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1.  Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma 
PLoS ONE  2014;9(6):e99144.
Background
Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation.
Methods
This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays.
Results
A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers.
Conclusions
These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease.
doi:10.1371/journal.pone.0099144
PMCID: PMC4055650  PMID: 24922518
2.  HAART-Associated Dyslipidemia Varies by Biogeographical Ancestry in the Multicenter AIDS Cohort Study 
Abstract
Highly active antiretroviral therapy (HAART) has been successful in delaying the progression to AIDS in HIV-1-infected individuals. Exposure to HAART can result in metabolic side effects, such as dyslipidemia, in a subset of recipients. Longitudinal data and frozen peripheral blood mononuclear cell pellets were obtained from 1,945 men enrolled in the Multicenter AIDS Cohort. Individuals were genotyped for ancestry informative markers (AIMs) and stratified by biogeographical ancestry (BGA). Then serum levels of total cholesterol (TCHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TRIG) were examined controlling for a number of HIV and HAART-related covariates using multivariate mixed-effects linear regression. HIV-1 infection, in the absence of HAART, was associated with altered lipid levels for all phenotypes tested when compared to HIV-negative men. HIV-1-infected men receiving HAART also had significantly different lipid levels compared to HIV-negative men, except for LDL-C. There were statistically significant interactions between BGA and HIV/HAART status for all lipids tested. BGA remained significantly associated with lipid levels after controlling for other HIV and HAART-related covariates. There was low concordance between self-reported race (SRR) and BGA in admixed populations. BGA performed better than SRR in our statistical models. Lipid profiles in untreated HIV-1-positive men and HIV-1-positive men receiving HAART differ from HIV-negative men and this effect varies by BGA. BGA performed better in our statistical analysis as a racial classifier but SRR remains a good clinical surrogate for BGA.
doi:10.1089/aid.2012.0169
PMCID: PMC3653392  PMID: 23343448
3.  Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts 
Background
Several lung diseases are increasingly recognized as comorbidities with HIV; however, few data exist related to the spectrum of respiratory symptoms, diagnostic testing, and diagnoses in the current HIV era. The objective of the study is to determine the impact of HIV on prevalence and incidence of respiratory disease in the current era of effective antiretroviral treatment.
Methods
A pulmonary-specific questionnaire was administered yearly for three years to participants in the Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS). Adjusted prevalence ratios for respiratory symptoms, testing, or diagnoses and adjusted incidence rate ratios for diagnoses in HIV-infected compared to HIV-uninfected participants were determined. Risk factors for outcomes in HIV-infected individuals were modeled.
Results
Baseline pulmonary questionnaires were completed by 907 HIV-infected and 989 HIV-uninfected participants in the MACS cohort and by 1405 HIV-infected and 571 HIV-uninfected participants in the WIHS cohort. In MACS, dyspnea, cough, wheezing, sleep apnea, and incident chronic obstructive pulmonary disease (COPD) were more common in HIV-infected participants. In WIHS, wheezing and sleep apnea were more common in HIV-infected participants. Smoking (MACS and WIHS) and greater body mass index (WIHS) were associated with more respiratory symptoms and diagnoses. While sputum studies, bronchoscopies, and chest computed tomography scans were more likely to be performed in HIV-infected participants, pulmonary function tests were no more common in HIV-infected individuals. Respiratory symptoms in HIV-infected individuals were associated with history of pneumonia, cardiovascular disease, or use of HAART. A diagnosis of asthma or COPD was associated with previous pneumonia.
Conclusions
In these two cohorts, HIV is an independent risk factor for several respiratory symptoms and pulmonary diseases including COPD and sleep apnea. Despite a higher prevalence of chronic respiratory symptoms, testing for non-infectious respiratory diseases may be underutilized in the HIV-infected population.
doi:10.1186/1471-2466-14-75
PMCID: PMC4021087  PMID: 24884738
AIDS; HIV; Pulmonary disease; Chronic obstructive; Respiratory tract diseases; Sleep apnea syndromes
4.  Lower Adiponectin is Associated with Subclinical Cardiovascular Disease among HIV-infected Men 
AIDS (London, England)  2014;28(6):901-909.
Objective
To examine if altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons.
Design
Nested cohort study.
Methods
We studied HIV-infected(HIV+) and HIV-uninfected(HIV−) men in the Multicenter AIDS Cohort Study with noncontrast CT to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus and CVD risk factors (RFs).
Results
Significant findings were limited to adiponectin. HIV+ men (n=493) had lower adiponectin levels than HIV− men (n=250) after adjusting for CVD RFs (p<0.0001), which became non-significant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV+ men, lower adiponectin levels were associated with higher CD4+ T cell counts (p= 0.004), longer duration of antiretroviral therapy (p= 0.006) and undetectable HIV RNA levels (p = 0.04) after adjusting for age, race and CVD RFs; only CD4+ cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis > 50% (p <0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV+ and of mixed plaque in HIV− men.
Conclusions
Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.
doi:10.1097/QAD.0000000000000186
PMCID: PMC3967406  PMID: 24401646
Adipokines; adiponectin; leptin; heart; subclinical coronary atherosclerosis; metabolic side effects of HIV infection; coronary CT angiography; cardiac CT
5.  Factors Affecting Glomerular Filtration Rate, as Measured by Iohexol Disappearance, in Men with or at Risk for HIV Infection 
PLoS ONE  2014;9(2):e86311.
Objective
Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD).
Design
Cross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(−)) men (n = 258) in the Multicenter AIDS Cohort Study.
Methods
iGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR).
Results
Median iGFR was higher among HIV(+) than HIV(−) men (109 vs. 106 ml/min/1.73 m2, respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m2) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(−) men; predictors of CKD were similar using iGFR and eGFR.
Conclusions
iGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR.
doi:10.1371/journal.pone.0086311
PMCID: PMC3917840  PMID: 24516530
6.  Morning free and total testosterone in HIV-infected men: implications for the assessment of hypogonadism 
Background
Hypogonadism is common among HIV-infected men, even among men receiving antiretroviral therapy (ART). Our objective in this study was to determine the prevalence of biochemical hypogonadism among HIV-infected men compared with HIV-uninfected controls. We also examined the use of free testosterone (FT) and total testosterone (TT) measurements in the assessment of biochemical hypogonadism in HIV-infected and –uninfected men.
Methods
This was a cross-sectional analysis from the Multicenter AIDS Cohort Study (MACS). TT levels were measured from archived serum using liquid chromatography-tandem mass spectrometry. FT was calculated from TT and sex hormone-binding globulin (SHBG) (measured by radioimmunoassay) using the Vermeulen equation. Biochemical hypogonadism was defined as having low TT, low FT, or both.
Results
Of 945 men in the MACS Cardiovascular Substudy, T assays were not performed in 89 because of insufficient/no stored serum (n = 18) or use of T replacement therapy (TRT) (n = 71). 530 men had morning (AM) T measurements; 364 (68.7%) were HIV-infected. The prevalence of biochemical hypogonadism was similar in HIV-infected (34/364 = 9.3%) and HIV-uninfected (12/166 = 7.2%) men. Prevalence of hypogonadism, when men on TRT (n = 71) were included in the group of hypogonadal men, was higher in HIV-infected (104/434 = 24.0%) compared with HIV-uninfected (13/167 = 7.8%) men (p < 0.0001). Of 34 HIV-infected men with biochemical hypogonadism not on TRT, 11 (32.4%) had normal TT, but low FT. Of 12 HIV-uninfected men with biochemical hypogonadism not on TRT, none were in this category (p = 0.04) – all had low TT.
Conclusions
The prevalence of biochemical hypogonadism in our sample of HIV-infected men was approximately 10%, with a substantial proportion of these men having a normal TT, but low FT. The measurement of AM FT, rather than TT, in the assessment of hypogonadism in HIV-infected men will likely increase diagnostic sensitivity and should be recommended.
doi:10.1186/1742-6405-11-6
PMCID: PMC3900935  PMID: 24450960
Testosterone; Sex hormone binding globulin; HIV; Hypogonadism
7.  The Impact of Impaired Kidney Function and HIV Infection on the Risk of Anemia 
AIDS Research and Human Retroviruses  2012;28(12):1666-1671.
Abstract
Chronic kidney disease and HIV infection both independently increase the risk of anemia. It is not known if individuals with both HIV infection and kidney dysfunction are at greater than expected risk of anemia resulting from the combined effect of these factors. Men from the Multicenter AIDS Cohort Study with AIDS-free time after 1996 were included in the analysis if they had an initial hemoglobin value greater than 13 g/dl and available serum creatinine measurements for the estimation of glomerular filtration rate. Hemoglobin data were fit parametrically using a linear mixed effects model and effects of medication use on hemoglobin levels were removed using censoring methods. The effect of both HIV infection and glomerular filtration rate less than 60 ml/min/1.73 m2 on the mean hemoglobin value was assessed. The risk of having anemia (hemoglobin level falling below 13 g/dl) was estimated. There were 862 HIV-infected and 1,214 HIV-uninfected men who contributed to the analysis. Hemoglobin values across all 17,341 person-visits, adjusting for age, were generally lower in HIV-infected AIDS-free men with impaired kidney function by −0.22 g/dl (95% CI: −0.42, −0.03) compared to men with either HIV infection or impaired kidney function, but not both. HIV-infected AIDS-free men with impaired kidney function have a higher risk of anemia by 1.2% compared to HIV-uninfected men with normal kidney function. Comorbid conditions and medication use did not explain this increase in risk. HIV infection and impaired kidney function have a combined impact on lowering hemoglobin levels, resulting in a higher risk of anemia.
doi:10.1089/aid.2011.0188
PMCID: PMC3505063  PMID: 22632256
8.  The Parametric G-Formula to Estimate the Effect of Highly Active Antiretroviral Therapy on Incident AIDS or Death 
Statistics in medicine  2012;31(18):2000-2009.
SUMMARY
The parametric g-formula can be used to contrast the distribution of potential outcomes under arbitrary treatment regimes. Like g-estimation of structural nested models and inverse probability weighting of marginal structural models, the parametric g-formula can appropriately adjust for measured time-varying confounders that are affected by prior treatment. However, there have been few implementations of the parametric g-formula to date. Here, we apply the parametric g-formula to assess the impact of highly active antiretroviral therapy on time to AIDS or death in two US-based HIV cohorts including 1,498 participants. These participants contributed approximately 7,300 person-years of follow-up of which 49% was exposed to HAART and 382 events occurred; 259 participants were censored due to drop out. Using the parametric g-formula, we estimated that antiretroviral therapy substantially reduces the hazard of AIDS or death (HR=0.55; 95% confidence limits [CL]: 0.42, 0.71). This estimate was similar to one previously reported using a marginal structural model 0.54 (95% CL: 0.38, 0.78). The 6.5-year difference in risk of AIDS or death was 13% (95% CL: 8%, 18%). Results were robust to assumptions about temporal ordering, and extent of history modeled, for time-varying covariates. The parametric g-formula is a viable alternative to inverse probability weighting of marginal structural models and g-estimation of structural nested models for the analysis of complex longitudinal data.
doi:10.1002/sim.5316
PMCID: PMC3641816  PMID: 22495733
Cohort study; Confounding; g-formula; HIV/AIDS; Monte Carlo methods
9.  Herpes simplex virus type 2 (HSV-2) as a coronary atherosclerosis risk factor in HIV-infected men: Multicenter AIDS Cohort Study 
Atherosclerosis  2012;223(2):433-436.
We assessed associations of herpes simplex virus types 1 and 2 (HSV-1 and -2), cytomegalovirus (CMV), and human herpesvirus 8 (HHV-8) infection with subclinical coronary atherosclerosis in 291 HIV-infected men in the Multicenter AIDS Cohort Study. Coronary artery calcium (CAC) was measured by non-contrast coronary CT imaging. Markers for herpesviruses infection were measured in frozen specimens collected 10-12 years prior to case identification. Multivariable logistic regression models and ordinal logistic regression models were performed. HSV-2 seropositivity was associated with coronary atherosclerosis (adjusted odds ratio [AOR] =4.12, 95% confidence interval [CI] =1.58-10.85) after adjustment for age, race/ethnicity, cardiovascular risk factors, and HIV infection related factors. Infection with a greater number of herpesviruses was associated with elevated CAC levels (AOR=1.58, 95% CI=1.06-2.36). Our findings suggest HSV-2 may be a risk factor for subclinical coronary atherosclerosis in HIV-infected men. Infection with multiple herpesviruses may contribute to the increased burden of atherosclerosis.
doi:10.1016/j.atherosclerosis.2012.03.002
PMCID: PMC3392500  PMID: 22472456
herpesvirus; HSV-2; atherosclerosis; HIV-1/AIDS; risk factors
10.  Replication of RYR3 gene polymorphism association with cIMT among HIV-infected whites 
AIDS (London, England)  2012;26(12):1571-1573.
To replicate the association of variants in RYR3 gene with common carotid intima-media thickness (cIMT), a surrogate marker of atherosclerosis, we genotyped single nucleotide polymorphisms (SNPs) rs2229116 and rs7177922 in a sub-population of 244 HIV-positive and HIV-negative men. SNP rs2229116 was associated with common cIMT in HIV infected white men after adjusting for age and use of stavudine (d4T). The association was more evident at younger ages and decreased among older individuals.
doi:10.1097/QAD.0b013e328355359f
PMCID: PMC3606588  PMID: 22627881
11.  Low physical function as a risk factor for incident diabetes mellitus and insulin resistance 
Future virology  2011;6(4):439-449.
Data from 1790 HIV-infected and uninfected men in the Multicenter AIDS Cohort Study (MACS) were analyzed to evaluate relationships between physical function, incident diabetes mellitus (DM) and insulin resistance among HIV-infected and -uninfected men. DM was defined in two ways, using less stringent and more stringent criteria. The 10-item Physical Functioning Scale from the Short Form-36 Health Survey measured baseline physical function. Cumulative DM incidence was highest among HIV-uninfected and HIV-infected men with low physical function. Physical function was a risk factor for DM in HIV-uninfected men and remained so after controlling for BMI, DM family history and race. Among HIV-infected men, physical function was an independent risk factor for DM using the less stringent diabetes definition. This study supports our previous findings that low physical function is an important risk factor for DM in the MACS cohort.
doi:10.2217/fvl.11.15
PMCID: PMC3690565  PMID: 23805163
AIDS; diabetes mellitus; HIV; insulin resistance; physical function
12.  Self-reported low physical function is associated with diabetes mellitus and insulin resistance in HIV-positive and HIV-negative men 
Future HIV therapy  2008;2(6):539-549.
Aim
To investigate the association between self-reported physical function (as a surrogate for physical activity) and diabetes mellitus (DM) and insulin resistance (IR) among HIV-positive and -negative men.
Method
A total of 384 HIV-negative and 274 HIV-positive men from the Pitt Men’s Study contributed data. DM was defined by fasting serum glucose levels. IR was calculated using the homeostasis model assessment. The Physical Functioning 10 Scale from the Short Form-36 Health Survey measured physical function. Multivariate logistic regression assessed the independent association between physical function and DM and IR.
Results
Physical function, older age and Black race were associated with DM in multivariate analyses. Physical function/HIV interaction, older age, higher body mass index, HIV infection and Black race were associated with IR in multivariate analyses.
Conclusion
Self-reported low physical function is associated with DM and IR in HIV-negative and -positive men.
PMCID: PMC3690631  PMID: 23805164
diabetes mellitus; HIV-positive; insulin resistance; physical function
13.  Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study 
AIDS (London, England)  2008;22(13):1589-1599.
Objective
To evaluate the association of HIV infection and cumulative exposure to highly active antiretroviral therapy (HAART) with the presence and extent of coronary artery calcification (CAC).
Design
A cross-sectional study of 947 male participants (332 HIV-seronegative, 84 HAART-naive and 531 HAART-experienced HIV-infected) from the Multicenter AIDS Cohort Study.
Methods
The main outcome was CAC score calculated as the geometric mean of the Agatston scores of two computed tomography replicates. Presence of CAC was defined as calcification score above 10, and extent of CAC by the score for those with CAC present. Multivariable regression was used to evaluate the association between HIV infection and HAART and presence and extent of calcification.
Results
Increasing age was most strongly associated with both prevalence and extent of CAC for all study groups. After adjustment for age, race, family history, smoking, high-density lipoprotein-C, low-density lipoprotein-C and hypertension, HIV infection (odds ratio, 1.35; 95% confidence interval, 0.70, 2.61) and long-term HAART use (odds ratio, 1.33; 95% confidence interval, 0.87, 2.05) increased the odds for presence of CAC. In contrast, after adjustment for these covariates, the extent of CAC was lower among HAART users. Among those not taking lipid-lowering therapy, HAART usage of at least 8 years was associated with significantly reduced CAC scores (relative CAC score, 0.43; 95% confidence interval, 0.24, 0.79).
Conclusion
HAART use may have different effects on the presence and extent of coronary calcification. Although prevalence of calcification was marginally increased among long-term HAART users, the extent of calcification was significantly reduced among HAART users compared with HIV-seronegative controls.
doi:10.1097/QAD.0b013e328306a6c5
PMCID: PMC3633463  PMID: 18670218
14.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
Objective
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Design
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Methods
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Results
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
Conclusion
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
doi:10.1371/journal.pone.0058812
PMCID: PMC3595204  PMID: 23554932
15.  Marginal Structural Models for Case-Cohort Study Designs to Estimate the Association of Antiretroviral Therapy Initiation With Incident AIDS or Death 
American Journal of Epidemiology  2012;175(5):381-390.
To estimate the association of antiretroviral therapy initiation with incident acquired immunodeficiency syndrome (AIDS) or death while accounting for time-varying confounding in a cost-efficient manner, the authors combined a case-cohort study design with inverse probability-weighted estimation of a marginal structural Cox proportional hazards model. A total of 950 adults who were positive for human immunodeficiency virus type 1 were followed in 2 US cohort studies between 1995 and 2007. In the full cohort, 211 AIDS cases or deaths occurred during 4,456 person-years. In an illustrative 20% random subcohort of 190 participants, 41 AIDS cases or deaths occurred during 861 person-years. Accounting for measured confounders and determinants of dropout by inverse probability weighting, the full cohort hazard ratio was 0.41 (95% confidence interval: 0.26, 0.65) and the case-cohort hazard ratio was 0.47 (95% confidence interval: 0.26, 0.83). Standard multivariable-adjusted hazard ratios were closer to the null, regardless of study design. The precision lost with the case-cohort design was modest given the cost savings. Results from Monte Carlo simulations demonstrated that the proposed approach yields approximately unbiased estimates of the hazard ratio with appropriate confidence interval coverage. Marginal structural model analysis of case-cohort study designs provides a cost-efficient design coupled with an accurate analytic method for research settings in which there is time-varying confounding.
doi:10.1093/aje/kwr346
PMCID: PMC3282878  PMID: 22302074
acquired immunodeficiency syndrome; case-cohort studies; cohort studies; confounding bias; HIV; pharmacoepidemiology; selection bias
16.  Factors affecting brain structure in men with HIV disease in the post-HAART era 
Neuroradiology  2011;54(2):113-121.
Introduction
The purpose of this study was to characterize brain volumetric differences in HIV seropositive and seronegative men and to determine effects of age, cardiovascular risk, and HIV infection on structural integrity.
Methods
Magnetic resonance imaging was used to acquire high-resolution neuroanatomic data in 160 men aged 50 years and over, including 84 HIV seropositive and 76 seronegative controls. Voxel-based morphometry was used to derive volumetric measurements at the level of the individual voxel. Data from a detailed neuropsychological test battery were recombined into four summary scores representing psychomotor speed, visual memory, verbal memory, and verbal fluency.
Results
Both age and HIV status had a significant effect on both gray matter (GM) and white matter (WM) volume. The age-related GM atrophy was primarily in the superior temporal and inferior frontal regions; the HIV-related GM loss included the posterior and inferior temporal lobes, the parietal lobes, and the cerebellum. Among all subjects, the performance on neuropsychological tests, as indexed by a summary variable, was related to the volume of both the GM and WM. Contrary to our predictions, the CVD variables were not linked to brain volume in statistically adjusted models.
Conclusion
In the post-HAART era, having HIV infection is still linked to atrophy in both GM and WM. Secondly, advancing age, even in this relatively young cohort, is also linked to changes in GM and WM volume. Thirdly, CNS structural integrity is associated with overall cognitive functions, regardless of the HIV infection status of the study volunteers.
doi:10.1007/s00234-011-0854-2
PMCID: PMC3154580  PMID: 21424708
MRI; Cognition; HIV; Age; Voxel-based morphometry
17.  Cancer incidence in the Multicenter AIDS Cohort Study before and during the HAART era: 1984–2007 
Cancer  2010;116(23):5507-5516.
Background
The incidence of Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) among human immunodeficiency virus (HIV)-infected individuals declined following the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s, but the cancer risk associated with HIV infection during the HAART era remains to be clarified.
Methods
We compared cancer incidence among HIV-infected and -uninfected participants in the Multicenter AIDS Cohort Study (MACS) between 1984 and 2007 to the expected incidence using US population-based data from the Surveillance, Epidemiology, and End Results (SEER) Program, and we compared age and race adjusted cancer incidence rates by HIV status and over time within the MACS. Exact statistical methods were used for all analyses.
Results
933 incident cancers were observed during 77,320 person-years of follow-up. Compared to SEER, MACS HIV-infected men had significantly (p<0.05) elevated rates of KS (standardized incidence ratio (SIR)=139.10), NHL (SIR=36.80), Hodgkin’s lymphoma (HL) (SIR=7.30), and anal cancer (SIR=25.71). Within MACS, HIV infection was independently associated with each of these cancers across the entire follow-up period, and KS (incidence rate ratio (IRR)=54.93), NHL (IRR=11.18), and anal cancer (IRR=18.50) were each significantly elevated among HIV-infected men during the HAART era. Among these men, the incidence of KS and NHL declined (IRR=0.13 and 0.23, respectively), anal cancer incidence increased (IRR=5.84), and HL incidence remained statistically unchanged (IRR=0.75) from the pre-HAART to the HAART era.
Conclusion
Cancer risk remains elevated among HIV-infected men who have sex with men, highlighting the continuing need for appropriate cancer screening in this population.
doi:10.1002/cncr.25530
PMCID: PMC2991510  PMID: 20672354
HIV infection; cancer incidence; malignancy; AIDS-defining malignancy; HAART
18.  Sex Hormones, Insulin Resistance, and Diabetes Mellitus among Men with or at Risk for HIV Infection 
Objective
To examine the relationship of free testosterone (FT) and sex hormone-binding globulin (SHBG) with insulin resistance and diabetes mellitus (DM) in HIV disease.
Design
Cross-sectional analysis from 322 HIV-uninfected and 534 HIV-infected men in the Multicenter AIDS Cohort Study.
Methods
The main outcomes were DM and Homeostasis model assessment–insulin resistance (HOMA-IR). DM was defined as fasting serum glucose (FG) ≥ 126 or self-reported DM and use of DM medications. Homeostasis model assessment–insulin resistance (HOMA-IR) was calculated from FG and fasting insulin.
Results
Compared with HIV-uninfected men in our sample, HIV-infected men were younger, with lower BMI, and more often black. HIV-infected men had lower FT (p < 0.001) and higher SHBG (p < 0.0001). The adjusted odds ratio for DM was 1.98 (95% CI 1.04–3.78); mean adjusted log HOMA-IR was 0.21 units higher in HIV-infected men (p < 0.0001). Log SHBG, but not log FT, was associated with DM (OR = 0.44, 95% CI 0.25, 0.80) in both groups. Log FT and log SHBG were inversely related to insulin resistance (p < 0.05 for both) independent of HIV.
Conclusions
Compared to HIV-uninfected men, HIV-infected men had lower FT, higher SHBG, and more insulin resistance and DM. Lower FT and lower SHBG were associated with insulin resistance regardless of HIV serostatus. This suggests that sex hormones play a role in the pathogenesis of glucose abnormalities among HIV-infected men.
doi:10.1097/QAI.0b013e3182278c09
PMCID: PMC3175332  PMID: 21705912
Testosterone; Sex Hormone-Binding Globulin; Insulin Resistance; Diabetes Mellitus; HIV
19.  Serologic responses to Pneumocystis Proteins in Human Immunodeficiency Virus Patients With and Without Pneumocystis jirovecii Pneumonia 
Background
Immune responses to Pneumocystis jirovecii are not well understood in HIV infection, but antibody responses to proteins may be useful as a marker of Pneumocystis risk or presence of Pneumocystis pneumonia (PcP).
Design
Retrospective analysis of a prospective cohort
Methods
Enzyme-linked immunosorbent assays of antibodies to recombinant Pneumocystis proteins of major surface glycoprotein fragments (MsgC1, C3, C8, and C9) and of antibody titers to recombinant kexin protein (KEX1) were performed on three sequential serum samples up to 18 months prior to and three samples after first AIDS-defining illness from Multicenter AIDS Cohort Study participants and compared between those who had PcP or a non-PcP AIDS-defining illness.
Results
Fifty-four participants had PcP and 47 had a non-PcP AIDS-defining illness. IgG levels to MsgC fragments were similar between groups prior to first AIDS-defining illness, but the PcP group had higher levels of IgG to MsgC9 (median units/ml 50.2 vs. 22.2, p=0.047) post-illness. Participants with PcP were more likely to have an increase in MsgC3 (OR 3.9, p=0.02), MsgC8 (OR 5.5, p=0.001), and MsgC9 (OR 4.0, p=0.007). The PcP group was more likely to have low KEX1 IgG prior to development of PcP (OR 3.6, p=0.048) independent of CD4 cell count and to have an increase in high IgG titers to KEX1 after PcP.
Conclusion
HIV-infected individuals develop immune responses to both Msg and kexin proteins after PcP. Low KEX1 IgG titers may be a novel marker of future PcP risk before CD4 cell count has declined below 200 cells/μl.
doi:10.1097/QAI.0b013e3182167516
PMCID: PMC3150634  PMID: 21372726
HIV; Acquired Immunodeficiency Syndrome; Pneumocystis; serology
20.  Subcortical brain atrophy persists even in HAART-regulated HIV disease 
Brain imaging and behavior  2011;5(2):77-85.
The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy.
doi:10.1007/s11682-011-9113-8
PMCID: PMC3082694  PMID: 21264551
HIV; MRI; Gray matter; Basal ganglia
21.  Asymptomatic Primary Merkel Cell Polyomavirus Infection among Adults 
Emerging Infectious Diseases  2011;17(8):1371-1380.
TOC Summary: This virus may be part of normal human flora and harmless in most adults.
Merkel cell polyomavirus (MCV) is a recently discovered virus that causes 80% of Merkel cell carcinomas. We examined data for 564 gay/bisexual male participants >18 years of age in the Multicenter AIDS Cohort Study in Pittsburgh, Pennsylvania, USA, and found that 447 (79.3%) were MCV-antibody positive at initial enrollment. Of the 117 MCV-seronegative men, 31 subsequently seroconverted over a 4-year follow-up period, corresponding to a 6.6% annual conversion rate. MCV immunoglobulin G levels remained detectable up to 25 years after exposure. No signs, symptoms, or routine diagnostic test results were associated with MCV infection, and no correlation between HIV infection or AIDS progression and MCV infection was noted. An initial correlation between chronic hepatitis B virus infection and MCV prevalence could not be confirmed among MCV seroconverters or in studies of a second hepatitis B virus–hyperendemic cohort from Qidong, China. In adults, MCV is typically an asymptomatic, common, and commensal viral infection that initiates rare cancers after virus (rather than host cell) mutations.
doi:10.3201/eid1708.110079
PMCID: PMC3381535  PMID: 21801612
viruses; MSM; men who have sex with men; Merkel cell polyomavirus; MCV; Merkel cell carcinoma; MCPyV; epidemiology; seroconversion; Pennsylvania; USA; China; HIV/AIDS and other retroviruses; research
22.  Augmentation Pressure and Subendocardial Viability Ratio are associated with microalbuminuria and with poor renal function in type 1 diabetes 
This report explores the hypothesis that arterial stiffness indices, which predict cardiovascular disease, might also correlate with microalbuminuria (MA) in type 1 diabetes (T1D), and thus have potential for risk assessment. Three pulse wave analysis indices, measured using the SphygmoCor device, were evaluated on 144 participants with childhood-onset T1D. These variables, augmentation index (AIx) and augmentation pressure (AP), and subendocardial viability ratio (SEVR, an estimate of myocardial perfusion) were each analyzed cross-sectionally in relation to both prevalent MA (defined as albumin excretion rate (AER)=20–199 μg/min) and renal function (assessed by both estimated glomerular filtration rate (eGFR) and serum cystatin C). AP and SEVR were each univariately associated with AER, eGFR and cystatin C. Lower SEVR was also independently related to the presence of microalbuminuria and degree of albuminuria within normo- and microalbuminuric participants. SEVR, not AP, was independently and negatively associated with both measures of renal function. SEVR is a better predictor of AER than brachial blood pressure measures in those without clinical proteinuria, indicating a potential use for pulse wave analysis in the early detection of individuals at risk for cardiovascular and renal complication of T1D.
doi:10.1177/1479164110375297
PMCID: PMC3047589  PMID: 20605853
pulse wave analysis; type 1 diabetes; microalbuminuria; renal disease; kidney function; arterial stiffness
23.  Time Scale and Adjusted Survival Curves for Marginal Structural Cox Models 
American Journal of Epidemiology  2010;171(6):691-700.
Typical applications of marginal structural time-to-event (e.g., Cox) models have used time on study as the time scale. Here, the authors illustrate use of time on treatment as an alternative time scale. In addition, a method is provided for estimating Kaplan-Meier–type survival curves for marginal structural models. For illustration, the authors estimate the total effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome (AIDS) or death in 1,498 US men and women infected with human immunodeficiency virus and followed for 6,556 person-years between 1995 and 2002; 323 incident cases of clinical AIDS and 59 deaths occurred. Of the remaining 1,116 participants, 77% were still under observation at the end of follow-up. By using time on study, the hazard ratio for AIDS or death comparing always with never using highly active antiretroviral therapy from the marginal structural model was 0.52 (95% confidence interval: 0.35, 0.76). By using time on treatment, the analogous hazard ratio was 0.44 (95% confidence interval: 0.32, 0.60). In time-to-event analyses, the choice of time scale may have a meaningful impact on estimates of association and precision. In the present example, use of time on treatment yielded a hazard ratio further from the null and more precise than use of time on study as the time scale.
doi:10.1093/aje/kwp418
PMCID: PMC2877453  PMID: 20139124
acquired immunodeficiency syndrome; antiretroviral therapy, highly active; bias (epidemiology); causal inference; confounding factors (epidemiology); proportional hazards model; survival curve; survival time
24.  Cardiovascular Autonomic Neuropathy, HDL Cholesterol, and Smoking Correlate With Arterial Stiffness Markers Determined 18 Years Later in Type 1 Diabetes 
Diabetes Care  2009;33(3):652-657.
OBJECTIVE
To examine the relationship between cardiovascular autonomic neuropathy and pulse waveform analysis (PWA) measures of arterial stiffness in a childhood-onset type 1 diabetes population.
RESEARCH DESIGN AND METHODS
Cardiac autonomic nerve function was measured in the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes by heart rate variability (R-R interval) during deep breathing and expressed as expiration-to-inspiration (E/I) ratio. Other cardiovascular and diabetes factors were also assessed. PWA was performed using SphgymoCor Px on 144 participants at the 18-year follow-up examination. Univariate and multivariate analyses for associations between baseline nerve function and other cardiovascular and diabetes-related factors were performed for augmentation index (AIx), augmentation pressure (AP), and subendocardial viability ratio (SEVR), a surrogate marker of myocardial perfusion.
RESULTS
E/I ratio correlated negatively with both AIx (r = −0.18, P = 0.03) and AP (r = −0.32, P < 0.001) and positively with SEVR (r = 0.47, P < 0.001) univariately. Lower baseline E/I ratio, HDL cholesterol, and a history of smoking were associated with higher follow-up (18 years later) AIx and AP and lower SEVR in multivariate analyses. Higher baseline HbA1 was also associated with higher AP and lower SEVR multivariately.
CONCLUSIONS
Cardiovascular autonomic neuropathy is associated with increased arterial stiffness measures and decreased estimated myocardial perfusion in those with type 1 diabetes some 18 years later. This association persists after adjustment for potential confounders as well as for baseline HbA1, HDL cholesterol, and smoking history, which were also associated with these PWA measures.
doi:10.2337/dc09-1936
PMCID: PMC2827525  PMID: 20040653
25.  Subcortical brain atrophy persists even in HAART-regulated HIV disease 
Brain Imaging and Behavior  2011;5(2):77-85.
The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy.
Electronic supplementary material
The online version of this article (doi:10.1007/s11682-011-9113-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11682-011-9113-8
PMCID: PMC3082694  PMID: 21264551
HIV; MRI; Gray matter; Basal ganglia

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