), levonorgestrel-containing oral contraceptive, levonorgestrel-containing IUD and unexposed controls (n = 58 participants). None of the contraceptives was associated with higher rates of HIV-1 entry into female reproductive tract cells compared to control samples from the mid-luteal phase.

Association between Use of Methadone, Other Central Nervous System Depressants, and QTc Interval-Prolonging Medications and Risk of Mortality in a Large Cohort of Women Living with or at Risk for Human Immunodeficiency Virus Infection.

STUDY OBJECTIVE: To evaluate the association between use of methadone, other central nervous system (CNS) depressants, and QTc interval-prolonging medications and risk of mortality among human immunodeficiency virus (HIV)-infected and at-risk HIV-uninfected women. DESIGN: Multicenter, prospective, observational cohort study (Women's Interagency HIV Study [WIHS]). PARTICIPANTS: A total of 4150 women enrolled in the WIHS study between 1994 and 2014 who were infected (3119 women) or not infected (1031 women) with HIV. MEASUREMENTS AND MAIN RESULTS: Data on medication utilization were collected from all study participants via interviewer-administered surveys at 6-month intervals (1994-2014). Mortality was confirmed by National Death Index data. With age defining the time scale for the analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality in HIV-infected and -uninfected women and non-acquired immunodeficiency syndrome (AIDS) deaths in HIV-infected women. A total of 1046 deaths were identified, of which 429 were considered non-AIDS deaths. Use of benzodiazepines, CNS depressants (excluding methadone), and number of medications with conditional QTc interval-prolonging effects were each associated with all-cause mortality in multivariate models of HIV-infected women: hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.60, p=0.037; HR 1.61, 95% CI 1.35-1.92, p<0.0001; and HR 1.15 per drug, 95% CI 1.00-1.33, p=0.047, respectively. Other explanatory variables for all-cause mortality in this model included HIV viral load, CD4+  cell count, renal function, hemoglobin and albumin levels, HIV treatment era, employment status, existence of depressive symptoms, ever use of injection drugs, and tobacco smoking. Of interest, use of CNS depressants (excluding methadone) was also associated with non-AIDS deaths (HR 1.49, 95% CI 1.49-2.2, p<0.0001). Although use of benzodiazepines and conditional QT interval-prolonging medications were associated with increased risk of non-AIDS mortality (HR 1.32 and 1.25, respectively), the effect was not statistically significant (p>0.05). CONCLUSION: In this cohort of HIV-infected and at-risk HIV-uninfected women, use of benzodiazepines, CNS depressants, and conditional QTc interval-prolonging medications were associated with a higher risk of mortality independent of methadone and other well-recognized mortality risk factors. Care must be taken to assess risk when prescribing these medications in this underserved and at-risk patient population.

Viremia Trajectories of HIV in HIV-Positive Women in the United States, 1994-2017.

Importance: Viral suppression of HIV is an important treatment goal to decrease morbidity, mortality, and risk of transmission to others. Objective: To characterize longitudinal HIV viral load outcomes among women enrolled in the Women's Interagency HIV Study (WIHS). Design, Setting, and Participants: A prospective cohort study of HIV-positive women with semiannual study visits and a minimum of 5 follow-up visits was conducted from 1994 to 2017. The WIHS sites included in this analysis are in Brooklyn and Bronx, New York; Chicago, Illinois; San Francisco, California; and Washington, DC. Main Outcomes and Measures: Women were categorized into groups based on their probability of achieving viral load suppression below 200 copies/mL using logistic trajectory modeling. Multinomial regression analysis was used to identify factors associated with placement in the group with the highest probability of viremia. Results: At baseline, the mean (SD) age of the 1989 women was 36.9 (8.0) years, mean CD4+ T-lymphocyte count was 467/mm3, median (interquartile range) HIV RNA was 6200.0 (384.5-41 678.0) copies/mL, and 1305 women (65.6%) were African American. Three trajectory groups were identified with low (568 [28.6%]), intermediate (784 [39.4%]), and high (637 [32.0%]) probability of viremia above 200 copies/mL. The mean (SD) cumulative years of viral suppression were 18.7 (4.0) years, 12.2 (3.1) years, and 5.8 (2.9) years in the respective groups. Factors associated with high probability of viremia included younger age (odds ratio [OR]. 0.99; 95% CI, 0.98-0.99; P = .03), African American race (odds ratio [OR], 2.43; 95% CI, 1.75-3.37), P < .001), Hispanic race/ethnicity (OR, 1.50; 95% CI, 1.03-2.19; P = .04), increased levels of depressive symptoms (OR, 1.17; 95% CI, 1.01-1.36; P = .03), drug use (OR, 1.23; 95% CI, 1.01-1.51; P = .04), lower CD4+ T-lymphocyte counts (OR, 95% CI, 0.82; 0.80-0.85; P < .001), and unstable housing (OR, 1.25, 95% CI, 1.03-1.50; P = .02). Between 2015 and 2017, 71.2% of women demonstrated sustained viral suppression: 89.6% (310 of 346) of those with low viremia, 83.4% (346 of 415) with intermediate, and 35.2% (112 of 318) with high probability of viremia. Conclusions and Relevance: This longitudinal approach suggested that the probability of viremia decreased substantially over time for most participants, including among women with earlier histories of incomplete viral suppression. The findings from this study suggest that continued efforts are needed to address mental health, social, behavioral and structural factors that were identified as associated with high probability of HIV viremia over time.

HIV infection is an independent risk factor for decreased 6-minute walk test distance.

BACKGROUND: Ambulatory function predicts morbidity and mortality and may be influenced by cardiopulmonary dysfunction. Persons living with HIV (PLWH) suffer from a high prevalence of cardiac and pulmonary comorbidities that may contribute to higher risk of ambulatory dysfunction as measured by 6-minute walk test distance (6-MWD). We investigated the effect of HIV on 6-MWD. METHODS: PLWH and HIV-uninfected individuals were enrolled from 2 clinical centers and completed a 6-MWD, spirometry, diffusing capacity for carbon monoxide (DLCO) and St. George's Respiratory Questionnaire (SGRQ). Results of 6-MWD were compared between PLWH and uninfected individuals after adjusting for confounders. Multivariable linear regression analysis was used to determine predictors of 6-MWD. RESULTS: Mean 6-MWD in PLWH was 431 meters versus 462 in 130 HIV-uninfected individuals (p = 0.0001). Older age, lower forced expiratory volume (FEV1)% or lower forced vital capacity (FVC)%, and smoking were significant predictors of decreased 6-MWD in PLWH, but not HIV-uninfected individuals. Lower DLCO% and higher SGRQ were associated with lower 6-MWD in both groups. In a combined model, HIV status remained an independent predictor of decreased 6-MWD (Mean difference = -19.9 meters, p = 0.005). CONCLUSIONS: HIV infection was associated with decreased ambulatory function. Airflow limitation and impaired diffusion capacity can partially explain this effect. Subjective assessments of respiratory symptoms may identify individuals at risk for impaired physical function who may benefit from early intervention.

Tropheryma whipplei colonization in HIV-infected individuals is not associated with lung function or inflammation.

Studies demonstrate that Tropheryma whipplei (T. whipplei) is present in the lungs of healthy individuals without acute respiratory symptoms or acute respiratory infection and is more common in the lungs of HIV-infected individuals and in smokers. The impact of T. whipplei colonization in the lung on local inflammation and pulmonary dysfunction in HIV-infected individuals is currently unknown. In this study, we performed specific polymerase chain reaction (PCR) and sequencing for T. whipplei in bronchoalveolar lavage (BAL) and induced sputum (IS) samples in 76 HIV-infected participants from three clinical sites. Pulmonary function and proinflammatory cytokine and chemokine levels in BAL were measured. Frequency of T. whipplei in either BAL or IS was 43.4%. The sensitivity and specificity of IS compared to BAL for detection of T. whipplei was 92.3% and 84.2%, respectively, and isolates of T. whipplei in the BAL and IS in the same subject shared genetic identity. Pulmonary function measures were not associated with T. whipplei colonization, and proinflammatory cytokine and chemokine levels in BAL and plasma as well as percentages of inflammatory cells in BAL and IS were not higher in colonized individuals. Overall, these results indicate that T. whipplei colonization in the lung is common, but may not be associated with decreased pulmonary function or inflammation in HIV-infected individuals.

Prolonged Amenorrhea and Resumption of Menses in Women with HIV.

OBJECTIVE: To compare etiologies of prolonged amenorrhea in a cohort of HIV-infected women with a cohort of similar uninfected at-risk women. MATERIALS AND METHODS: Women from the Women's Interagency HIV Study were seen every 6 months, and completed surveys including questions about their menstruation. Those who reported no vaginal bleeding for at least 1 year ("prolonged amenorrhea") with subsequent resumption of bleeding were compared with women in whom bleeding had stopped permanently ("menopause"). Characteristics associated with reversible prolonged amenorrhea were ascertained. RESULTS: Of 828 women with prolonged amenorrhea, 37.6% had reversible amenorrhea and 62.4% never resumed menses. HIV-seropositive women with prolonged amenorrhea were significantly younger at cessation of menses than HIV-negative women (p < 0.0001). Of those with reversible prolonged amenorrhea, approximately half were taking medications associated with amenorrhea, including 95 (30.6%) hormonal contraception, 80 (25.7%) opiates/stimulants, 16 (5.1%) psychotropic medications, and 6 (1.9%) chemotherapy. HIV-seropositive women were less likely to have medications as a cause of amenorrhea than seronegative women (p = 0.02). In multivariable analysis, women with reversible prolonged amenorrhea of unknown etiology were younger (p < 0.0001), more often obese (p = 0.03), and less educated (p = 0.01) than those with permanent amenorrhea. Among HIV-seropositive women, markers of severe immunosuppression were not associated with prolonged amenorrhea. CONCLUSION: Women with HIV infection have unexplained prolonged amenorrhea more often than at-risk seronegative women. This is especially common among obese, less-educated women. Prolonged amenorrhea in the HIV-seropositive women should be evaluated and not be presumed to be to the result of menopause.

Factors Associated With Progression of Lung Function Abnormalities in HIV-Infected Individuals.

BACKGROUND: HIV is an independent risk factor for chronic obstructive pulmonary disease; however, baseline risk factors for lung function decline remain largely unknown in this population. METHODS: HIV-infected participants in the Pittsburgh Lung HIV Cohort with at least 3 pulmonary function measurements between 2007 and 2016 were included. Pulmonary function testing including postbronchodilator (BD) spirometry and diffusion capacity for carbon monoxide (DLco) was performed every 18 months. We used a mixed-effect linear model to evaluate factors associated with pulmonary function testing and DLco decline and logistic regression models to evaluate factors associated with rapid FEV1 decline (defined as >80 mL per year) and any DLco decline. RESULTS: Two hundred eighty-five HIV-infected participants were included. Median baseline CD4 cell count was 521 cells per micro liter, 61.9% had an undetectable HIV viral load at baseline, and 78.5% were receiving ART. Approximately 20% of participants met Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for a diagnosis of chronic obstructive pulmonary disease at baseline. Older age and baseline GOLD stage 1 compared with stage 0 were associated with faster decline in post-BD FEV1%, whereas female sex was associated with slower decline. Similarly, female sex was associated with slower decline in DLco%. HIV-related factors including CD4 cell count, viral load, and ART use were not significantly associated with pulmonary function decline. CONCLUSIONS: Older age, male sex, and higher baseline GOLD stage were associated with more rapid post-BD FEV1% decline in HIV-infected individuals.

Measuring associations between the microbiota and repeated measures of continuous clinical variables using a lasso-penalized generalized linear mixed model.

BACKGROUND: Human microbiome studies in clinical settings generally focus on distinguishing the microbiota in health from that in disease at a specific point in time. However, microbiome samples may be associated with disease severity or continuous clinical health indicators that are often assessed at multiple time points. While the temporal data from clinical and microbiome samples may be informative, analysis of this type of data can be problematic for standard statistical methods. RESULTS: To identify associations between microbiota and continuous clinical variables measured repeatedly in two studies of the respiratory tract, we adapted a statistical method, the lasso-penalized generalized linear mixed model (LassoGLMM). LassoGLMM can screen for associated clinical variables, incorporate repeated measures of individuals, and address the large number of species found in the microbiome. As is common in microbiome studies, when the number of variables is an order of magnitude larger than the number of samples LassoGLMM can be imperfect in its variable selection. We overcome this limitation by adding a pre-screening step to reduce the number of variables evaluated in the model. We assessed the use of this adapted two-stage LassoGLMM for its ability to determine which microbes are associated with continuous repeated clinical measures.We found associations (retaining a non-zero coefficient in the LassoGLMM) between 10 laboratory measurements and 43 bacterial genera in the oral microbiota, and between 2 cytokines and 3 bacterial genera in the lung. We compared our associations with those identified by the Wilcoxon test after dichotomizing our outcomes and identified a non-significant trend towards differential abundance between high and low outcomes. Our two-step LassoGLMM explained more of the variance seen in the outcome of interest than other variants of the LassoGLMM method. CONCLUSIONS: We demonstrated a method that can account for the large number of genera detected in microbiome studies and repeated measures of clinical or longitudinal studies, allowing for the detection of strong associations between microbes and clinical measures. By incorporating the design strengths of repeated measurements and a prescreening step to aid variable selection, our two-step LassoGLMM will be a useful analytic method for investigating relationships between microbes and repeatedly measured continuous outcomes.

Cognitive Burden of Common Non-antiretroviral Medications in HIV-Infected Women.

OBJECTIVE: The aging HIV population has increased comorbidity burden and consequently non-antiretroviral medication utilization. Many non-antiretroviral medications have known neurocognitive-adverse effects ("NC-AE medications"). We assessed the cognitive effects of NC-AE medications in HIV+ and HIV- women. METHODS: One thousand five hundred fifty-eight participants (1037 HIV+; mean age 46) from the Women's Interagency HIV Study completed a neuropsychological test battery between 2009 and 2011. The total number of NC-AE medications and subgroups (eg, anticholinergics) were calculated based on self-report. Generalized linear models for non-normal data were used to examine the cognitive burden of medications and factors that exacerbate these effects. RESULTS: HIV+ women reported taking more NC-AE medications vs. HIV- women (P < 0.05). NC-AE medication use altogether was not associated with cognitive performance. However, among NC-AE medication subgroups, anticholinergic-acting medications, but not opioids or anxiolytics/anticonvulsants, were negatively associated with performance. HIV status moderated the association between these NC-AE medication subgroups and performance (P's < 0.05). HIV-serostatus differences (HIV- < HIV+) in global, learning, fluency, and motor function were greatest among women taking >1 anticholinergic medications. HIV-serostatus differences in performance on learning and psychomotor speed were also greatest among women taking 1 or more anxiolytics/anticonvulsants and 1 or more opioids, respectively. CONCLUSIONS: HIV+ women have increased cognitive vulnerabilities to anticholinergic, anxiolytic/anticonvulsant, and opioid medications. Potential synergy between these medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider these specific types of medications as a contributor to impaired cognitive performance in HIV+ women and assess the cost/benefit of treatment dosage for underlying conditions.

Use of Nonantiretroviral Medications That May Impact Neurocognition: Patterns and Predictors in a Large, Long-Term HIV Cohort Study.

BACKGROUND: Neurocognitive impairment is a frequent and often disabling comorbidity of HIV infection. In addition to antiretroviral therapies, individuals with HIV infection may commonly use nonantiretroviral medications that are known to cause neurocognitive adverse effects (NC-AE). The contribution of NC-AE to neurocognitive impairment is rarely considered in the context of HIV and could explain part of the variability in neurocognitive performance among individuals with HIV. SETTING: Women's Interagency HIV Study, a prospective, multisite, observational study of US women with and without HIV. METHODS: After a literature review, 79 medications (excluding statins) with NC-AE were identified and reported by Women's Interagency HIV Study participants. We examined factors associated with self-reported use of these medications over a 10-year period. Generalized estimating equations for binary outcomes were used to assess sociodemographic, behavioral, and clinical characteristics associated with NC-AE medication use. RESULTS: Three thousand three hundred women (71% with HIV) and data from ∼42,000 visits were studied. HIV infection was associated with NC-AE medication use (odds ratio = 1.52; 95% confidence interval: 1.35 to 1.71). After adjustment for HIV infection status, other predictors of NC-AE medication use included having health insurance, elevated depressive symptoms, prior clinical AIDS, noninjection recreational drug use, and an annual household income of <$12,000 (Ps < 0.004). NC-AE medication use was less likely among women who drank 1-7 or 8-12 alcoholic drinks/week (vs. abstaining) (P < 0.04). CONCLUSIONS: HIV infection was associated with NC-AE medication use, which may influence determinations of HIV-associated neurocognitive impairment. Providers should consider the impact of NC-AE medications when evaluating patients with HIV and concurrent neurocognitive symptoms.

Comparing pharmacologic measures of tenofovir exposure in a U.S. pre-exposure prophylaxis randomized trial.

CLINICAL TRIAL REGISTRATION: Clinical Trials.gov NCT00131677.

A Genome-Wide Association Study Identifies a Candidate Gene Associated With Atazanavir Exposure Measured in Hair.

Hair provides a direct measure of long-term exposure of atazanavir (ATV). We report the results of the first genome-wide association study (GWAS) of ATV exposure measured in hair in an observational cohort representative of US women living with HIV; the Women's Interagency HIV Study. Approximately 14.1 million single nucleotide polymorphisms (SNPs) were analyzed in linear regression-based GWAS, with replication, adjusted for nongenetic predictors collected under conditions of actual use of ATV in 398 participants. Lastly, the PharmGKB database was used to identify pharmacogene associations with ATV exposure. The rs73208473, within intron 1 of SORCS2, resulted in a 0.46-fold decrease in ATV exposure, with the strongest association (P = 1.71×10-8 ) in GWAS. A priori pharmacogene screening did not identify additional variants statistically significantly associated with ATV exposure, including those previously published in ATV plasma candidate pharmacogene studies. The findings demonstrate the potential value of pharmacogenomic GWAS in ethnically diverse populations under conditions of actual use.