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1.  Pulmonary Function in HIV-Infected Recreational Drug Users in the Era of Anti-Retroviral Therapy 
Individuals with HIV infection commonly have pulmonary function abnormalities, including airflow obstruction and diffusion impairment, which may be more prevalent among recreational drug users. To date, the relationship between drug use and pulmonary function abnormalities among those with HIV remains unclear.
To determine associations between recreational drug use and airflow obstruction, diffusion impairment, and radiographic emphysema in men and women with HIV.
Cross-sectional analysis of pulmonary function and self-reported recreational drug use data from a cohort of 121 men and 63 women with HIV. Primary outcomes were the presence (yes/no) of: 1) airflow obstruction, (pre- or post-bronchodilator forced expiratory volume in 1 second/forced vital capacity<0.70); 2) moderate diffusion impairment (diffusing capacity for carbon monoxide <60% predicted); and 3) radiographic emphysema (>1% of lung voxels <−950 Hounsfield units). Exposures of interest were frequency of recreational drug use, recent (since last study visit) drug use, and any lifetime drug use. We used logistic regression to determine associations between recreational drug use and the primary outcomes.
HIV-infected men and women reported recent recreational drug use at 56.0% and 31.0% of their study visits, respectively, and 48.8% of men and 39.7% of women reported drug use since their last study visit. Drug use was not associated with airway obstruction or radiographic emphysema in men or women. Recent crack cocaine use was independently associated with moderate diffusion impairment in women (odds ratio 17.6; 95% confidence interval 1.3–249.6, p=0.03).
In this cross-sectional analysis, we found that recreational drug use was common among HIV-infected men and women and recent crack cocaine use was associated with moderate diffusion impairment in women. Given the increasing prevalence of HIV infection, any relationship between drug use and prevalence or severity of chronic pulmonary diseases could have a significant impact on HIV and chronic disease management.
PMCID: PMC4318265  PMID: 25664201
HIV; COPD; Emphysema; Diffusion impairment; Drug use; Pulmonary function; Cocaine
2.  Self-Reported Body Fat Change in HIV-Infected Men Is a Marker of Decline in Physical Health-Related Quality of Life with Aging, Independent of Co-Morbidity 
PLoS ONE  2014;9(12):e114166.
Self-perception of changes in body fat among HIV+ persons is associated with decreased health related quality of life in cross-sectional studies. The longitudinal impact of body fat changes on health related quality of life, while accounting for comorbidity and anatomic location or severity of body fat changes, is unknown.
This was a longitudinal analysis of HIV+ and HIV- Multicenter AIDS Cohort Study (MACS) participants who completed questionnaires assessing self-perceived body fat changes (baseline visit) and a health related quality of life (Short Form-36) at baseline and then ≥5 years later.
Relationships between body fat changes and change in Short Form-36 Physical and Mental Component Summary scores were investigated using mixed-model regression.
We studied 270 HIV+ and 247 HIV- men. At baseline, ≥50% of HIV+ men reported body fat changes; physical component but not mental component summary scores were lower among HIV+ men who reported moderate/severe leg or abdominal fat changes (p<0.05). At follow-up, physical component summary scores were significantly lower among men with face, leg, or abdominal fat changes compared to men without perceived fat changes (p<0.05). No significant changes were seen in mental component scores by fat change location or severity. In the final model, body fat changes at any site or severity were significant predictors of a decline in physical component summary score (p<0.05), independent of demographics or comorbidities. Mental component summary score was not associated with body fat changes, but higher mental component summary score was associated with increasing age and time.
Negative self-perceived body fat changes were associated with decline in physical health related quality of life, independent of comorbidities, and may be a marker of an increased risk for physical function decline with aging.
PMCID: PMC4250188  PMID: 25436612
3.  HIV Infection is associated with reduced pulmonary diffusing capacity 
Journal of acquired immune deficiency syndromes (1999)  2013;64(3):10.1097/QAI.0b013e3182a9215a.
Prior studies comparing abnormalities in pulmonary function between HIV-infected and HIV-uninfected persons in the current era are limited.
To determine the pattern and severity of impairment in pulmonary function in HIV-infected compared to HIV-uninfected individuals.
Cross-sectional analysis of 300 HIV-infected and 289 HIV-uninfected men enrolled from 2009-2011 in two clinical centers of the Lung HIV Study. Participants completed pre- and post-bronchodilator spirometry, diffusing capacity (DLCO) measurement, and standardized questionnaires.
Most participants had normal airflow; 18% of HIV-infected and 16% of HIV-uninfected men had airflow obstruction. The mean percent predicted DLCO was 69% in HIV-infected vs. 76% in HIV-uninfected men (p<0.001). A moderately to severely reduced DLCO of ≤60% was observed in 30% of HIV-infected compared to 18% of HIV-uninfected men (p<0.001), despite the fact that 89% of those with HIV were on antiretroviral therapy. A reduced DLCO was significantly associated with HIV and CD4 cell count in linear regression adjusting for smoking and other confounders. The DLCO was lowest in HIV-infected men with CD4 cell counts <200 compared to those with CD4 cell counts ≥200 and to HIV-uninfected men. Respiratory symptoms of cough, phlegm and dyspnea were more prevalent in HIV-infected patients particularly those with abnormal pulmonary function compared to HIV-uninfected patients.
HIV infection is an independent risk factor for reduced DLCO, particularly in individuals with a CD4 cell count below 200. Abnormalities in pulmonary function among HIV-infected patients manifest clinically with increased respiratory symptoms. Mechanisms accounting for the reduced DLCO require further evaluation.
PMCID: PMC3845879  PMID: 23979001
Pulmonary function; FEV1; DLCO; gas exchange; COPD; HIV/AIDS
4.  Risk Factors for Fatty Liver in the Multicenter AIDS Cohort Study 
Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase the risk of fatty liver disease. We determined the prevalence of and risk factors for fatty liver by comparing HIV-infected men with HIV-uninfected men who have sex with men in the Multicenter AIDS Cohort Study (MACS).
In 719 MACS participants who consumed less than three alcoholic drinks daily, fatty liver was defined as a liver-to-spleen attenuation ratio < 1 on noncontrast computed tomography (CT). We genotyped single nucleotide polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and in other genes previously associated with nonalcoholic fatty liver disease. Risk factors for fatty liver were determined using multivariable logistic regression.
Among 254 HIV-uninfected men and 465 HIV-infected men, 56 % were White with median age 53 years and median body mass index 25.8 kg/m 2. The vast majority of HIV-infected men (92 %) were on ART, and 87 % of the HIV-infected men were treated with a nucleoside reverse transcriptase inhibitor for a median duration of 8.5 years. Overall, 15 % of the cohort had fatty liver, which was more common in the HIV-uninfected compared with the HIV-infected men (19 vs. 13 %, P= 0.02). In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR) = 0.44, P= 0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR = 2.06, P= 0.005), more abdominal visceral adipose tissue (OR = 1.08 per 10 cm2, P< 0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥ 4.9 (OR = 2.50, P= 0.001). Among HIV-infected men, PNPLA3 (rs738409) non-CC genotype was associated with a higher prevalence of fatty liver (OR = 3.30, P= 0.001) and cumulative dideoxynucleoside exposure (OR = 1.44 per 5 years, P= 0.02).
CT-defined fatty liver is common among men at risk for HIV infection and is associated with greater visceral adiposity, HOMA-IR, and PNPLA3 (rs738409). Although treated HIV infection was associated with a lower prevalence of fatty liver, prolonged exposure to dideoxynucleo side analogs is associated with higher prevalence.
PMCID: PMC4133993  PMID: 24642579
5.  Associations between HIV Infection and Subclinical Coronary Atherosclerosis: The Multicenter AIDS Cohort Study (MACS) 
Annals of internal medicine  2014;160(7):458-467.
Coronary artery disease (CAD) has been associated with HIV infection; however data are not consistent.
We performed cardiac CT to determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.
Cross-sectional study within the Multicenter AIDS Cohort Study(MACS).
HIV-infected (n=618) and –uninfected (n=383) men who have sex with men (MSM) had non-contrast and contrast enhanced cardiac CT if they were between 40–70 years, weighed <300 pounds, and had no history of coronary revascularization.
Presence and extent, for those with plaque, of coronary artery calcium (CAC) on non-contrast CT, and of any plaque, non-calcified, mixed or calcified plaque and stenosis on CT angiography.
1001 men underwent non-contrast CT of whom 759 had coronary CT angiography. After adjusting for age, race, center, and cohort, HIV-infected men had a greater prevalence of CAC [Prevalence ratio(PR)=1.21, 95% confidence interval (CI) 1.08–1.35, p=0.001], and any plaque [PR=1.14(1.05–1.24),p=0.001], including non-calcified plaque [PR=1.28(1.13–1.45),p<0.001) and mixed plaque [PR=1.35(1.10–1.65),p=0.004] than HIV-uninfected men. Associations between HIV-infection and any plaque and non-calcified plaque remained significant (p<0.005) after CAD risk factor adjustment. HIV-infected men also had a greater extent of non-calcified plaque after CAD risk factor adjustment (p=0.026). HIV-infected men had a greater prevalence of coronary artery stenosis>50% than HIV-uninfected men [PR=1.48(1.06–2.07),p=0.020), but not after CAD risk factor adjustment. Longer duration of highly active antiretroviral therapy [PR=1.09(1.02–1.17), p=0.007,per year] and lower nadir CD4+ T-cell count [PR=0.80(0.69–0.94),p=0.005, per 100 cells] were associated with coronary stenosis>50%.
Coronary artery plaque, especially non-calcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.
Cross-sectional observational study design and inclusion of only men.
Primary Funding Source
PMCID: PMC4143766  PMID: 24687069
6.  Lipodystrophy and Inflammation Predict Later Grip Strength in HIV-Infected Men: The MACS Body Composition Substudy 
AIDS Research and Human Retroviruses  2013;29(8):1138-1145.
Body fat changes in HIV-infected persons are associated with increased systemic inflammation and increased mortality. It is unknown whether lipodystrophy is also associated with declines in physical function. Between 2001 and 2003, 33 HIV-infected men with evidence of lipodystrophy (LIPO+), 23 HIV-infected men without lipodystrophy (LIPO−), and 33 seronegative men were recruited from the Multicenter AIDS Cohort Study (MACS) for the Body Composition substudy. Visceral adipose tissue (VAT) was assessed by quantitative computed tomography. Lean body mass (LBM) and extremity fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was estimated by Homeostatic Model Assessment (HOMA). Serum interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptors I and II (sTNFRI and sTNFRII), and highly sensitive C-reactive protein (hs-CRP) concentrations were quantified from archived serum samples. These measurements were correlated with grip strength measured in 2007 using linear regression. At the substudy visit, the LIPO+ group had higher HOMA, sTNFRI, sTNFRII, and IL-6 levels than the LIPO− group. In 2007, the LIPO+ group had lower median grip strength than the LIPO− group (34.4 vs. 42.7 kg, p=0.002). Multivariable analysis of HIV+ men showed older age, lower LBM, higher sTNFRII concentrations, and LIPO+ status [adjusted mean difference −4.9 kg (p=0.045)] at the substudy visit were independently associated with lower subsequent grip strength. Inflammation, lower LBM, and lipodystrophy in HIV-infected men were associated with lower subsequent grip strength. These findings suggest that inflammation may contribute to declines in functional performance, independent of age.
PMCID: PMC3715766  PMID: 23550976
7.  Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons 
Rotger, Margalida | Glass, Tracy R. | Junier, Thomas | Lundgren, Jens | Neaton, James D. | Poloni, Estella S. | van 't Wout, Angélique B. | Lubomirov, Rubin | Colombo, Sara | Martinez, Raquel | Rauch, Andri | Günthard, Huldrych F. | Neuhaus, Jacqueline | Wentworth, Deborah | van Manen, Danielle | Gras, Luuk A. | Schuitemaker, Hanneke | Albini, Laura | Torti, Carlo | Jacobson, Lisa P. | Li, Xiuhong | Kingsley, Lawrence A. | Carli, Federica | Guaraldi, Giovanni | Ford, Emily S. | Sereti, Irini | Hadigan, Colleen | Martinez, Esteban | Arnedo, Mireia | Egaña-Gorroño, Lander | Gatell, Jose M. | Law, Matthew | Bendall, Courtney | Petoumenos, Kathy | Rockstroh, Jürgen | Wasmuth, Jan-Christian | Kabamba, Kabeya | Delforge, Marc | De Wit, Stephane | Berger, Florian | Mauss, Stefan | de Paz Sierra, Mariana | Losso, Marcelo | Belloso, Waldo H. | Leyes, Maria | Campins, Antoni | Mondi, Annalisa | De Luca, Andrea | Bernardino, Ignacio | Barriuso-Iglesias, Mónica | Torrecilla-Rodriguez, Ana | Gonzalez-Garcia, Juan | Arribas, José R. | Fanti, Iuri | Gel, Silvia | Puig, Jordi | Negredo, Eugenia | Gutierrez, Mar | Domingo, Pere | Fischer, Julia | Fätkenheuer, Gerd | Alonso-Villaverde, Carlos | Macken, Alan | Woo, James | McGinty, Tara | Mallon, Patrick | Mangili, Alexandra | Skinner, Sally | Wanke, Christine A. | Reiss, Peter | Weber, Rainer | Bucher, Heiner C. | Fellay, Jacques | Telenti, Amalio | Tarr, Philip E.
We show in human immunodeficiency virus–positive persons that the coronary artery disease effect of an unfavorable genetic background is comparable to previous studies in the general population, and comparable in size to traditional risk factors and antiretroviral regimens known to increase cardiovascular risk.
Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection.
Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort.
Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD.
Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.
PMCID: PMC3669528  PMID: 23532479
HIV infection; coronary artery disease; genetics; traditional risk factors; antiretroviral therapy
8.  Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma 
PLoS ONE  2014;9(6):e99144.
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.
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.
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.
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.
PMCID: PMC4055650  PMID: 24922518
9.  HAART-Associated Dyslipidemia Varies by Biogeographical Ancestry in the Multicenter AIDS Cohort Study 
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.
PMCID: PMC3653392  PMID: 23343448
10.  Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts 
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.
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.
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.
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.
PMCID: PMC4021087  PMID: 24884738
AIDS; HIV; Pulmonary disease; Chronic obstructive; Respiratory tract diseases; Sleep apnea syndromes
11.  Lower Adiponectin is Associated with Subclinical Cardiovascular Disease among HIV-infected Men 
AIDS (London, England)  2014;28(6):901-909.
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.
Nested cohort study.
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).
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.
Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.
PMCID: PMC3967406  PMID: 24401646
Adipokines; adiponectin; leptin; heart; subclinical coronary atherosclerosis; metabolic side effects of HIV infection; coronary CT angiography; cardiac CT
12.  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.
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).
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.
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).
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.
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.
PMCID: PMC3917840  PMID: 24516530
13.  Morning free and total testosterone in HIV-infected men: implications for the assessment of hypogonadism 
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.
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.
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.
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.
PMCID: PMC3900935  PMID: 24450960
Testosterone; Sex hormone binding globulin; HIV; Hypogonadism
14.  The Impact of Impaired Kidney Function and HIV Infection on the Risk of Anemia 
AIDS Research and Human Retroviruses  2012;28(12):1666-1671.
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.
PMCID: PMC3505063  PMID: 22632256
15.  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.
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.
PMCID: PMC3641816  PMID: 22495733
Cohort study; Confounding; g-formula; HIV/AIDS; Monte Carlo methods
16.  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.
PMCID: PMC3392500  PMID: 22472456
herpesvirus; HSV-2; atherosclerosis; HIV-1/AIDS; risk factors
17.  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.
PMCID: PMC3606588  PMID: 22627881
18.  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.
PMCID: PMC3690565  PMID: 23805163
AIDS; diabetes mellitus; HIV; insulin resistance; physical function
19.  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.
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.
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.
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.
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
20.  Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study 
AIDS (London, England)  2008;22(13):1589-1599.
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).
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.
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.
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).
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.
PMCID: PMC3633463  PMID: 18670218
21.  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.
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).
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.
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.
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).
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.
PMCID: PMC3595204  PMID: 23554932
22.  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.
PMCID: PMC3282878  PMID: 22302074
acquired immunodeficiency syndrome; case-cohort studies; cohort studies; confounding bias; HIV; pharmacoepidemiology; selection bias
23.  Factors affecting brain structure in men with HIV disease in the post-HAART era 
Neuroradiology  2011;54(2):113-121.
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.
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.
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.
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.
PMCID: PMC3154580  PMID: 21424708
MRI; Cognition; HIV; Age; Voxel-based morphometry
24.  Cancer incidence in the Multicenter AIDS Cohort Study before and during the HAART era: 1984–2007 
Cancer  2010;116(23):5507-5516.
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.
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.
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.
Cancer risk remains elevated among HIV-infected men who have sex with men, highlighting the continuing need for appropriate cancer screening in this population.
PMCID: PMC2991510  PMID: 20672354
HIV infection; cancer incidence; malignancy; AIDS-defining malignancy; HAART
25.  Sex Hormones, Insulin Resistance, and Diabetes Mellitus among Men with or at Risk for HIV Infection 
To examine the relationship of free testosterone (FT) and sex hormone-binding globulin (SHBG) with insulin resistance and diabetes mellitus (DM) in HIV disease.
Cross-sectional analysis from 322 HIV-uninfected and 534 HIV-infected men in the Multicenter AIDS Cohort Study.
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.
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.
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.
PMCID: PMC3175332  PMID: 21705912
Testosterone; Sex Hormone-Binding Globulin; Insulin Resistance; Diabetes Mellitus; HIV

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