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1.  Associations between HIV Infection and Subclinical Coronary Atherosclerosis: The Multicenter AIDS Cohort Study (MACS) 
Annals of internal medicine  2014;160(7):458-467.
Background
Coronary artery disease (CAD) has been associated with HIV infection; however data are not consistent.
Objective
We performed cardiac CT to determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.
Design
Cross-sectional study within the Multicenter AIDS Cohort Study(MACS).
Participants
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.
Measurements
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.
Results
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%.
Conclusions
Coronary artery plaque, especially non-calcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.
Limitations
Cross-sectional observational study design and inclusion of only men.
Primary Funding Source
NHLBI and NIAID
doi:10.7326/M13-1754
PMCID: PMC4143766  PMID: 24687069
2.  Predictors of the Isolated Hepatitis B Core Antibody Pattern in HIV-Infected and -Uninfected Men in the Multicenter AIDS Cohort Study 
The isolated hepatitis B core antibody (anti-HBc) pattern was generally stable, associated with human immunodeficiency virus and hepatitis C virus infection, and most commonly transitioned to or from a pattern of past infection. The isolated anti-HBc pattern likely represents resolved hepatitis B virus infection with low or undetected anti-HBs.
Background. The significance of hepatitis B core antibody (anti-HBc) without hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs) is unclear.
Methods. This cohort study included men enrolled in the Multicenter AIDS Cohort to determine clinical and laboratory predictors of isolated anti-HBc.
Results. A total of 2286 subjects (51% human immunodeficiency virus [HIV]–infected) were followed over 3.9 years. Overall, 16.9% (387) had at least 1 visit with isolated anti-HBc. The isolated anti-HBc pattern was stable 84% of the time, and transitioned to or from a pattern of past infection (anti-HBc and anti-HBs). Isolated anti-HBc was associated with HIV infection (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.73–2.79) and hepatitis C virus (HCV; OR, 4.21; 95% CI; 2.99–5.91). The HCV association was stronger for chronic HCV infection (OR, 6.76; 95% CI, 5.08–8.99) than for cleared HCV (OR, 3.03; 95% CI, 1.83–5.03). HIV infection, chronic HCV, and cleared HCV infection all remained associated with isolated anti-HBc in multivariable models (OR, 1.74; 95% CI, 1.33–2.29; OR, 6.24; 95% CI, 4.62–8.42; and OR, 2.77; 95% CI, 1.65–4.66, respectively). Among HIV-infected subjects, highly active antiretroviral therapy was negatively associated (OR, 0.79; 95% CI, .66–.95) with isolated anti-HBc.
Conclusions. Isolated anti-HBc is associated with HIV and HCV coinfection, especially active HCV replication, and most commonly occurs as a transition to or from the pattern of natural immunity (anti-HBc and anti-HBs). The isolated anti-HBc pattern likely represents resolved HBV infection with low or undetected anti-HBs.
doi:10.1093/cid/cis908
PMCID: PMC3552525  PMID: 23090927
hepatitis B core antibody; human immunodeficiency virus; hepatitis C; highly active antiretroviral therapy
3.  Transcriptome analysis of HIV-infected peripheral blood monocytes: gene transcripts and networks associated with neurocognitive functioning 
Journal of neuroimmunology  2013;265(0):10.1016/j.jneuroim.2013.09.016.
Immunologic dysfunction, mediated via monocyte activity, has been implicated in the development of HIV-associated neurocognitive disorder (HAND). We hypothesized that transcriptome changes in peripheral blood monocytes relate to neurocognitive functioning in HIV+ individuals, and that such alterations could be useful as biomarkers of worsening HAND.
METHODS
mRNA was isolated from the monocytes of 86 HIV+ adults and analyzed with the Illumina HT-12 v4 Expression BeadChip. Neurocognitive functioning, HAND diagnosis, and other clinical and virologic variables were determined. Data were analyzed using standard expression analysis and weighted gene co-expression network analysis (WGCNA).
RESULTS
Neurocognitive functioning was correlated with multiple gene transcripts in the standard expression analysis. WGCNA identified two nominally significant co-expression modules associated with neurocognitive functioning, which were enriched with genes involved in mitotic processes and translational elongation.
CONCLUSIONS
Multiple modified gene transcripts involved in inflammation, cytoprotection, and neurodegeneration were correlated with neurocognitive functioning. The associations were not strong enough to justify their use as biomarkers of HAND; however, the associations of two co-expression modules with neurocognitive functioning warrants further exploration.
doi:10.1016/j.jneuroim.2013.09.016
PMCID: PMC3855455  PMID: 24094461
HIV-associated neurocognitive disorder; NeuroAIDS; monocyte; IL6R; KEAP1; LRP12; CSNK1A1; WGCNA
4.  Acute HIV-1 Seroconversion with an Unusual Plasma Biomarker Profile 
Clinical and Vaccine Immunology : CVI  2013;20(11):1774-1777.
An unusual case of acute primary HIV-1 infection in a man with a high plasma viral load, a 51-fold increase in C-reactive protein, and antibodies against only gp160 is described. Numerous serum cytokine concentrations were elevated during HIV-1 seroconversion.
doi:10.1128/CVI.00366-13
PMCID: PMC3837784  PMID: 24006141
5.  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.
Objective
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.
Design
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.
Methods
Relationships between body fat changes and change in Short Form-36 Physical and Mental Component Summary scores were investigated using mixed-model regression.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0114166
PMCID: PMC4250188  PMID: 25436612
6.  Risk Factors for Fatty Liver in the Multicenter AIDS Cohort Study 
OBJECTIVES
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).
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1038/ajg.2014.32
PMCID: PMC4133993  PMID: 24642579
7.  Antiretroviral Therapy-Induced Changes in Plasma Lipids and the Risk of Kidney Dysfunction in HIV-Infected Men 
AIDS Research and Human Retroviruses  2013;29(10):1346-1352.
Abstract
In the context of HIV, the initiation of effective antiretroviral therapy (ART) has been found to increase the risk of dyslipidemia in HIV-infected individuals, and dyslipidemia has been found to be a risk factor for kidney disease in the general population. Therefore, we examined changes in lipid profiles in HIV-infected men following ART initiation and the association with future kidney dysfunction. HIV-infected men from the Multicenter AIDS Cohort Study initiating ART between December 31, 1995 and September 30, 2011 with measured lipid and serum creatinine values pre-ART and post-ART were selected. The associations between changes in total cholesterol or high-density lipoprotein following ART initiation and the estimated change in glomerular filtration rate (eGFR) over time were assessed using piecewise linear mixed effects models. There were 365 HIV-infected men who contributed to the analysis. In the adjusted models, at 3 years post-ART, those with changes in total cholesterol >50 mg/dl had an average decrease in eGFR of 2.6 ml/min/1.73 m2 per year (p<0.001) and at 5 years post-ART, the average decrease was 2.4 ml/min/1.73 m2 per year (p=0.008). This decline contrasted with the estimates for those with changes in total cholesterol ≤50 mg/dl: 1.4 ml/min/1.73 m2 decrease per year (p<0.001) and 0.1 ml/min/1.73 m2 decrease per year (p=0.594) for the same time periods, respectively. Large decreases in high-density lipoprotein (a decline of greater than 5 mg/dl) were not associated with declines in eGFR. These results indicate that large ART-related increases in total cholesterol may be a risk factor for kidney function decline in HIV-infected men. Should these results be generalizable to the broader HIV population, monitoring cholesterol changes following the initiation of ART may be important in identifying HIV-infected persons at risk for kidney disease.
doi:10.1089/aid.2012.0253
PMCID: PMC3785801  PMID: 23758574
8.  The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy 
AIDS (London, England)  2013;27(13):2101-2110.
Objective
To assess whether CD8+ T-cell activation predicts risk of AIDS and non-AIDS morbidity during suppressive antiretroviral therapy (ART).
Design
Post-hoc analyses of ART-naïve subjects in prospective ART studies. Subjects with HIV-RNA levels ≤ 200 copies/mL and CD8+ T-cell activation data (%CD38+HLA-DR+) at year-one of ART were selected to determine years 2–5 incidence of AIDS and non-AIDS events.
Methods
We censored data at time of ART interruption or virologic failure. Inverse probability of censoring weighted logistic regression was used to correct for informative censoring.
Results
We included 1025 subjects; 82% were men, median age 38 years, pre-ART CD4 count 255 cells/mm3, and year-one activated CD8+ T-cells 24%. Of these, 752 had 5 years of follow-up; 379 remained on ART and had no confirmed plasma HIV-RNA >200 copies/mL. The overall probability of an AIDS or non-AIDS event in years 2–5 was estimated at 13% (95%-confidence interval [CI] 10–15%), had everyone remained on suppressive ART. Higher year-one activated CD8+ T-cell percentage increased the probability of subsequent events (Odds-Ratio 1.22 per 10% higher [95%-CI 1.04–1.44]); this effect was not significant after adjusting for age. Among those age ≥ 50 years (n=108 at year 1), the probability of an event in years 2–5 was 37% and the effect of CD8+ T-cell activation was more apparent (Odds-Ratio=1.42, p=0.02 unadjusted and adjusted for age).
Conclusions
CD8+ T-cell activation is prognostic of clinical events during suppressive ART although this association is confounded by age. The consequences of HIV-associated immune activation may be more important in those age ≥50 years.
doi:10.1097/QAD.0b013e32836191b1
PMCID: PMC3933027  PMID: 24326304
Antiretroviral Therapy; HIV/AIDS; CD8+T-cell activation; virologic suppression; loss to follow-up; observational data
9.  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.
Abstract
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.
doi:10.1089/aid.2013.0020
PMCID: PMC3715766  PMID: 23550976
10.  Incident Hepatitis C Virus Infection in Men Who Have Sex With Men: A Prospective Cohort Analysis, 1984–2011 
In the United States, incident hepatitis C among men who have sex with men has been ongoing since at least 1984. Risk factors included unprotected receptive anal intercourse with multiple partners, HIV infection, and lower CD4 T-cell count among HIV-infected men.
Background Prospective characterization of hepatitis C virus (HCV) transmission in both human immunodeficiency virus (HIV)–infected and –uninfected men who have sex with men (MSM) over the entire HIV epidemic has not been comprehensively conducted.
Methods To determine the trends in and risk factors associated with incident HCV in MSM since 1984, 5310 HCV antibody (anti-HCV)–negative MSM in the Multicenter AIDS Cohort Study were prospectively followed during 1984–2011 for anti-HCV seroconversion.
Results During 55 343 person-years (PYs) of follow-up, there were 115 incident HCV infections (incidence rate, 2.08/1000 PYs) scattered throughout the study period. In a multivariable analysis with time-varying covariates, older age (incidence rate ratio [IRR], 1.40/10 years, P < .001), enrollment in the later (2001–2003) recruitment period (IRR, 3.80, P = .001), HIV infection (IRR, 5.98, P < .001), drinking >13 alcoholic drinks per week (IRR, 1.68, P < .001), hepatitis B surface antigen positivity (IRR, 1.68, P < .001), syphilis (IRR, 2.95, P < .001), and unprotected receptive anal intercourse with >1 male partner (IRR, 3.37, P < .001) were independently associated with incident HCV. Among HIV-infected subjects, every 100 cell/mm3 increase in CD4 count was associated with a 7% (P = .002) decrease in the HCV incidence rate up to a CD4 count of 500 cells/mm3, whereas there was no association with highly active antiretroviral therapy.
Conclusions The spread of HCV among both HIV-infected and -uninfected MSM in the United States has been ongoing since the beginning of the HIV epidemic. In HIV-infected men with <500 CD4+ T cells, the HCV incidence rate was inversely proportional to CD4 T-cell count.
doi:10.1093/cid/cit197
PMCID: PMC3669529  PMID: 23532480
incident HCV; sexual transmission; MSM
11.  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
12.  Readmissions at a Public Safety Net Hospital 
PLoS ONE  2014;9(3):e91244.
Objective
We aimed to determine factors related to avoidability of 30-day readmissions at our public, safety net hospital in the United States (US).
Methods
We prospectively reviewed medical records of adult internal medicine patients with scheduled and unscheduled 30-day readmissions. We also interviewed patients if they were available. An independent panel used pre-specified, objective criteria to adjudicate potential avoidability.
Results
Of 153 readmissions evaluated, 68% were unscheduled. Among these, 67% were unavoidable, primarily due to disease progression and development of new diagnoses. Scheduled readmissions accounted for 32% of readmissions and most (69%) were clinically appropriate and unavoidable. The scheduled but avoidable readmissions (31%) were attributed largely to limited resources in our healthcare system.
Conclusions
Most readmissions at our public, safety net hospital were unavoidable, even among our unscheduled readmissions. Surprisingly, one-third of our overall readmissions were scheduled, the majority reflecting appropriate management strategies designed to reduce unnecessary hospital days. The scheduled but avoidable readmissions were due to constrained access to non-emergent, expensive procedures that are typically not reimbursed given our system’s payor mix, a problem which likely plague other safety net systems. These findings suggest that readmissions do not necessarily reflect inadequate medical care, may reflect resource constraints that are unlikely to be addressable in systems caring for a large burden of uninsured patients, and merit individualized review.
doi:10.1371/journal.pone.0091244
PMCID: PMC3949745  PMID: 24618829
13.  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
14.  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
15.  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
16.  Use of Cardiac CT Angiography Imaging in an Epidemiology Study – the Methodology of the Multicenter AIDS Cohort Study Cardiovascular Disease Substudy 
Objective
The methodology for use of cardiac CT angiography (CTA) in low risk populations is not well defined. In order to present a reference for future studies, we present CTA methodology that is being used in an epidemiology study- the Multicenter AIDS Cohort Study (MACS).
Methods
The Multicenter AIDS Cohort Study (MACS) is an on-going multicenter prospective, observational cohort study. The MACS Cardiovascular Disease substudy plans to enroll 800 men (n= 575 HIV seropositive and n= 225 HIV seronegative) age 40-75 years for coronary atherosclerosis imaging using cardiac CTA. The protocol includes heart rate (HR) optimization with beta blockers; use of proper field of view; scan length limitation; prospective ECG-gating using the lowest beam voltage possible. All scans are evaluated for presence, extent, and composition of coronary atherosclerosis, left atrial volumes, left ventricular volume and mass and non-coronary cardiac pathology.
Results
The first 498 participants had an average radiation dose of 2.5±1.6 milliSieverts (mSv) for the cardiac CTA study. Overall quality of scans was fair to excellent in 98.6% of studies. There were three significant adverse events- two allergic reactions to contrast and one subcutaneous contrast extravasation.
Conclusion
Cardiac CTA was safe and afforded a low effective radiation exposure to these asymptomatic research participants and provides valuable cardiovascular endpoints for scientific analysis. The cardiac CTA methodology described here may serve as a reference for use in future epidemiology studies aiming to assess coronary atherosclerosis and cardiac anatomy in low risk populations while minimizing radiation exposure.
doi:10.5152/akd.2013.065
PMCID: PMC3673004  PMID: 23376648
CT angiography; radiation dose; epidemiological study
17.  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
18.  HIV Monoinfection Is Associated With Increased Aspartate Aminotransferase-to-Platelet Ratio Index, a Surrogate Marker for Hepatic Fibrosis 
The Journal of Infectious Diseases  2012;205(6):1005-1013.
Background. Although liver disease commonly causes morbidity and mortality among human immunodeficiency virus (HIV)–infected individuals, data are limited on its prevalence in HIV monoinfection. We used the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate marker of hepatic fibrosis to characterize liver disease in the Multicenter AIDS Cohort Study.
Methods. Men were categorized based on their HIV and viral hepatitis status: uninfected (n = 1170), HIV monoinfected (n = 509), viral hepatitis monoinfected (n = 74), and HIV–viral hepatitis coinfected (n = 66).
Results. The median APRI in the HIV-monoinfected group was similar to that in the hepatitis-monoinfected group (0.42 vs 0.43; P > .05), higher than in the uninfected group (0.42 vs 0.27; P < .001) but lower than in the coinfected group (0.42 vs 1.0; P < .001). On multivariable analysis, HIV infection (1.39-fold increase [FI]; P < .001), viral hepatitis infection (1.52-FI; P < .001), and the interaction between HIV and viral hepatitis infections were independently associated with a higher APRI (1.57-FI; P < .001). Among the HIV-infected men, viral hepatitis coinfection (2.34-FI; P < .001), HIV RNA ≥100 000 copies/mL (1.26-FI; P = .007), and CD4 count ≤200 cells/mL (1.23-FI; P = .022) were independently associated with a higher APRI.
Conclusions. HIV and viral hepatitis are independently associated with an increased APRI. Further studies are needed to understand the biological basis for the association between HIV and liver disease.
doi:10.1093/infdis/jir885
PMCID: PMC3282573  PMID: 22291196
19.  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
20.  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
21.  A Controlled Investigation of Optimal Internal Medicine Ward Team Structure at a Teaching Hospital 
PLoS ONE  2012;7(4):e35576.
Background
The optimal structure of an internal medicine ward team at a teaching hospital is unknown. We hypothesized that increasing the ratio of attendings to housestaff would result in an enhanced perceived educational experience for residents.
Methods
Harbor-UCLA Medical Center (HUMC) is a tertiary care, public hospital in Los Angeles County. Standard ward teams at HUMC, with a housestaff∶attending ratio of 5∶1, were split by adding one attending and then dividing the teams into two experimental teams containing ratios of 3∶1 and 2∶1. Web-based Likert satisfaction surveys were completed by housestaff and attending physicians on the experimental and control teams at the end of their rotations, and objective healthcare outcomes (e.g., length of stay, hospital readmission, mortality) were compared.
Results
Nine hundred and ninety patients were admitted to the standard control teams and 184 were admitted to the experimental teams (81 to the one-intern team and 103 to the two-intern team). Patients admitted to the experimental and control teams had similar age and disease severity. Residents and attending physicians consistently indicated that the quality of the educational experience, time spent teaching, time devoted to patient care, and quality of life were superior on the experimental teams. Objective healthcare outcomes did not differ between experimental and control teams.
Conclusions
Altering internal medicine ward team structure to reduce the ratio of housestaff to attending physicians improved the perceived educational experience without altering objective healthcare outcomes.
doi:10.1371/journal.pone.0035576
PMCID: PMC3330818  PMID: 22532860
22.  Age and Racial / Ethnic Differences in the Prevalence of Reported Symptoms in HIV-Infected Persons on Antiretroviral Therapy 
Few studies have evaluated age and racial/ethnic differences in the prevalence of symptoms in HIV infection. Thus, the objective of this study was to compare the prevalence of gastrointestinal, metabolic, general malaise, neurologic, or other self-reported symptoms by age and race/ethnicity among 1,574 HIV-infected women enrolled in the Women’s Interagency HIV Study and 955 HIV-infected men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study. All patients had known dates of initiation of highly-active antiretroviral therapy. It was observed that women ≥50 years were less likely to experience gastrointestinal symptoms (24% vs. 27%, multivariable p=0.024), but more likely to experience general malaise (47% vs. 37%; multivariable p=0.004), neurologic (44% vs. 38%; multivariable p=0.048), or other symptoms (40% vs. 28%; multivariable P<0.001) compared to women <40 years of age. Only neurologic symptoms had a higher prevalence among older MSM (52% vs. 37%; multivariable P=0.002), largely driven by paresthesias (48% vs. 31%; multivariable p=0.004), the most common individual symptom reported by men. Caucasian women generally had the highest prevalence of symptoms and African-American women had the lowest prevalence. Few racial/ethnic differences were noted for MSM. Depression and a prior diagnosis of AIDS were the strongest and most consistent predictors of clinical symptoms in both cohorts. In summary, the prevalence of reported symptoms varies with patient race/ethnicity, age, and modifiable factors such as depression and HIV disease stage. Clinicians should consider these factors when counseling patients regarding potential adverse effects of antiretrovirals or symptoms associated with HIV disease.
doi:10.1016/j.jpainsymman.2008.08.007
PMCID: PMC2858004  PMID: 19329274
Highly active antiretroviral therapy; symptoms; gender; race/ethnicity; aging
23.  Hepatitis B and long-term HIV outcomes in co-infected HAART recipients 
AIDS (London, England)  2009;23(14):1881-1889.
Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of highly active antiretroviral therapy (HAART). The impact of CH-B on long-term HAART outcomes has not been fully characterized.
Methods
To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study (MACS) were retrospectively analyzed. Subjects were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS defining illnesses, CD4 rise, and HIV suppression was assessed using regression analysis.
Results
Of 816 men followed for a median of 7 years on HAART, 350 were never HBV infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death (8.3/1000 person-years (PYs)). It was highest in those with CH-B (17/1000 PYs, 95% CI 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% CI 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared to those never infected (P=0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted HR 4.1, p=0.04). There was no significant difference in AIDS defining events, HIV RNA suppression, and CD4 increase.
Conclusion
In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART.
doi:10.1097/QAD.0b013e32832e463a
PMCID: PMC2861825  PMID: 19550291
hepatitis B; HIV; HAART; CD4; mortality; isolated core hepatitis B
24.  Interaction between RANTES promoter variant and CCR5Δ32 favors recovery from hepatitis B 
Recovery from acute hepatitis B virus (HBV) infection occurs in 95% of adult-acquired infections. A 32-base pair deletion in CCR5 (CCR5Δ32), which encodes for a nonfunctional receptor, increases the likelihood of recovery. Using 181 subjects with persistent HBV infection and 316 who had recovered, we tested the hypothesis that an epistatic interaction between functional polymorphisms in RANTES (a CCR5 ligand) and CCR5 impacts recovery. Specific models designed to assess individual contributions of compound genotypes demonstrated that the only combination associated with recovery from an HBV infection was RANTES -403A with CCR5Δ32 (OR 0.36, P= 0.02). Since the phenotypic consequence of -403A is reported to be higher levels of RANTES, we propose a model where excess RANTES in combination with low CCR5 favor recovery from an HBV infection, which will require validation through functional testing. “This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org.”
PMCID: PMC2650505  PMID: 19017985
Viral infection; chemokines; human
25.  Asymptomatic Sexually Transmitted Infections in HIV-Infected Men Who Have Sex with Men: Prevalence, Incidence, Predictors, and Screening Strategies 
AIDS Patient Care and STDs  2008;22(12):947-954.
Abstract
Sexually transmitted infections (STIs) have increased among men who have sex with men (MSM) and are associated with unsafe sex practices, intrinsic morbidity, and enhanced genital shedding and transmission of HIV. Screening for asymptomatic STIs is recommended as part of the HIV prevention efforts, however, optimal screening strategies among HIV-infected MSM have not been well defined. In this study, conducted from April 2004 to September 2006, 212 HIV-infected MSM from two urban HIV clinics were screened for asymptomatic STIs. Testing for Neisseria gonorrhea and Chlamydia trachomatis from pharynx, rectum, and urine, as well as serologic testing for syphilis were performed initially, and then after 6 and 12 months. A self-administered questionnaire was used to assess possible predictors of incident asymptomatic STIs. A cost analysis was performed to assess different screening strategies for detecting incident STIs. The baseline prevalence of STIs was 14% (n = 29; 95% confidence interval [CI] 9%–19%) and the incidence of new infections was 20.8 cases per 100 person years (95% CI 14.8–28.4 cases per 100 person years). Younger age, higher CD4 cell count, and marijuana use were associated with increased risk of acquiring an asymptomatic STI. The laboratory cost to detect one positive STI did not significantly differ between once- and twice-yearly screening. However, almost half of all incident STIs were detected at the 6-month screening visit, potentially resulting in an increased duration of infectivity if these cases remained undiagnosed. In conclusion, prevalent and incident asymptomatic STIs are common among HIV-infected MSM. Our data support current Center for Disease Control and Prevention STI guidelines that recommend routine screening at increased frequency for HIV-infected MSM.
doi:10.1089/apc.2007.0240
PMCID: PMC2929381  PMID: 19072101

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