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1.  Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009 
Hanna, David B. | Buchacz, Kate | Gebo, Kelly A. | Hessol, Nancy A. | Horberg, Michael A. | Jacobson, Lisa P. | Kirk, Gregory D. | Kitahata, Mari M. | Korthuis, P. Todd | Moore, Richard D. | Napravnik, Sonia | Patel, Pragna | Silverberg, Michael J. | Sterling, Timothy R. | Willig, James H. | Lau, Bryan | Althoff, Keri N. | Crane, Heidi M. | Collier, Ann C. | Samji, Hasina | Thorne, Jennifer E. | Gill, M. John | Klein, Marina B. | Martin, Jeffrey N. | Rodriguez, Benigno | Rourke, Sean B. | Gange, Stephen J. | Benson, A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Platt, Aaron | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Abraham, Alison G. | Lau, Bryan | Althoff, Keri N. | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
doi:10.1093/cid/cit003
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
2.  Increases in Duration of First HAART over Time (1996-2009) and Associated Factors in the Multicenter AIDS Cohort Study 
Background:
Antiretroviral regimens (ART) changes occur frequently among HIV-infected persons. Duration and type of initial highly active antiretroviral therapy (HAART) and factors associated with regimen switching were evaluated in the Multicenter AIDS cohort Study.
Methods:
Participants were classified according to the calendar period of HAART initiation: T1 (1996-2001), T2 (2002-2005) and T3 (2006-2009). Kaplan Meier curves depicted time from HAART initiation to first regimen changes within 5.5 years. Cox proportional hazards regression models were used to examine factors associated with time to switching.
Results:
Of 1009 participants, 796 changed regimen within 5.5 years after HAART initiation. The percentage of participants who switched declined from 85% during T1 to 49 % in T3., The likelihood of switching in T3 decreased by 50% (p<0.01) compared to T1 after adjustment for pre-HAART ART use, age, race and CD4 count. Incomplete HIV suppression decreased over time (p<0.01) but predicted switching across all time periods. Lower HAART adherence (≤ 95% of prescribed doses) was predictive of switching only in T1. In T2, central nervous system symptoms predicted switching (RH = 1.7, p= 0.012). Older age at HAART initiation was associated with increased switching in T1 (RH=1.03 per year increase) and decreased switching in T2 (RH = 0.97 per year increase).
Conclusions:
During the first 15 years of the HAART era, initial HAART regimen duration lengthened and regimen discontinuation rates diminished. Both HIV RNA non-suppression and poor adherence predicted switching prior to 2001 while side effects that were possibly ART-related were more prominent during T2.
doi:10.1097/QAI.0b013e3182a99a0d
PMCID: PMC3896869  PMID: 24419062
3.  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
4.  Rapid and Sustainable Detoxication of Airborne Pollutants by Broccoli Sprout Beverage: Results of a Randomized Clinical Trial in China 
Broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can generate the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases (GSTs) and other cytoprotective enzymes. A broccoli sprout-derived beverage providing daily doses of 600 μmol glucoraphanin and 40 μmol sulforaphane was evaluated for magnitude and duration of pharmacodynamic action in a 12-week randomized clinical trial. Two hundred and ninety-one study participants were recruited from the rural He-He Township, Qidong, in the Yangtze River delta region of China, an area characterized by exposures to substantial levels of airborne pollutants. Exposure to air pollution has been associated with lung cancer and cardiopulmonary diseases. Urinary excretion of the mercapturic acids of the pollutants, benzene, acrolein, and crotonaldehyde, were measured before and during the intervention using liquid chromatography tandem mass spectrometry. Rapid and sustained, statistically significant (p ≤ 0.01) increases in the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde were found in those receiving broccoli sprout beverage compared with placebo. Excretion of the benzene-derived mercapturic acid was higher in participants who were GSTT1-positive compared to the null genotype, irrespective of study arm assignment. Measures of sulforaphane metabolites in urine indicated that bioavailability did not decline over the 12-week daily dosing period. Thus, intervention with broccoli sprouts enhances the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.
doi:10.1158/1940-6207.CAPR-14-0103
PMCID: PMC4125483  PMID: 24913818
Air pollution; broccoli; sulforaphane; benzene; chemoprevention
5.  Comparison of Racial Differences in Plaque Composition and Stenosis among HIV Positive and Negative Men from the Multicenter Aids Cohort Study (MACS) 
The American journal of cardiology  2014;114(3):369-375.
Previous studies demonstrated that blacks have less coronary artery calcification (CAC) than whites. We evaluated racial differences in plaque composition and stenosis in the Multicenter AIDS Cohort Study (MACS). HIV positive and negative men completed non-contrast cardiac CT if they were 40–70 years, weighed <300 pounds, and had no prior history of cardiac surgery or revascularization, and if eligible, coronary CT angiography (CTA). There were 1001 men who underwent CT scans and 759 men had CTA. We measured CAC on non-contrast CT, and total plaque, non-calcified, calcified, and mixed plaque, and identified coronary stenosis >50% on CTA. The association of presence and extent of plaque with race was determined after adjustment for HIV serostatus, cardiovascular risk factors and measures of socioeconomic status. The prevalences of any plaque on CTA and non-calcified plaque were not different between black and white men; however, black men had lower prevalences of CAC (Prevalence ratio (PR)=0.79, p=0.01), calcified plaque (PR=0.69, p=0.002), and stenosis >50% (PR=0.59, p=0.009). There were no associations between black race and extent of plaque in fully adjusted models. Using log-linear regression, black race was associated with a lower extent of any plaque on CTA in HIV positive men (estimate=−0.24, p=0.051) but not in HIV negative men (0.12, p=0.50, HIV interaction p=0.005). In conclusion, a lower prevalence of CAC in black compared to white men appears to reflect less calcification of plaque and stenosis rather than a lower overall prevalence of plaque.
doi:10.1016/j.amjcard.2014.04.049
PMCID: PMC4143765  PMID: 24929623
Epidemiology; plaque; coronary angiography; coronary artery disease; HIV
6.  Epicardial Fat is Associated with Duration of Antiretroviral Therapy and Coronary Atherosclerosis: The Multicenter AIDS Cohort Study 
AIDS (London, England)  2014;28(11):1635-1644.
Objective
Cytokines released by epicardial fat are implicated in the pathogenesis of atherosclerosis. HIV infection and anti-retroviral therapy have been associated with changes in body fat distribution and coronary artery disease. We sought to determine if HIV infection is associated with greater epicardial fat and if epicardial fat is associated with subclinical coronary atherosclerosis.
Design
We studied 579 HIV-infected and 353 HIV-uninfected men age 40 to 70 years with non-contrast computed tomography (CT) to measure epicardial adipose tissue volume (EAT) and coronary artery calcium (CAC). Total plaque score (TPS), and plaque subtypes (non-calcified, calcified and mixed) were measured by coronary CT angiography in 706 men.
Methods
We evaluated the association between EAT and HIV serostatus, and the association of EAT with subclinical atherosclerosis, adjusting for age, race and serostatus and with additional cardiovascular (CV) risk factors and tested for modifying effects of HIV serostatus.
Results
HIV-infected men had greater EAT than HIV-uninfected men (p=0.001). EAT was positively associated with duration of antiretroviral therapy (p=0.02), specifically AZT (p<0.05). EAT was associated with presence of any coronary artery plaque (p=0.006) and non-calcified plaque (p=0.001), adjusting for age, race, serostatus and CV risk factors. Among men with CAC, EAT was associated with CAC extent (p=0.006). HIV serostatus did not modify associations between EAT and either CAC extent or presence of plaque.
Conclusions
Greater epicardial fat volume in HIV-infected men and its association with coronary plaque and antiretroviral therapy duration suggest potential mechanisms that might lead to increased risk for cardiovascular disease in HIV.
doi:10.1097/QAD.0000000000000116
PMCID: PMC4169787  PMID: 24809732
Imaging; plaque; risk factors; HIV; ART
7.  Disparities in the Quality of HIV Care When Using US Department of Health and Human Services Indicators 
Althoff, Keri N. | Rebeiro, Peter | Brooks, John T. | Buchacz, Kate | Gebo, Kelly | Martin, Jeffrey | Hogg, Robert | Thorne, Jennifer E. | Klein, Marina | Gill, M. John | Sterling, Timothy R. | Yehia, Baligh | Silverberg, Michael J. | Crane, Heidi | Justice, Amy C. | Gange, Stephen J. | Moore, Richard | Kitahata, Mari M. | Horberg, Michael A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Kenneth H. | Hogg, Robert S. | Richard Harrigan, P. | Montaner, Julio SG | Cescon, Angela | Samji, Hasina | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Moore, Richard D. | Carey, John T. | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann N. | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M.John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | Althoff, Keri N. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Morton, Liz | McReynolds, Justin | Lober, William B. | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
doi:10.1093/cid/ciu044
PMCID: PMC3967825  PMID: 24463281
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression
8.  A comparison of ad hoc methods to account for non-cancer AIDS and deaths as competing risks when estimating the effect of HAART on incident cancer AIDS among HIV-infected men 
Journal of clinical epidemiology  2009;63(4):459-467.
Objective
We compared three ad hoc methods to estimate the marginal hazard of incident cancer AIDS in a highly active antiretroviral therapy (1996–2006) relative to a monotherapy/combination therapy (1990–1996) calendar period, accounting for other AIDS events and deaths as competing risks.
Study Design and Setting
Among 1911 HIV+ men from the Multicenter AIDS Cohort Study, 228 developed cancer AIDS and 745 developed competing risks in 14,202 person-years from 1990–2006. Method 1 censored competing risks at the time they occurred, method 2 excluded competing risks, and method 3 censored competing risks at the date of analysis.
Results
The age, race and infection duration adjusted hazard ratios (HRs) for cancer AIDS were similar for all methods (HR≅0.15). We estimated bias and CI coverage of each method with Monte Carlo simulation. On average across 24 scenarios, method 1 produced less biased estimates than methods 2 or 3.
Conclusions
When competing risks are independent of the event of interest, only method 1 produced unbiased estimates of the marginal HR, though independence cannot be verified from the data. When competing risks are dependent, method 1 generally produced the least biased estimates of the marginal HR for the scenarios explored; however, alternative methods may be preferred.
doi:10.1016/j.jclinepi.2009.08.003
PMCID: PMC2837111  PMID: 19880284
Competing risks; epidemiology; HIV; highly active antiretroviral therapy; cancer
9.  Association between Free Testosterone Levels and Anal Human Papillomavirus Types 16/18 Infections in a Cohort of Men Who Have Sex with Men 
PLoS ONE  2015;10(3):e0119447.
Background
Human papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown.
Methods
Free testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing.
Results
Participants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty-four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence=17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/18 infection in unadjusted and adjusted analyses.
Conclusions
Higher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study.
doi:10.1371/journal.pone.0119447
PMCID: PMC4368778  PMID: 25794147
10.  SNP screening of central MHC identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi’s sarcoma 
Genes and immunity  2014;15(6):424-429.
The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi’s sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and HHV-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls.
We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a 4-fold increase of risk (OR= 4.09; 95% CI: 1.90–8.80; p= 0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI: 2.54–43.6; p=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120 Kb-long haplotype (OR=1.52; 95% CI: 1.01–2.28; p=0.047) formed by rs7029 A>G (GPANK1 3’UTR), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 readthrough) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.
doi:10.1038/gene.2014.42
PMCID: PMC4174341  PMID: 25008864
11.  The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation 
AIDS (London, England)  2015;29(4):463-471.
Objectives
To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation.
Design
Prospective cohort study.
Methods
Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1,697 men during 8,903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984–2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV+, HAART-naïve (NAI); and HAART-exposed with HIV RNA suppressed to <50 copies/mL plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at one year.
Results
Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (p<0.002) from NEG values: CXCL10, CRP, sCD14, sTNFR2, TNF-α, sCD27, sGP130, IL-8, CCL13, BAFF, GM-CSF, and IL-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Conclusions
Biomarkers of inflammation and immune activation moved toward HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
doi:10.1097/QAD.0000000000000545
PMCID: PMC4311407  PMID: 25630041
Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Biological Markers; Inflammation; Prospective Studies; Male
12.  Association between systemic inflammation and obstructive sleep apnea in men with or at risk for HIV infection 
Antiviral therapy  2014;19(8):725-733.
Background
To determine whether markers of systemic inflammation are associated with the presence of moderate-to-severe obstructive sleep apnea (OSA), and whether this association differs based on HIV and HIV treatment status.
Methods
HIV-uninfected men (HIV−; n=60), HIV-infected men receiving HAART (HIV+/HAART; n=58), and HIV-infected men not receiving HAART (HIV+/ No HAART; n=41) underwent polysomnograpy and measurement of plasma levels of TNF-alpha, soluble TNF-alpha receptors I and II (sTNFRI and sTNFRII) and IL-6. The relationship between moderate-severe OSA (respiratory disturbance index ≥15 apnea/hypopnea events/hour) and inflammatory markers was assessed with multivariable regression models.
Results
Compared to the HIV− men, HIV+/HAART men and HIV+/No HAART men had higher levels of TNF-alpha, sTNFRI, and sTNFRII, independent of age, race, smoking status, obstructive lung disease (OLD), and BMI. Moderate-to-severe OSA was present in 48% of the sample (HIV−:57%; HIV+/HAART: 41%; HIV+/No HAART: 44%). Among the HIV+/No HAART men, but not in the other groups, TNF-alpha, sTNFRII, and IL-6 levels were higher in those with moderate-severe OSA compared to men with no-to-mild OSA after adjustment for age, race, smoking status, OLD, and BMI. Within this group, the association of high TNF-alpha concentrations with moderate-severe OSA was also independent of CD4 cell count and plasma HIV RNA concentration.
Conclusions
Compared to HIV-infected men on HAART and HIV-uninfected men, markers of systemic inflammation were higher in HIV-infected men not receiving HAART. In these men, TNF-alpha was significantly related to obstructive sleep apnea, independent of HIV-related covariates.
doi:10.3851/IMP2745
PMCID: PMC4130807  PMID: 24518040
13.  HIV therapy, metabolic and cardiovascular health are associated with glomerular hyperfiltration in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2014;28(3):377-386.
Objective
Diabetes and hypertension, common conditions in antiretroviral (ART) treated HIV-infected individuals, are associated with glomerular hyperfiltration, which precedes the onset of proteinuria and accelerated kidney function decline. In the Multicenter AIDS Cohort Study, we examined the extent to which hyperfiltration is present and associated with metabolic, cardiovascular, HIV and treatment risk factors among HIV-infected men.
Design
Cross-sectional cohort using direct measurement of glomerular filtration rate (GFR) by iohexol plasma clearance for 367 HIV-infected men and 241 HIV-uninfected men who were free of CKD.
Methods
Hyperfiltration was defined as GFR >140 ml/min/1.73m2 - 1 ml/min/1.73m2 per each year over age 40. Multivariate logistic regression was used to estimate the odds ratios (OR) of prevalent hyperfiltration for metabolic, cardiovascular, HIV and cumulative ART exposure factors.
Results
Among subjects without CKD, the prevalence of hyperfiltration was higher for HIV-infected participants (25%) compared to uninfected participants (17%; p=0.01). HIV infection was associated with hyperfiltration (OR: 1.70, 95%CI: 1.11, 2.61) and modified the association between diabetes and hyperfiltration, such that the association among HIV-uninfected men (OR: 2.56 95%CI: 1.33, 5.54) was not observed among HIV-infected men (OR: 1.19, 95%CI: 0.69, 2.05). These associations were independent of known risk factors for hyperfiltration. Indicators of hyperglycemia and hypertension were also associated with hyperfiltration as was cumulative zidovudine exposure.
Conclusions
Hyperfiltration, a potential modifiable predictor of kidney disease progression, is common among ART-treated HIV-infected men. HIV infection is associated with significant odds of hyperfiltration in addition to known risk factors for kidney damage.
doi:10.1097/QAD.0000000000000094
PMCID: PMC3972628  PMID: 24670523
Glomerular hyperfiltration; glomerular filtration rate; HIV; antiretroviral therapy; iohexol
14.  A candidate gene approach for virally-induced cancer with application to HIV-related Kaposi’s sarcoma 
Like other members of the γ-herpesvirus family, human herpes virus 8 (HHV-8), the etiologic agent of classic and HIV-related Kaposi’s sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including 7 cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84–3.92; Bonferroni-adjusted p= 9.9×10−3−2.6×10−4), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This “proof of concept” study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS
doi:10.1002/ijc.28351
PMCID: PMC4007164  PMID: 23818101
Kaposi’s sarcoma; Immunodeficiency; Herpes Virus 8; Multifactor Dimensionality Reduction; Polymorphism; Genetic association
15.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
doi:10.1093/infdis/jit373
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
16.  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
17.  Reduced Aflatoxin Exposure Presages Decline in Liver Cancer Mortality in an Endemic Region of China 
Primary liver cancer (PLC) is the third leading cause of cancer mortality globally. In endemic areas of sub-Saharan Africa and Asia PLC largely arises from chronic infection with hepatitis B virus (HBV) and ingestion of aflatoxins. While synergistic interactions between these two risk factors have been observed in cohort studies in China, here we determined the impact of agricultural reforms in the 1980s leading to diminished maize consumption and implementation of subsidized universal vaccination against HBV in the 2000s on PLC primary prevention. A population-based cancer registry was used to track PLC mortality in Qidong, China and was compared to the timeline of HBV immunization. Randomly selected serum samples from archived cohort collections from the 1980s to present were analyzed for aflatoxin biomarkers. Greater than 50% reductions in PLC mortality rates occurred across birth cohorts from the 1960s to the 1980s for Qidongese less than 35 years of age although all were born before universal vaccination of newborns. Median levels of the aflatoxin biomarker decreased from 19.3 pg/mg albumin in 1989 to undetectable (<0.5 pg/mg) by 2009. A population attributable benefit of 65% for reduced PLC mortality was estimated from a government facilitated switch of dietary staple from maize to rice; 83% of this benefit was in those infected with HBV. Food policy reforms in China resulted in a dramatic decrease in aflatoxin exposure, which, independent of HBV vaccination, reduced liver cancer risk. The extensive HBV vaccine coverage now in place augurs even greater risk reductions in the future.
doi:10.1158/1940-6207.CAPR-13-0168
PMCID: PMC3800239  PMID: 23963804
aflatoxin; primary prevention; liver cancer
18.  Cause-specific mortality among HIV-infected individuals, by CD4+ cell count at HAART initiation, compared with HIV-uninfected individuals 
AIDS (London, England)  2014;28(2):257-265.
Objectives
To compare the proportion, timing and hazards of non-AIDS death and AIDS death among men and women who initiated HAART at different CD4+ cell counts to mortality risks of HIV-uninfected persons with similar risk factors.
Design
Prospective cohort studies.
Methods
We used parametric mixture models to compare proportions of AIDS and non-AIDS mortality and ages at death, and multivariable Cox models to compare cause-specific hazards of mortality, across levels of CD4+ cell count at HAART initiation (≤200 cells/μl: ‘late’, 201–350 cells/μl: ‘intermediate’, >350 cells/μl: ‘early’) and with HIV-uninfected individuals from the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study. We used multiple imputation methods to address lead-time bias in sensitivity analysis.
Results
Earlier initiators were more likely to die of non-AIDS causes (early: 78%, intermediate: 74%, late: 49%), and at older ages (median years 72, 69, 66), relative to later initiators. Estimated median ages at non-AIDS death for each CD4+ cell count category were lower than that estimated for the HIV-uninfected group (75 years). In multivariable analysis, non-AIDS death hazard ratios relative to early initiators were 2.15 for late initiators (P < 0.01) and 1.66 for intermediate initiators (P = 0.01); AIDS death hazard ratios were 3.26 for late initiators (P <0.01) and 1.20 for intermediate initiators (P = 0.28). Strikingly, the adjusted hazards for non-AIDS death among HIV-uninfected individuals and early initiators were nearly identical (hazard ratio 1.01). Inferences were unchanged after adjustment for lead-time bias.
Conclusion
Results suggest the possibility of reducing the risk of non-AIDS mortality among HIV-infected individuals to approximate that faced by comparable HIV-uninfected individuals.
doi:10.1097/QAD.0000000000000078
PMCID: PMC4164055  PMID: 24105030
antiretroviral therapy; bias; CD4+ cell count; cohort studies; competing risks; mortality; statistical
19.  Sleep Disordered Breathing, Fatigue, and Sleepiness in HIV-Infected and -Uninfected Men 
PLoS ONE  2014;9(7):e99258.
Study Objectives
We investigated the association of HIV infection and highly active antiretroviral therapy (HAART) with sleep disordered breathing (SDB), fatigue, and sleepiness.
Methods
HIV-uninfected men (HIV−; n = 60), HIV-infected men using HAART (HIV+/HAART+; n = 58), and HIV-infected men not using HAART (HIV+/HAART−; n = 41) recruited from two sites of the Multicenter AIDS cohort study (MACS) underwent a nocturnal sleep study, anthropometric assessment, and questionnaires for fatigue and the Epworth Sleepiness Scale. The prevalence of SDB in HIV- men was compared to that in men matched from the Sleep Heart Health Study (SHHS).
Results
The prevalence of SDB was unexpectedly high in all groups: 86.7% for HIV−, 70.7% for HIV+/HAART+, and 73.2% for HIV+/HAART−, despite lower body-mass indices (BMI) in HIV+ groups. The higher prevalence in the HIV− men was significant in univariate analyses but not after adjustment for BMI and other variables. SDB was significantly more common in HIV− men in this study than those in SHHS, and was common in participants with BMIs <25 kg/m2. HIV+ men reported fatigue more frequently than HIV− men (25.5% vs. 6.7%; p = 0.003), but self-reported sleepiness did not differ among the three groups. Sleepiness, but not fatigue, was significantly associated with SDB.
Conclusions
SDB was highly prevalent in HIV− and HIV+ men, despite a normal or slightly elevated BMI. The high rate of SDB in men who have sex with men deserves further investigation. Sleepiness, but not fatigue, was related to the presence of SDB. Clinicians caring for HIV-infected patients should distinguish between fatigue and sleepiness when considering those at risk for SDB, especially in non-obese men.
doi:10.1371/journal.pone.0099258
PMCID: PMC4084642  PMID: 24991815
20.  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.
doi:10.1093/cid/cit196
PMCID: PMC3669528  PMID: 23532479
HIV infection; coronary artery disease; genetics; traditional risk factors; antiretroviral therapy
21.  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
22.  A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A 
Human Molecular Genetics  2013;22(9):1903-1910.
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions.
Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity.
A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect.
Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
doi:10.1093/hmg/ddt033
PMCID: PMC3613165  PMID: 23372042
23.  Incidence and epidemiology of anal cancer in the Multicenter AIDS Cohort Study (MACS) 
Objective
To examine the incidence and risk factors for anal cancer in a multicenter cohort of HIV-positive and negative men who have sex with men followed between 1984 and 2006 (MACS).
Methods
Prospective analysis using Poisson regression and Cox proportional hazard models, and a nested case-control study using conditional logistic regression.
Results
There were 28 cases of anal cancer among the 6,972 men who were evaluated. The incidence rate was significantly higher in HIV-positive men than in HIV-negative men (IR= 69 vs. 14 per 100,000 person-years). Among HIV-positive men, anal cancer incidence was higher in the HAART era than the pre-HAART era (IR=137 vs. 30 per 100,000 person-years). In multivariate analysis restricted to the HAART era, anal cancer risk increased significantly with HIV infection (RH=4.7, 95%CI=1.3–17), and increasing number of unprotected receptive anal sex partners at the first three study visits (p-trend=0.03). Among HIV-positive men, current HAART use did not decrease anal cancer risk.
Conclusion
HIV-positive men had increased risk of anal cancer. Improved survival of HIV-positive individuals following HAART initiation may allow for sufficient time for human papillomavirus (HPV) associated anal dysplasias to develop into malignancies, thus explaining the increased incidence of anal cancer in the HAART era.
doi:10.1097/QAI.0b013e31817aebfe
PMCID: PMC3991563  PMID: 18614927
anal; rectal; cancer; incidence; MACS; sexual risk; HAART
24.  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
25.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
doi:10.1097/QAD.0b013e328332d5b1
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma

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