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1.  Physical Activity and Its Association with Insulin Resistance in Multicenter AIDS Cohort Study Men 
AIDS Research and Human Retroviruses  2015;31(12):1250-1256.
Abstract
The association between physical activity (PA), degree of insulin resistance (IR), and HIV infection is unclear. We hypothesized that PA might differentially affect the degree of IR through the direct and indirect influences of HIV, antiretroviral medications, and sociodemographic characteristics. The International Physical Activity Questionnaire (IPAQ) was administered to Multicenter AIDS Cohort Study (MACS) participants from 4/2010 to 3/2011 to generate metabolic equivalents (METs) total score and PA category. We determined the concurrent homeostatic model assessment IR (mmol/liter) (HOMA-IR) value from fasting glucose and insulin. We examined the HIV-PA relationship using quantile regression and the HIV-PA-HOMA-IR value relationship using linear regression. Among the 1,281 men, the proportions of men in the low (25% in HIV+ vs. 23% in HIV−), moderate (26% vs. 27%), and high (49% vs. 49%) PA categories were similar by HIV status. The HOMA-IR value was higher among the HIV+ men (p<0.001), and both HIV infection and low PA were associated with a higher degree of IR (p<0.0001 and p=0.0007). However, the PA-HOMA-IR value interaction was not different by HIV status. The HOMA-IR value was higher among HIV+ men although the PA was similar. It is unknown if more exercise will overcome the metabolic derangements associated with HIV and its treatment.
doi:10.1089/aid.2015.0027
PMCID: PMC4663644  PMID: 26334673
2.  Determining Survey Satisficing of Online Longitudinal Survey Data in the Multicenter AIDS Cohort Study: A Group-Based Trajectory Analysis 
Background
Survey satisficing occurs when participants respond to survey questions rapidly without carefully reading or comprehending them. Studies have demonstrated the occurrence of survey satisficing, which can degrade survey quality, particularly in longitudinal studies.
Objective
The aim of this study is to use a group-based trajectory analysis method to identify satisficers when similar survey questions were asked periodically in a long-standing cohort, and to examine factors associated with satisficing in the surveys having sensitive human immunodeficiency virus (HIV)-related behavioral questions.
Methods
Behavioral data were collected semiannually online at all four sites of the Multicenter AIDS Cohort Study (MACS) from October 2008 through March 2013. Based on the start and end times, and the word counts per variable, response speed (word counts per second) for each participant visit was calculated. Two-step group-based trajectory analyses of the response speed across 9 study visits were performed to identify potential survey satisficing. Generalized linear models with repeated measures were used to investigate the factors associated with satisficing on HIV-related behavioral surveys.
Results
Among the total 2138 male participants, the median baseline age was 51 years (interquartile range, 45-58); most of the participants were non-Hispanic white (62.72%, 1341/2138) and college graduates (46.59%, 996/2138), and half were HIV seropositive (50.00%, 1069/2138). A total of 543 men (25.40%, 543/2138) were considered potential satisficers with respect to their increased trajectory tendency of response speed. In the multivariate analysis, being 10 years older at the baseline visit increased the odds of satisficing by 44% (OR 1.44, 95% CI 1.27-1.62, P<.001). Compared with the non-Hispanic white participants, non-Hispanic black participants were 122% more likely to satisfice the HIV-related behavioral survey (OR 2.22, 95% CI 1.69-2.91, P<.001), and 99% more likely to do so for the other race/ethnicity group (OR 1.99, 95% CI 1.39-2.83, P<.001). Participants with a high school degree or less were 67% more likely to satisfice the survey (OR 1.67, 95% CI 1.26-2.21, P<.001) compared with those with a college degree. Having more than one sex partner and using more than one recreational drug reduced the odds of satisficing by 24% (OR 0.76, 95% CI 0.61-0.94, P=.013) and 28% (OR 0.72, 95% CI 0.55-0.93, P=.013), respectively. No statistically significant association of HIV serostatus with satisficing was observed.
Conclusions
Using a group-based trajectory analysis method, we could identify consistent satisficing on HIV-related behavioral surveys among participants in the MACS, which was associated with being older, being non-white, and having a lower education level; however, there was no significant difference by HIV serostatus. Methods to minimize satisficing using longitudinal survey data are warranted.
doi:10.2196/publichealth.5240
PMCID: PMC5014543  PMID: 27503107
ACASI; cohort studies; data collection; data quality; group-based trajectory analysis; reading speed; survey satisficing
3.  Long-Term Cigarette Smoking Trajectories Among HIV-Seropositive and Seronegative MSM in the Multicenter AIDS Cohort Study 
AIDS and behavior  2016;20(8):1713-1721.
Objective
To examine the association between demographic characteristics and long-term smoking trajectory group membership among HIV-seropositive and HIV-seronegative men who have sex with men (MSM).
Methods
A cohort of 6,552 MSM from the Multicenter AIDS Cohort Study (MACS) were asked detailed information about their smoking history since their last follow-up. Group-based trajectory modeling was used to examine smoking behavior and identify trajectory group membership. Because participants enrolled after 2001 were more likely to be younger, HIV-seronegative, non-Hispanic black, and have a high school diploma or less, we also assessed time of enrollment in our analysis.
Results
Participants were grouped into 4 distinct smoking trajectory groups: persistent nonsmoker (n=3,737 [55.9%]), persistent light smoker (n=663 [11.0%]), heavy smoker to nonsmoker (n=531 [10.0%]), and persistent heavy smoker (n=1,604 [23.1%]). Compared with persistent nonsmokers, persistent heavy smokers were associated with being enrolled in 2001 and later (adjusted odds ratio [aOR], 2.35; 95% CI, 2.12-2.58), having a high school diploma or less (aOR, 3.22; 95% CI, 3.05-3.39), and being HIV-seropositive (aOR, 1.17; 95% CI, 1.01-1.34). These associations were statistically significant across all trajectory groups for time of enrollment and education but not for HIV serostatus.
Conclusions
The overall decrease of smoking as shown by our trajectory groups is consistent with the national trend. Characteristics associated with smoking group trajectory membership should be considered in the development of targeted smoking cessation interventions among MSM and people living with HIV.
doi:10.1007/s10461-016-1343-8
PMCID: PMC4945456  PMID: 26922718
4.  Association of HIV, HCV and Liver Fibrosis Severity with IL-6 and CRP levels 
AIDS (London, England)  2015;29(11):1325-1333.
Background
Hepatitis C infection (HCV) is associated with chronic inflammation; yet studies show greater IL-6 but lower CRP levels. We determined whether liver fibrosis severity and HCV replication affect the ability of IL-6 to stimulate production of CRP from the liver.
Methods
We used multivariable generalized linear regression to examine the association of HIV, HCV and transient elastography-measured liver stiffness (LS) with IL-6 and CRP in participants (164 HIV-monoinfected; 10 HCV-monoinfected; 73 HIV/HCV-coinfected; 59 neither infection) of the Women's Interagency HIV Study. Significant fibrosis was defined as LS>7.1 kiloPascals.
Results
IL-6 was positively correlated with CRP levels in all women, but CRP levels were lower in HCV-infected women (with and without HIV infection) at all levels of IL-6. HCV-infected women with fibrosis had nearly 2.7-fold higher IL-6 levels compared to controls (95% Confidence Interval [CI]:146%, 447%); HCV-infected women without fibrosis had IL-6 levels that were similar to controls. By contrast, CRP was 28% lower in HCV-infected women with fibrosis (95% CI:-55%, 15%) and 47% lower in HCV-infected women without fibrosis (95% CI:-68%,-12%). Among the HCV-infected women, higher HCV RNA levels were associated with 9% lower CRP levels per doubling (95% CI: -18%, 0%).
Conclusion
Liver fibrosis severity is associated with greater IL-6 levels, but the stimulatory effect of IL-6 on CRP appears to be blunted by HCV replication rather than by liver fibrosis severity. Investigation of the potential CRP rebound after HCV RNA eradication and persistent liver fibrosis on organ injury is needed.
doi:10.1097/QAD.0000000000000654
PMCID: PMC4478137  PMID: 25870985
HIV; HCV; transient elastography; CRP; IL-6
5.  EFFECTS OF SYNDEMICS ON HIV VIRAL LOAD AND MEDICATION ADHERENCE IN THE MULTICENTER AIDS COHORT STUDY 
AIDS (London, England)  2015;29(9):1087-1096.
OBJECTIVES
To determine associations between intertwining epidemics (syndemics) and HIV medication adherence and viral load levels among HIV-positive men who have sex with men (MSM); and to test whether adherence mediates the relationship between syndemics and viral load.
DESIGN
We analyzed participant data collected between 2003—2009 from the Multicenter AIDS Cohort Study, a prospective HIV/AIDS cohort study in four U.S. cities.
METHODS
We conducted longitudinal analyses (repeated measures mixed models) to assess if differences in viral load levels, undetectable viral load, and self-reported HIV medication adherence were associated with count of syndemic conditions (substance use, depression symptoms, and sexual risk behavior, range 0 to 3), adjusting for race/ethnicity, age, and income. Mediation analyses were conducted using structural equation modeling and the SAS %mediate macro.
RESULTS
Syndemics count was associated with higher viral loads (p<.0001) and lower adherence (p<.0001). Increased counts of concomitant syndemics were associated with viral load (p <.01), detectable viral load (p <.05), and adherence (p <.001). Black MSM experienced worse outcomes across domains than White MSM (p <.0001) and experienced higher overall rates of syndemics (p<.01). Adherence significantly mediated the relationship between syndemics and viral load, accounting for an estimated 32.3% of the effect (p<.05).
CONCLUSIONS
Effectively lowering viral load levels among MSM has implications for both HIV/AIDS prevention and care. Our findings suggest that integrating substance use interventions, mental health care, and sexual risk prevention into standard HIV care may be necessary to optimize treatment and Treatment as Prevention (TasP) models.
doi:10.1097/QAD.0000000000000657
PMCID: PMC4739626  PMID: 25870981
HIV/AIDS; antiretroviral therapy; drug users; viral load; sexual behavior; psychosocial factors; men who have sex with men
6.  Association of Hepatitis C Virus Infection With CD4/CD8 Ratio in HIV-Positive Women 
Supplemental Digital Content is Available in the Text.
Background:
Recent studies reported that the CD4/CD8 T-cell ratio is inversely associated with biomarkers traditionally used to measure immune activation and systemic inflammation in highly active antiretroviral therapy–treated HIV-infected (HIV+) patients. The relation of hepatitis C virus (HCV) coinfection with the CD4/CD8 ratio in HIV+ patients is unknown.
Methods:
We examined 50,201 CD4/CD8 ratios measured over 20 years in 3 groups of HIV+ women enrolled in the Women's Interagency HIV Study: HCV antibody negative (n = 1734), cleared HCV (n = 231), and chronic HCV (n = 751) in multivariate models. IFNL4-ΔG genotype and HCV viral load were also considered.
Results:
Compared with HCV antibody negative status, chronic HCV infection was associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification (β = −0.08; P = 0.002). Cleared HCV (β = −0.10; P = 0.0009), but not IFNL4-ΔG genotype or HCV viral load, was also associated with lower CD4/CD8 ratios when HIV viral load was suppressed to the lower limit of quantification.
Conclusions:
The association of HCV coinfection with CD4/CD8 ratio is consistent with previously observed associations of HCV coinfection with biomarkers traditionally used to measure immune activation and systemic inflammation in HIV+ patients. These data provide additional support for the use of CD4/CD8 ratio for routine monitoring of immune activation and inflammation in HIV+ patients, including those with HIV/HCV coinfection; however, the unexpected association between cleared HCV and lower CD4/CD8 ratio requires additional study.
doi:10.1097/QAI.0000000000000928
PMCID: PMC4874499  PMID: 27183178
CD4/CD8; hepatitis C virus; HCV; HIV; inflammation; immune activation
7.  Trends and Predictors of Cigarette Smoking Among HIV Seropositive and Seronegative Men: The Multicenter AIDS Cohort Study 
AIDS and behavior  2016;20(3):622-632.
We measured the trend of cigarette smoking among HIV-seropositive and seronegative men over time from 1984-2012. Additionally, we examined the demographic correlates of smoking and smoking consumption. 6,577 men who have sex with men (MSM) from the Multicenter AIDS Cohort Study (MACS) were asked detailed information about their smoking history since their visit. Prevalence of smoking and quantity smoked was calculated yearly from 1984-2012. Poisson regression with robust error variance was used to estimate prevalence ratios of smoking in univariate and multivariate models. In 2012, 11.8% and 36.9% of men who were enrolled in the MACS before 2001 or during or after 2001 smoked cigarettes, respectively. In the multivariate analysis, black, non-Hispanic, lower education, enrollment wave, alcohol use, and marijuana use were positively associated with current smoking in MSM. HIV serostatus was not significant in the multivariate analysis. However, HIV variables, such as detectable viral load, were positively associated. Though cigarette smoking has declined over time, the prevalence still remains high among subgroups. There is still a need for tailored smoking cessation programs to decrease the risk of smoking in HIV-seropositive men who have sex with men.
doi:10.1007/s10461-015-1099-6
PMCID: PMC4760908  PMID: 26093780
8.  Depression and Sexual Dysfunction among HIV-Positive and HIV-Negative Men Who Have Sex With Men: Mediation by Use of Antidepressants and Recreational Stimulants 
Archives of sexual behavior  2014;44(2):399-409.
Erectile dysfunction (ED) and other forms of sexual dysfunction are highly prevalent among HIV+ men who have sex with men (MSM). Research has not previously identified the mechanisms by which depression may be associated with sexual dysfunction among HIV-positive and HIV-seronegative (HIV-negative) MSM. The present study examined the role of antidepressant use, stimulant use, and smoking as mediators of the relation between depression and sexual dysfunction among HIV-positive and HIV-negative MSM. Participants enrolled in the Multicenter AIDS Cohort Study (MACS), an ongoing prospective study of the natural and treated histories of HIV infection among MSM in the United States, completed a modified version of the International Index of Erectile Function for MSM. The study sample included 1,363 participants, with 619 HIV-positive men and 744 HIV-negative men. A structural equation model examined depression as a predictor of subsequent sexual dysfunction, mediated by antidepressant use, stimulant use, and smoking. Depression predicted subsequent sexual function among both HIV-negative and HIV-positive MSM. This effect appeared to be both a direct effect and an indirect effect via antidepressant use. Findings suggest that antidepressant medication use may partially explain sexual dysfunction among MSM.
doi:10.1007/s10508-014-0279-1
PMCID: PMC4177518  PMID: 24671728
Depression; Sexual Dysfunction; SSRIs; Men Who Have Sex With Men; Erectile Dysfunction; sexual orientation
9.  Associations between Tobacco, Alcohol, and Drug Use with Coronary Artery Plaque among HIV-Infected and Uninfected Men in the Multicenter AIDS Cohort Study 
PLoS ONE  2016;11(1):e0147822.
Background
We characterized associations between smoking, alcohol, and recreational drug use and coronary plaque by HIV serostatus within the Multicenter AIDS Cohort Study (MACS).
Methods
MACS participants (N = 1005, 621 HIV+ and 384 HIV-) underwent non-contrast CT scanning to measure coronary artery calcium; 764 underwent coronary CT angiograms to evaluate plaque type and extent. Self-reported use of alcohol, tobacco, smoked/inhaled cocaine, methamphetamine, ecstasy, marijuana, inhaled nitrites, and erectile dysfunction drugs was obtained at semi-annual visits beginning 10 years prior to CT scanning. Multivariable logistic and linear regression models were performed, stratified by HIV serostatus.
Results
Among HIV+ men, current smoking, former smoking, and cumulative pack years of smoking were positively associated with multiple coronary plaque measures (coronary artery calcium presence and extent, total plaque presence and extent, calcified plaque presence, and stenosis >50%). Smoking was significantly associated with fewer plaque measures of comparable effect size among HIV- men; current smoking and calcified plaque extent was the only such association. Heavy alcohol use (>14 drinks/week) was associated with stenosis >50% among HIV+ men. Among HIV- men, low/moderate (1–14 drinks/week) and heavy alcohol use were inversely associated with coronary artery calcium and calcified plaque extent. Few significant associations between other recreational drug use and plaque measures were observed.
Conclusion
Smoking is strongly associated with coronary plaque among HIV+ men, underscoring the value of smoking cessation for HIV+ persons. Alcohol use may protect against coronary artery calcium and calcified plaque progression in HIV- (but not HIV+) men. Few positive associations were observed between recreational drug use and coronary plaque measures.
doi:10.1371/journal.pone.0147822
PMCID: PMC4727883  PMID: 26811937
10.  Relationship between Body Mass Index and Mortality in HIV-Infected HAART Users in the Women's Interagency HIV Study 
PLoS ONE  2015;10(12):e0143740.
Background
Early HIV studies suggested protective associations of overweight against mortality, yet data are lacking for the era of potent highly active antiretroviral therapy (HAART). We evaluated associations of pre-HAART initiation body mass index (BMI) with mortality among HAART-using women.
Methods
Prospective study of time to death after HAART initiation among continuous HAART users in the Women’s Interagency HIV Study. Unadjusted Kaplan–Meier and adjusted proportional hazards survival models assessed time to AIDS and non-AIDS death by last measured pre-HAART BMI.
Results
Of 1428 continuous HAART users 39 (2.7%) were underweight, 521 (36.5%) normal weight, 441 (30.9%) overweight, and 427 (29.9%) obese at time of HAART initiation. A total of 322 deaths occurred during median follow-up of 10.4 years (IQR 5.9–14.6). Censoring at non-AIDS death, the highest rate of AIDS death was observed among underweight women (p = 0.0003 for all 4 categories). In multivariate models, women underweight prior to HAART died from AIDS more than twice as rapidly vs. normal weight women (aHR 2.04, 95% CI 1.03, 4.04); but being overweight or obese (vs. normal weight) was not independently associated with AIDS death. Cumulative incidence of non-AIDS death was similar across all pre-HAART BMI categories.
Conclusions
Among continuous HAART-using women, being overweight prior to initiation was not associated with lower risk of AIDS or non-AIDS death. Being underweight prior to HAART was associated with over double the rate of AIDS death in adjusted analyses. Although overweight and obesity may be associated with many adverse health conditions, neither was predictive of mortality among the HAART-using women.
doi:10.1371/journal.pone.0143740
PMCID: PMC4689347  PMID: 26699870
11.  Trajectory analyses of virologic outcomes reflecting community-based HIV treatment in Washington DC 1994–2012 
BMC Public Health  2015;15:1277.
Background
Effective treatment of HIV since 1996 has reduced morbidity and mortality through virologic suppression. Combination antiretroviral therapy (cART) has been recognized as key to the prevention of drug resistance and the transmission of infection. We used eighteen years of virologic outcomes in a long-standing cohort of women to describe longitudinal viral load trajectories; and examine factors associated with sustained viremia and mortality.
Methods
We analyzed data from DC WIHS women with > four semiannual visits using a group-based logistic trajectory analysis approach to identify patterns of HIV RNA detection (>80 copies/mL or lower assay limit, and >1000 copies/mL). We verified findings using cumulative viral load suppression-years, explored group characteristics using generalized linear modeling with generalized estimating equations for repeated measures, and examined survival using the Kaplan-Meier and Cox proportional hazard analyses.
Results
329 women contributed 6633 visits between 1994 and 2012 and demonstrated high, moderate, and low probability patterns of HIV RNA detection (>80 copies/mL) in 40.7, 35.6, and 23.7 % of participant visits, respectively. Analysis of cumulative years of viral load suppression supported these observations. Kaplan-Meier survival analysis demonstrated high mortality of 31.1 % with sustained viremia, but no significant difference in mortality between intermittent viremia and non-viremia patterns, 6.9 and 4.9 % respectively. Mortality was associated with higher age, lower CD4+ T lymphocyte count, and sustained viremia by Cox multivariate analysis.
Conclusions
This ecologic study demonstrates the effectiveness of viral suppression, and conversely the association between viremia and mortality. In community delivery of cART for HIV care, distinct patterns of sustained viremia, intermittent viremia, and non-viremia were identified over nearly 18 years in the DC WIHS, capturing the dynamics and complexity of sustaining long-term HIV care. Persistent viremia was associated with lower CD4s and mortality, but surprisingly mortality was not different between continuous suppression and intermittent viremia. Classification of long-term virologic patterns such as these observed HIV treatment “careers” may provide a suitable framework to identify modifiable factors associated with treatment resilience and failure. Both individual and population interventions are needed to reduce transmission, prevent the emergence of drug resistance, and improve outcomes of community ART programs.
doi:10.1186/s12889-015-2653-x
PMCID: PMC4688953  PMID: 26695971
HIV; Viral suppression; Trajectory analysis; HIV treatment career
12.  Stimulant Use and Progression to AIDS or Mortality After The Initiation of Highly Active Anti-Retroviral Therapy 
Background
HIV-positive persons who use stimulants (e.g., methamphetamine) experience profound health disparities, but it remains unclear if these persist after highly active anti-retroviral therapy (HAART) initiation. Conducted within the Multicenter AIDS Cohort Study, this investigation examined if stimulant use is associated with progression to AIDS or all-cause mortality after the initiation of HAART.
Methods
Using marginal structural modeling, the cumulative proportion of visits where any stimulant use was reported (i.e., 0%, 1 – 49%, 50 – 99%, and 100%) was examined as a time-varying predictor of: 1) all-cause mortality; and 2) AIDS or all-cause mortality.
Results
Among the 1,313 men who have sex with men (MSM) who initiated HAART, findings showed no significant association of any level of stimulant use with all-cause mortality. A competing risks analysis indicated that no level of stimulant use was associated with increased AIDS-related or non-AIDS mortality separately. Among the 648 participants without AIDS at HAART initiation, a secondary analysis indicated that stimulant use at 50% or more of study visits was associated with a 1.5-fold increase in the odds of progression to AIDS or all-cause mortality (Adjusted OR = 1.54; 95% CI = 1.02 – 2.33, p < .05).
Conclusions
HIV-positive, stimulant-using MSM receiving HAART appear to face no greater overall risks for all-cause, AIDS-related, or non-AIDS mortality compared to non-users. However, men without AIDS at HAART initiation who more frequently reported stimulant use demonstrated modestly increased odds of progression to AIDS or all-cause mortality. Comprehensive approaches are needed to optimize the effectiveness of HAART with stimulant-using MSM.
doi:10.1097/QAI.0000000000000364
PMCID: PMC4232455  PMID: 25271387
Cocaine; HIV/AIDS; Methamphetamine; Mortality; Treatment as Prevention
13.  Inaccuracy of haemoglobin A1c among HIV-infected men: effects of CD4 cell count, antiretroviral therapies and haematological parameters 
Journal of Antimicrobial Chemotherapy  2014;69(12):3360-3367.
Background
There is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c − expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS).
Methods
Fasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c − expected HbA1c ≤−0.5%.
Results
Over 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (<500 cells/mm3); a regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or zidovudine; high mean corpuscular volume; and abnormal corpuscular haemoglobin.
Conclusion
HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to under-diagnosis and to under-treatment of established diabetes mellitus.
doi:10.1093/jac/dku295
PMCID: PMC4228777  PMID: 25096078
HbA1c; diabetes; mean corpuscular volume; glycosylated haemoglobin; HIV
14.  Systemic Cytokine and Interferon Responsiveness Patterns in HIV and HCV Mono and Co-Infections 
The role of host response-related factors in the fast progression of liver disease in individuals co-infected with HIV and HCV viruses remains poorly understood. This study compared patterns of cytokines, caspase-1 activation, endotoxin exposure in plasma as well as interferon signaling in peripheral blood mononuclear cells from HIV/HCV co-infected (HIV+/HCV+), HCV mono-infected (HIV−/HCV+), HIV mono-infected (HIV+/HCV−) female patients and HIV- and HCV-uninfected women (HIV−/HCV−) who had enrolled in the Women's Interagency HIV Study (WIHS). HIV+/HCV+ women had higher plasma levels of pro-inflammatory cytokines as well as caspase-1 compared with other groups. Both HIV+/HCV+ and HIV+/HCV− women had significantly higher sCD14 levels compared with other groups. Peripheral blood mononuclear cells from HCV mono-infected patients had reduced levels of phosphorylation of STAT1 compared with other groups as well as lower basal levels of expression of the IFN-stimulated genes, OAS1, ISG15, and USP18 (UBP43). Basal expression of USP18, a functional antagonist of ISG15, as well as USP18/ISG15 ratios were increased in the HIV+/HCV+ group compared with HIV−/HCV+ and HIV+/HCV− groups. A more pronounced systemic inflammatory profile as well as increased expression ratios of USP18 to ISG15 may contribute to the more rapid progression of liver disease in HIV+/HCV+ individuals.
doi:10.1089/jir.2014.0006
PMCID: PMC4217006  PMID: 24955730
15.  Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes 
PLoS ONE  2015;10(10):e0138827.
IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women’s Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)–infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV–1 and HSV–2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV–2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV–1 and 79.0% were positive for HSV–2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV–1 or HSV–2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV–2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV–2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.
doi:10.1371/journal.pone.0138827
PMCID: PMC4592222  PMID: 26431156
16.  Investigating the Effects of Metabolic Dysregulation on Hair Follicles: A Comparison of HIV-Infected Women With and Without Central Lipohypertrophy 
International journal of dermatology  2013;53(10):e443-e448.
Background
Normal lipid metabolism and functioning of the peroxisome proliferator activated receptor gamma (PPAR-gamma) in the sebaceous gland is critical to maintaining a normal hair follicle. Human immunodeficiency virus (HIV) infection affects lipid metabolism; some have hypothesized a link between PPAR-gamma function and lipodystrophy in HIV infection. Our objective was to determine whether lipodystrophy is associated with altered hair characteristics in HIV-infected women from the Women’s Interagency HIV Study (WIHS).
Methods
Hair characteristics and scalp inflammation were assessed by an interviewer-administered questionnaire. Central lipohypertrophy and peripheral lipoatrophy was defined by self report of moderate to severe fat gain in central body sites and fat loss in peripheral body sites, respectively confirmed by clinical examination. Additional covariates considered in the analyses included demographics, behavioral characteristics, medical history, and HIV-related factors.
Results
There were 1037 women with data on all study variables. 76 women reported central lipohypertrophy; only 4 women reported lipoatrophy. Women with central lipohypertrophy were more likely to be older, have a self-reported history of injection drug use, statin medication use, diabetes, elevated cholesterol, and have self-reported less hair and shorter eyelashes. After adjustment for age, central lipohypertrophy was associated with shorter eyelashes (OR 2.3; 95% CI 1.4-3.8).
Conclusions
Central lipohypertrophy was not associated with change in scalp hair texture or scalp inflammation in this cohort. Rather, we found an association between central lipohypertrophy and shorter eyelash length. This finding may be explained by an influence of prostaglandin E2 mediators on eyelash follicles.
doi:10.1111/ijd.12044
PMCID: PMC3785560  PMID: 23786579
eyelash; hair; HIV
17.  Direct and Indirect Serum Markers of Liver Fibrosis Compared with Transient Elastography among Women in the Women’s Interagency HIV Study 
Objective
The aim of this study was to determine the test characteristics of direct and indirect biomarkers for liver fibrosis compared with transient elastography (TE) among a group of human immunodeficiency virus (HIV)-infected and uninfected women with or without Hepatitis C virus (HCV) infection.
Methods
Women enrolled in the Women’s Interagency HIV Study (WIHS) from Washington DC, San Francisco, and Chicago with a body mass index (BMI)<35 underwent liver stiffness measurement using TE between October, 2010 and September, 2012. Serum samples were tested for hyaluronic acid to calculate the SHASTA and aspartate aminotransferase to platelet ratio index (APRI). Receiver operator characteristics (ROC) of significant liver fibrosis (liver stiffness ≥ 7.1 kPa by TE, correlating with a METAVIR fibrosis score of F2-F4) predicted by SHASTA and APRI were compared.
Results
Among 308 women, the median age was 48 years, BMI was 25.6, 67% were non-Hispanic black, 27% HCV+, and 78% HIV+. The overall prevalence of significant liver fibrosis was 20%, and among HIV+ women, 22%. Overall, there was no statistically significant difference in the area under ROC curve (AUROC) between SHASTA and APRI relative to significant fibrosis by TE. Among HCV+ women (with or without HIV), the AUROC ranged from 0.70–0.73 for both the SHASTA and APRI compared to TE. Both SHASTA and APRI were associated with significant misclassification with a false negative rate of 33–40% for significant fibrosis compared with TE among women with HCV infection, with or without HIV.
Conclusion
Both the SHASTA and APRI, direct and indirect serum biomarkers of liver fibrosis respectively, are comparable at detection of significant liver fibrosis among women with HCV infection, regardless of HIV status. However, there was a high false negative rate in detection of significant liver fibrosis of up to 40% which is a significant limitation of use of these biomarkers.
doi:10.4172/2155-6113.1000446
PMCID: PMC4524652  PMID: 26251759
HIV; HCV; Biomarkers; SHASTA; APRI; Transient elastography; WIHS; Women
18.  STUCK IN THE MIDDLE: LONGITUDINAL HIV-RELATED HEALTH DISPARITIES AMONG MEN WHO HAVE SEX WITH MEN AND WOMEN (MSMW) 
INTRODUCTION
Men who have sex with men and women (MSMW) have been shown in cross-sectional studies to suffer HIV-related health disparities above and beyond those found among men who have sex with men only (MSMO). We conducted a secondary data analysis over a 7-year time frame of participants in the Multicenter AIDS Cohort Study (MACS), a longstanding prospective cohort study, to examine whether MSMW had persistently higher rates of depression symptoms, polydrug use, and (among HIV positive MSM) HIV viral load levels compared with MSMO.
METHODS
Men were behaviorally defined as bisexual if they reported sexual activity with at least one male and one female partner between study waves 38-50. We used generalized mixed modeling with repeated measures to test differences in CES-D score, polydrug use, and viral load between sexually active MSMO (n=111) and MSMW (n=1514), adjusting for age, income, and race/ethnicity, and recent seroconversion.
RESULTS
MSMW were significantly more likely than MSMO to have higher CES-D scores, polydrug use, and viral load levels (all p-values <.01). Outcome trajectories did not differ significantly over time between these groups. Black and Hispanic HIV positive MSMW had higher viral load levels relative to White HIV positive MSMW (p-values<.01).
DISCUSSION
Compared with MSMO, MSMW in the MACS suffer from profound and persistent HIV-related health disparities across biological, behavioral, and psychosocial domains. Further qualitative and quantitative research contextualizing the pathways underlying these disparities is recommended for intervention development targeting MSMW at risk for HIV acquisition and transmission.
doi:10.1097/QAI.0000000000000143
PMCID: PMC4030741  PMID: 24662298
19.  Sexual risk trajectories among MSM in the United States: implications for pre-exposure prophylaxis delivery 
Background
Despite evidence supporting pre-exposure prophylaxis (PrEP) efficacy, there are concerns regarding the feasibility of widespread PrEP implementation among men who have sex with men (MSM). To inform the development of targeted PrEP delivery guidelines, we characterized sexual risk trajectories among HIV-negative MSM.
Methods
At semiannual visits from 2003–2011, HIV-negative MSM (N=419) participating in the Multicenter AIDS Cohort Study provided data on sexual risk behaviors since their last visit. Based on reported behaviors, participants were assigned a sexual risk behavior (SRB) score at each visit as follows: (0) no insertive or receptive anal intercourse (IAI/RAI), (1) no unprotected IAI/RAI (UIAI/URAI), (2) only UIAI, (3) URAI with 1 HIV-negative partner, (4) condom-serosorting, (5) condom-seropositioning, and (6) no seroadaptive behaviors. Group-based trajectory modeling was used to examine SRB scores (<4 vs. ≥4) and identify groups with distinct sexual risk trajectories.
Results
Three sexual risk trajectory groups were identified: low risk (N=264; 63.0%), moderate risk (N=96; 22.9%; mean duration of consecutive high risk intervals~1 year), and high risk (N=59; 14.1%; mean duration of consecutive high risk intervals~2 years). Compared to low risk group membership, high risk group membership was associated with younger age (in years) (adjusted odds ratio [AOR]=0.92, 95% confidence interval [CI]: 0.88–0.96), being White (AOR=3.67, 95% CI: 1.48–9.11), earning an income ≥$20,000 (AOR=4.98, 95% CI: 2.13–11.64), distress/depression symptoms (CESD≥16) (AOR=2.36, 95% CI: 1.14–4.92), and substance use (AOR=2.00, 95% CI: 1.01–3.97).
Conclusion
Screening for the socio-demographic and behavioral factors described above may facilitate targeted PrEP delivery during high risk periods among MSM.
doi:10.1097/QAI.0000000000000101
PMCID: PMC4026016  PMID: 24378726
sexual risk behavior; MSM; pre-exposure prophylaxis; trajectory analysis
20.  Hearing Loss among HIV-Seropositive and HIV-Seronegative Men and Women 
IMPORTANCE
Hearing sensitivity among adults has quality of life implications as individuals become older. There are limited data on hearing loss among aging HIV+ adults.
OBJECTIVES
1) To evaluate pure-tone hearing thresholds among HIV+ and HIV- adults with similar demographic characteristics. 2) To determine if HIV disease variables and antiretroviral therapy (ART) are associated with pure-tone threshold levels.
DESIGN, SETTING, AND PARTICIPANTS
262 men (117 HIV+) from the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study (MACS) and 134 women (105 HIV+) from the Washington, DC site of the Women's Interagency HIV Study (WIHS) participated. Pure-tone air-conduction thresholds were collected in a sound-treated room at octave frequencies from 250 through 8000 Hz, along with interoctave frequencies of 750, 3000, and 6000 Hz.
INTERVENTION(S)
None.
MAIN OUTCOME AND MEASURES
In each ear, a low-frequency pure-tone average (LPTA) was calculated using air-conduction thresholds at 250, 500, 1000, and 2000 Hz and a high-frequency PTA (HPTA) was calculated using air-conduction thresholds at 3000, 4000, 6000, and 8000 Hz. Linear mixed regression models tested the effect of HIV on hearing after adjusting for age, sex, race, and noise exposure history. Differential HIV effects for LPTA and HPTA and better/worse ear were also examined. CD4+ and CD8+ T-cell counts, log10 plasma HIV RNA concentrations, ever having had an AIDS-defining condition, and cumulative time on ART were included in the models for HIV+ participants only.
RESULTS
HPTA and LPTA were significantly higher (18% and 12%, respectively), for HIV+ participants compared to HIV- participants for the better ear. The direction of the effect was consistent across both the better and worse ear. There were no significant associations between HIV disease variables or treatment variables and LPTA or HPTA.
CONCLUSIONS AND RELEVANCE
HIV+ adults had significantly poorer lower and higher frequency hearing compared to HIV- adults. High frequency hearing loss is consistent with an accelerated aging (presbycusis); hearing loss in the low frequency range among middle-aged individuals is an unexpected finding. Since some vowels and consonants have predominantly low frequency acoustic energy, poorer hearing in lower frequencies may lead to increased communication difficulties in HIV+ individuals.
doi:10.1001/jamaoto.2014.3302
PMCID: PMC4369193  PMID: 25541676
Hearing loss; Human immunodeficiency virus (HIV); Antiretroviral therapy (ART); Multicenter AIDS Cohort Study (MACS); Women's Interagency HIV Study (WIHS)
21.  Echolucency of the Carotid Artery Intima‐Media Complex and Intima‐Media Thickness Have Different Cardiovascular Risk Factor Relationships: The Women's Interagency HIV Study 
Background
Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging.
Methods and Results
We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group.
Conclusions
Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.
doi:10.1161/JAHA.114.001405
PMCID: PMC4345869  PMID: 25699995
carotid arteries; epidemiology; immune system; risk factors; ultrasonics
22.  Changes in Body Mass Index Following HAART Initiation among HIV-Infected Women in the Women's Interagency HIV Study 
Objective
Examine changes in, and factors associated with changing body mass index (BMI) in women following highly active antiretroviral therapy (HAART) initiation.
Methods
1177 HIV-infected Women's Interagency HIV Study participants who contributed 10,754 years of follow-up following HAART initiation were studied. Changes in median BMI up to 15 years following HAART initiation, and the highest and lowest BMI reached following HAART initiation were summarized by pre-HAART BMI category (<18.5 [underweight], 18.5–<25.0 [normal weight], 25.0–<30.0 [overweight], 30.0–<40.0 [obese], and ≥ 40.0 [morbidly obese]). Multivariate mixed effects ordinal logistic regression estimated the degree of association of each exposure of interest with post-HAART BMI.
Results
Before HAART, 39% percent of women had normal BMI, 31% were overweight, 23% were obese, and 5% were morbidly obese. Following HAART initiation, median BMI change (per 5 years) was 0.21 kg/m2 (90% confidence interval [CI]: −1.33, 0.42) for those with normal pre-HAART BMI, 0.39 kg/m2 (90% CI: 0.15,0.66) for overweight, 0.31 kg/m2 (90% CI: −1.18,0.67) for obese, and −0.36kg/m2 for morbidly obese women. After initiating HAART, 40% with normal pre-HAART BMI became overweight at some point; of those overweight, 46% remained overweight and 47% became obese; 71% of obese women remained obese and 27% became morbidly obese. Each year of nucleoside analog reverse transcriptase inhibitor use was associated with a 3% decreased odds of reaching a higher BMI category (OR 0.97, 95% CI: 0.95, 0.99), while each year of protease inhibitor or non-nucleoside analog reverse transcriptase inhibitor use were associated with a 6% (OR 1.06, 95% CI: 1.04, 1.08) and 5%(OR 1.05, 95% CI: 1.01, 1.08) increased odds of having a higher BMI category, respectively.
Conclusions
Although overweight and obesity are highly prevalent in this large cohort of HIV-infected, minority women, HAART use was associated with only a modest increase in BMI over time.
doi:10.4172/2155-6113.1000323
PMCID: PMC4285631  PMID: 25580365
Obesity; Body mass index; HIV; Women; HAART; Women's interagency HIV study
23.  Perceptions of gender-based discrimination during surgical training and practice 
Medical Education Online  2015;20:10.3402/meo.v20.25923.
Background
Women represent 15% of practicing general surgeons. Gender-based discrimination has been implicated as discouraging women from surgery. We sought to determine women's perceptions of gender-based discrimination in the surgical training and working environment.
Methods
Following IRB approval, we fielded a pilot survey measuring perceptions and impact of gender-based discrimination in medical school, residency training, and surgical practice. It was sent electronically to 1,065 individual members of the Association of Women Surgeons.
Results
We received 334 responses from medical students, residents, and practicing physicians with a response rate of 31%. Eighty-seven percent experienced gender-based discrimination in medical school, 88% in residency, and 91% in practice. Perceived sources of gender-based discrimination included superiors, physician peers, clinical support staff, and patients, with 40% emanating from women and 60% from men.
Conclusions
The majority of responses indicated perceived gender-based discrimination during medical school, residency, and practice. Gender-based discrimination comes from both sexes and has a significant impact on women surgeons.
doi:10.3402/meo.v20.25923
PMCID: PMC4317470  PMID: 25652117
gender discrimination; women; sexual harassment; surgery; work discrimination; women in medicine
24.  The Association of Self-perception of Body Fat Changes and Quality of Life in the Women’s Interagency HIV Study 
AIDS care  2013;25(12):10.1080/09540121.2013.793265.
Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1,671 HAART-using HIV-seropositive women (mean age 40 ± 8 years; 54% African American, 24% reporting ≤ 95% HAART adherence) from the Women’s Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites is associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects.
doi:10.1080/09540121.2013.793265
PMCID: PMC3769511  PMID: 23656440
body image perception; lipoatrophy; lipohypertrophy; Quality of life; HIV-seropositive women; HAART
25.  Association of HIV Infection, Hepatitis C Virus Infection, and Metabolic Factors With Liver Stiffness Measured by Transient Elastography 
The Journal of Infectious Diseases  2013;208(11):1776-1783.
Background. Few studies have examined the relationship of human immunodeficiency virus (HIV) monoinfection and its associated perturbations with liver fibrosis.
Methods. Using multivariable linear regression, we examined the demographic, behavioral, metabolic and viral factors associated with transient elastography–measured liver stiffness in 314 participants (165 HIV positive/hepatitis C virus [HCV] negative, 78 HIV positive/HCV positive, 14 HIV negative/HCV positive, 57 HIV negative/HCV negative) in the Women's Interagency HIV Study.
Results. Compared with HIV negative/HCV negative women, HIV positive/HCV positive women had higher median liver stiffness values (7.1 vs 4.4 kPa; P < .001); HIV positive/HCV negative and HIV negative/HCV negative women had similar liver stiffness values (both 4.4 kPa; P = .94). HIV/HCV coinfection remained associated with higher liver stiffness values (74% higher; 95% confidence interval [CI], 49–104) even after multivariable adjustment. Among HCV positive women, waist circumference (per 10-cm increase) was associated with 18% (95% CI, 7.5%–30%) higher liver stiffness values after multivariable adjustment; waist circumference showed little association among HIV positive/HCV negative or HIV negative/HCV negative women. Among HIV positive/HCV negative women, history of AIDS (13%; 95% CI, 4% –27%) and HIV RNA (7.3%; 95% CI, 1.59%–13.3%, per 10-fold increase) were associated with greater liver stiffness.
Conclusions. HCV infection but not HIV infection is associated with greater liver stiffness when infected women are compared with those with neither infection. Our finding that waist circumference, a marker of central obesity, is associated with greater liver stiffness in HIV/HCV-coinfected but not HIV-monoinfected or women with neither infection suggests that in the absence of HCV-associated liver injury the adverse effects of obesity are lessened.
doi:10.1093/infdis/jit357
PMCID: PMC3814832  PMID: 23901097
HIV; HCV; liver fibrosis; transient elastography; obesity; women

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