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1.  Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts 
Background
Several lung diseases are increasingly recognized as comorbidities with HIV; however, few data exist related to the spectrum of respiratory symptoms, diagnostic testing, and diagnoses in the current HIV era. The objective of the study is to determine the impact of HIV on prevalence and incidence of respiratory disease in the current era of effective antiretroviral treatment.
Methods
A pulmonary-specific questionnaire was administered yearly for three years to participants in the Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS). Adjusted prevalence ratios for respiratory symptoms, testing, or diagnoses and adjusted incidence rate ratios for diagnoses in HIV-infected compared to HIV-uninfected participants were determined. Risk factors for outcomes in HIV-infected individuals were modeled.
Results
Baseline pulmonary questionnaires were completed by 907 HIV-infected and 989 HIV-uninfected participants in the MACS cohort and by 1405 HIV-infected and 571 HIV-uninfected participants in the WIHS cohort. In MACS, dyspnea, cough, wheezing, sleep apnea, and incident chronic obstructive pulmonary disease (COPD) were more common in HIV-infected participants. In WIHS, wheezing and sleep apnea were more common in HIV-infected participants. Smoking (MACS and WIHS) and greater body mass index (WIHS) were associated with more respiratory symptoms and diagnoses. While sputum studies, bronchoscopies, and chest computed tomography scans were more likely to be performed in HIV-infected participants, pulmonary function tests were no more common in HIV-infected individuals. Respiratory symptoms in HIV-infected individuals were associated with history of pneumonia, cardiovascular disease, or use of HAART. A diagnosis of asthma or COPD was associated with previous pneumonia.
Conclusions
In these two cohorts, HIV is an independent risk factor for several respiratory symptoms and pulmonary diseases including COPD and sleep apnea. Despite a higher prevalence of chronic respiratory symptoms, testing for non-infectious respiratory diseases may be underutilized in the HIV-infected population.
doi:10.1186/1471-2466-14-75
PMCID: PMC4021087  PMID: 24884738
AIDS; HIV; Pulmonary disease; Chronic obstructive; Respiratory tract diseases; Sleep apnea syndromes
2.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
Objective
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Design
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Methods
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Results
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
Conclusion
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
doi:10.1371/journal.pone.0058812
PMCID: PMC3595204  PMID: 23554932
3.  Spontaneous Clearance of the Hepatitis C Virus Among Men Who Have Sex With Men 
Among men who have sex with men, the probability of and factors associated with spontaneous hepatitis C virus (HCV) clearance differ between sexually and percutaneously acquired infections. Determining the reasons for these differences could be important for HCV vaccine development.
Background. The probability of spontaneous hepatitis C virus (HCV) clearance ranges from 11% to 49%. Our previous cross-sectional study suggests that mode of acquisition explains some of this heterogeneity. We performed this prospective study to determine factors associated with spontaneous HCV clearance among men who have sex with men (MSM).
Methods. A mixture-cure model was used to evaluate the probability of spontaneous HCV clearance among 101 MSM in the Multicenter AIDS Cohort Study with acute HCV infection between 1984 and 2012.
Results. Spontaneous HCV clearance occurred in 46% of MSM (49% in non-injection drug users [IDUs] and 23% in IDUs). In the multivariable analysis, age <30 years (clearance ratio [CR] = 2.43; 95% confidence interval [CI], 1.53–3.87) and being human immunodeficiency virus (HIV) uninfected (CR = 2.97; 95% CI, 1.98–4.46) were independently associated with spontaneous clearance. Among men aged ≥30 years, being HIV uninfected, not having unprotected anal intercourse, older age, and being on highly active antiretroviral therapy were independently associated with higher clearance. The interferon lambda rs12979860 single nucleotide polymorphism (SNP) was not associated with spontaneous clearance among the 88 MSM who were not active IDUs (CR = 0.74; 95% CI, .46–1.21 for CC vs CT/TT genotype).
Conclusions. The high probability of spontaneous HCV clearance together with the lack of an association between the rs12979860 SNP and spontaneous clearance among MSM who do not use injection drugs suggests that the immune mechanisms involved with a successful response to acute HCV differ by mode of virus acquisition. Understanding potential mechanistic differences could be important for HCV vaccine development.
doi:10.1093/cid/civ562
PMCID: PMC4599393  PMID: 26175521
hepatitis C virus; HIV; IL28B; injection drug use; MSM
4.  LUNG CANCER INCIDENCE AND SURVIVAL AMONG HIV-INFECTED AND UNINFECTED WOMEN AND MEN 
AIDS (London, England)  2015;29(10):1183-1193.
Objectives
To determine the lung cancer incidence and survival time among HIV-infected and uninfected women and men.
Design
Two longitudinal studies of HIV infection in the United States.
Methods
Data from 2,549 women in the Women’s Interagency HIV Study (WIHS) and 4,274 men in the Multicenter AIDS Cohort Study (MACS), all with a history of cigarette smoking, were analyzed. Lung cancer incidence rates and incidence rate ratios were calculated using Poisson regression analyses. Survival time was assessed using Kaplan-Meier and Cox proportional hazard analyses.
Results
Thirty-seven women and 23 men developed lung cancer (46 HIV-infected and 14 HIV-uninfected) during study follow-up. In multivariable analyses, the factors that were found to be independently associated with a higher lung cancer incidence rate ratios were older age, less education, 10 or more pack-years of smoking, and a prior diagnosis of AIDS pneumonia (vs. HIV-uninfected women). In an adjusted Cox model that allowed for different hazard functions for each cohort, a history of injection drug use was associated with shorter survival, and a lung cancer diagnosis after 2001 was associated with longer survival. In an adjusted Cox model restricted to HIV-infected participants, nadir CD4 lymphocyte cell count <200 was associated with shorter survival time.
Conclusions
Our data suggest that pulmonary damage and inflammation associated with HIV infection may be etiologic for the increased risk of lung cancer. Encouraging and assisting younger HIV-infected smokers to quit and to sustain cessation of smoking is imperative to reduce the lung cancer burden in this population.
doi:10.1097/QAD.0000000000000690
PMCID: PMC4457511  PMID: 25888645
AIDS; HIV infection; incidence; lung cancer; survival
5.  Differences in hepatitis C virus (HCV) prevalence and clearance by mode of acquisition among men who have sex with men (MSM) 
Journal of viral hepatitis  2013;21(10):696-705.
Objective
To compare the characteristics associated with hepatitis C virus (HCV) antibody (anti-HCV) prevalence and HCV clearance between injection drug using (IDU) and non-IDU men who have sex with men (MSM).
Methods
Stored serum and plasma samples were tested for anti-HCV and HCV RNA to determine the HCV status of 6925 MSM at enrollment into the Multicenter AIDS Cohort Study (MACS). Prevalence and clearance ratios (PR and CR) were calculated to determine the characteristics associated with HCV prevalence and clearance. Multivariable analyses were performed using Poisson regression methods with robust variance estimation.
Results
Anti-HCV prevalence was significantly higher among IDU than non-IDU MSM (42.9% vs. 4.0%) while clearance was significantly lower among IDU MSM (11.5% vs. 34.5% among non-IDU MSM). HIV infection, Black race, and older age were independently associated with higher prevalence in both groups while smoking, transfusion history, and syphilis were significantly associated with prevalence only among non-IDU MSM. The rs12979860-C/C genotype was the only characteristic independently associated with HCV clearance in both groups, but the effects of both rs12979860-C/C genotype (CR=4.16 IDUs vs. 1.71 non-IDUs; p=0.03) and HBsAg positivity (CR=5.06 IDUs vs. 1.62 non-IDUs; p=0.03) were significantly larger among IDU MSM. HIV infection was independently associated with lower HCV clearance only among non-IDU MSM (CR=0.59, 95% CI=0.40–0.87).
Conclusions
IDU MSM have higher anti-HCV prevalence and lower HCV clearance than non-IDU MSM. Differences in the factors associated with HCV clearance suggest that the mechanisms driving the response to HCV may differ according to the mode of acquisition.
doi:10.1111/jvh.12198
PMCID: PMC4187219  PMID: 25280229
Hepatitis C; HIV; IFNL4; IL28B; Injection Drug Use; MSM
6.  Incident Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men From Pre-HAART to HAART Periods 
Annals of internal medicine  2015;163(9):673-680.
Background
Men who have sex with men (MSM) are at high risk for hepatitis B virus (HBV) infection. Data on the effect of highly active antiretroviral therapy (HAART) on incident HBV infection in HIV-infected and HIV-uninfected MSM are limited.
Objective
To determine predictors of incident HBV infection in MSM during pre-HAART and HAART periods.
Design
Observational cohort study.
Setting
Cohort of MSM who have, or are at risk for, HIV infection.
Patients
2375 HBV-uninfected MSM in the Multicenter AIDS Cohort Study.
Measurements
Poisson regression was used to compare incidence rates of HBV infection in the pre-HAART and HAART eras and to identify factors associated with incidence of HBV infection.
Results
In 25 322 person-years of follow-up, 244 incident HBV infections occurred. The unadjusted incidence rate was higher in HIV-infected MSM than in HIV-uninfected MSM (IRR, 1.9 [95% CI, 1.5 to 2.4]) and was significantly lower in the HAART era than in the pre-HAART era among HIV-infected (IRR, 0.2 [CI, 0.1 to 0.4]) and HIV-uninfected (IRR, 0.3 [CI, 0.2 to 0.4]) MSM. Age younger than 40 years (IRR, 2.3 [CI, 1.7 to 3.0]), more than 1 recent sexual partner (IRR, 3.1 [CI, 2.3 to 4.2]), and HIV infection (IRR, 2.4 [CI, 1.8 to 3.1]) were independently associated with higher incidence of HBV infection, whereas HBV vaccination was protective (IRR, 0.3 [CI, 0.2 to 0.4]). Highly active antiretroviral therapy with HIV RNA levels less than 400 copies/mL was associated with protection (IRR, 0.2 [CI, 0.1 to 0.5]), but HAART in those with HIV RNA levels of 400 copies/mL or greater was not.
Limitation
The observational nature limits inferences about causality.
Conclusion
Effective HAART is associated with lower incidence of HBV infection; however, even in the HAART era, incidence of HBV infection remains high among MSM.
Primary Funding Source
National Institute of Allergy and Infectious Diseases.
doi:10.7326/M15-0547
PMCID: PMC4630157  PMID: 26457744
7.  Risk of Breast Cancer with CXCR4-using HIV Defined by V3-Loop Sequencing  
Objective
Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures.
Methods
A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIVgp120-V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencing-based HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [False-Positive-Rate (FPR 3.5) and 2% X4 cutoff], and lower stringency DS (FPR 5.75, 15% X4 cut-off). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (κ) statistics. Case-control comparisons used exact P-values and conditional logistic regression.
Results
In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P=0.06, odds ratio 0.14, confidence interval 0.003-1.03). Smaller case-control prevalence differences were found with high-stringency DS (21% vs 36%, P=0.32), lower-stringency DS (16% vs 35%, P=0.18), and phenotyping (11% vs 31%, P=0.10). HIV-X4-tropism concordance was best between PS and lower-stringency DS (93%, κ=0.83). Other pairwise concordances were 82%-92% (κ=0.56-0.81). Concordance was similar among cases and controls.
Conclusions
HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency deep sequencing and was significantly associated with lower odds of breast cancer.
doi:10.1097/QAI.0000000000000400
PMCID: PMC4262599  PMID: 25321183
Chemokine receptors; HIV; AIDS; breast cancer; parallel sequencing; women
8.  Inaccuracy of haemoglobin A1c among HIV-infected men: effects of CD4 cell count, antiretroviral therapies and haematological parameters 
Journal of Antimicrobial Chemotherapy  2014;69(12):3360-3367.
Background
There is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c − expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS).
Methods
Fasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c − expected HbA1c ≤−0.5%.
Results
Over 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (<500 cells/mm3); a regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or zidovudine; high mean corpuscular volume; and abnormal corpuscular haemoglobin.
Conclusion
HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to under-diagnosis and to under-treatment of established diabetes mellitus.
doi:10.1093/jac/dku295
PMCID: PMC4228777  PMID: 25096078
HbA1c; diabetes; mean corpuscular volume; glycosylated haemoglobin; HIV
9.  Association of Chronic Hepatitis C Infection with T-Cell Phenotypes in HIV-Negative and HIV-Positive Women 
Background
Hepatitis C virus (HCV) viremia is thought to have broad, systemic effects on the cellular immune system that go beyond its impact on just those T-cells that are HCV-specific. However, prior studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV-negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV-positives did not address overall immune status (total CD4+ count).
Methods
We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T-cells, Tregs, and T-cell differentiation phenotypes (naïve, central memory (CM), effector memory (EM), and terminally differentiated effector). This included 158 HIV-negatives and 464 HIV-positives, of whom 18 and 63, respectively, were HCV viremic.
Results
In multivariate models of HIV-negatives, HCV viremia was associated with 25% fewer naïve CD4+ (P=0.03), 33% more EM CD4+ (P=0.0002) and 37% fewer CM CD8+ (P=0.02) T-cells. Among HIV-positives we observed only one of these three relationships: higher percentage of EM CD4+ among HCV viremic women. Further, the association with EM CD4+ among HIV-positives was limited to individuals with diminished immune status (total CD4+ count ≤500 cells/μL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV-positives with high CD4+ count, no significant associations were observed.
Conclusions
These data suggest that HCV viremia in HIV-negatives is associated with accelerated T-cell differentiation, but among HIV-positives the impact of HCV viremia is less straightforward and varies by total CD4+ count.
doi:10.1097/QAI.0000000000000310
PMCID: PMC4197408  PMID: 25314250
hepatitis C virus; HIV; T-cell; phenotype; activation; differentiation
10.  Serum Adipokine & Inflammatory Markers Before and After Liver Transplantation in Recipients with Major Cardiovascular Events 
In the non-transplant setting, aberrant serum adipokine levels associate with cardiovascular (CV) disease. The effects of liver transplantation (LT) on serum adipokine levels, and their association with post-LT CV disease have not been studied.
Methods
A nested case-control study of 77 patients with major CV events beyond 4 months post-LT had serum adiponectin, resistin, leptin, C-reactive protein and apolipoprotein levels measured prior to transplant and at 4, 12 and 24 months post-LT.
Results
Adiponectin and resistin levels decrease dramatically after LT in all patients. Recipients with CV disease achieved lower levels of adiponectin and higher levels of resistin, leptin, C-reactive protein and apolipoprotein B100 than controls. Pre-LT adiponectin level was associated with a 16% increase risk of CV event for every 1μg/mL decrement in adiponectin (HR 0.84, p=0.046). Pre-LT C-reactive protein (HR 1.03, p=0.047) and 12 month C-reactive protein (HR1.03, p=.029) were associated with CV events post-LT. Diabetes (HR 2.14, p=0.09), resistin (HR1.07, p=0.07) and Apolipoprotein B (HR 1.07, p=0.08) were associated with a non-significant increased risk of CV events in this small sample size.
Conclusion
Pre and post-LT changes in serum adipokine and inflammatory markers may be a signal for increased risk of CV events after liver transplantation, but further study is needed.
doi:10.1002/lt.23880
PMCID: PMC4072743  PMID: 24692322
Adiponectin; Leptin; Resistin; Apolipoprotein; morbidity; outcomes
11.  Cancer incidence in the Multicenter AIDS Cohort Study before and during the HAART era: 1984–2007 
Cancer  2010;116(23):5507-5516.
Background
The incidence of Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) among human immunodeficiency virus (HIV)-infected individuals declined following the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s, but the cancer risk associated with HIV infection during the HAART era remains to be clarified.
Methods
We compared cancer incidence among HIV-infected and -uninfected participants in the Multicenter AIDS Cohort Study (MACS) between 1984 and 2007 to the expected incidence using US population-based data from the Surveillance, Epidemiology, and End Results (SEER) Program, and we compared age and race adjusted cancer incidence rates by HIV status and over time within the MACS. Exact statistical methods were used for all analyses.
Results
933 incident cancers were observed during 77,320 person-years of follow-up. Compared to SEER, MACS HIV-infected men had significantly (p<0.05) elevated rates of KS (standardized incidence ratio (SIR)=139.10), NHL (SIR=36.80), Hodgkin’s lymphoma (HL) (SIR=7.30), and anal cancer (SIR=25.71). Within MACS, HIV infection was independently associated with each of these cancers across the entire follow-up period, and KS (incidence rate ratio (IRR)=54.93), NHL (IRR=11.18), and anal cancer (IRR=18.50) were each significantly elevated among HIV-infected men during the HAART era. Among these men, the incidence of KS and NHL declined (IRR=0.13 and 0.23, respectively), anal cancer incidence increased (IRR=5.84), and HL incidence remained statistically unchanged (IRR=0.75) from the pre-HAART to the HAART era.
Conclusion
Cancer risk remains elevated among HIV-infected men who have sex with men, highlighting the continuing need for appropriate cancer screening in this population.
doi:10.1002/cncr.25530
PMCID: PMC2991510  PMID: 20672354
HIV infection; cancer incidence; malignancy; AIDS-defining malignancy; HAART
12.  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
14.  Association between human immunodeficiency virus (HIV) infection and stiffness of the common carotid artery 
Background and purpose
Human immunodeficiency virus (HIV)-infected persons taking highly active antiretroviral therapy (HAART) may have an increased risk for cardiovascular-related events, although the underlying mechanism remains unclear. We tested the hypothesis that carotid arterial stiffness was higher among persons taking HAART compared to HAART-naïve and HIV-uninfected persons.
Methods
Between 2004 and 2006, we performed high resolution B-mode ultrasound on 2,789 HIV-infected and HIV-uninfected participants of the Women’s Interagency HIV Study (WIHS; 1865 women) and the Multicenter AIDS Cohort Study (MACS; 924 men) and determined carotid arterial distensibility, a direct measure of carotid arterial stiffness. We used generalized estimating equations to evaluate the association between distensibility and HIV infection, CD4+ cell count, and exposure to HAART adjusted for demographic, behavioral, and clinical characteristics.
Results
In multivariable analysis, distensibility was 4.3% lower (95% confidence interval (CI): -7.4% to -1.1%) among HIV-infected versus uninfected participants. Among HIV-infected participants with fewer than 200 CD4+ cells, distensibility was 10.5% lower (95% CI: -14.5% to -6.2%) than that among HIV-uninfected participants, and this effect did not differ significantly by cohort or race. Concurrent HAART use was independently associated with lower distensibility among MACS participants but not among WIHS participants.
Conclusions
Our finding that advanced HIV-related immunosuppression was associated with increased carotid arterial stiffness independent from the effects of traditional atherosclerosis risk factors suggests that the etiologic mechanism underlying reports of an increased cardiovascular disease risk among HIV-infected individuals might involve HIV-related immunosuppression leading to vascular dysfunction and arterial stiffening.
doi:10.1161/STROKEAHA.110.583856
PMCID: PMC2972735  PMID: 20798374
atherosclerosis; cardiovascular disease; carotid arteries; HIV; epidemiology
15.  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
16.  Prevalence and Long-Term Effects of Occult Hepatitis B Virus Infection in HIV-Infected Women 
Occult hepatitis B virus (HBV) infection is of concern in human immunodeficiency virus (HIV)–infected persons. We observed that 2% of 400 HIV-infected women with antibodies to hepatitis B core antigen alone had occult HBV infection (i.e., detectable HBV DNA in the absence of HBV surface antigen). CD4 cell counts of <200 cells/mm3 were more common among occult HBV-infected women than among those without occult HBV infection. Aminotransferase levels did not appear to be associated with being positive for HBV DNA.
doi:10.1086/520989
PMCID: PMC4142488  PMID: 17712758
17.  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
18.  Patterns and Causes of Suboptimal Response to Tenofovir-Based Therapy in Individuals Coinfected With HIV and Hepatitis B Virus 
In this international prospective cohort of 165 individuals coinfected with HIV and hepatitis B virus (HBV), 3 patterns of suboptimal response to tenofovir therapy were identified: persistent viremia, viral rebound, and viral blips. Suboptimal adherence was associated with detectable HBV DNA, even when HIV was undetectable.
Background. Tenofovir (TDF) is effective for treatment of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) infection; however, some individuals have ongoing HBV viremia, the reasons for which are unclear. We determined the patterns and factors associated with detectable HBV DNA in HIV-HBV–coinfected subjects on highly active antiretroviral therapy (HAART).
Methods. One hundred sixty-five HIV-HBV–coinfected individuals from the United States, Australia, and Thailand, the majority of whom were on HAART at study entry, were prospectively followed semiannually for a median of 2.8 years. Logistic regression was used to determine factors associated with detectable HBV DNA.
Results. Anti-HBV regimens were TDF/emtricitabine (57%), lamivudine or emtricitabine (19%), or TDF monotherapy (13%). During follow-up, HBV DNA was detected at 21% of study visits and was independently associated with hepatitis B e antigen (HBeAg), HAART <2 years, CD4 <200 cells/mm3, detectable HIV RNA, reporting <95% adherence, and anti-HBV regimen. TDF/emtricitabine was less likely to be associated with detectable HBV than other regimens, including TDF monotherapy (odds ratio, 2.79; P = .02). In subjects on optimal anti-HBV therapy (TDF/emtricitabine) and with undetectable HIV RNA, HBeAg, CD4 <200 mm3, and reporting <95% adherence remained associated with detectable HBV DNA. Three main patterns of HBV viremia were observed: persistent HBV viremia, viral rebound (>1 log from nadir), and viral blips. No TDF resistance was identified.
Conclusions. Tenofovir/emtricitabine was superior to other anti-HBV regimens in long-term HBV suppression. HBV viremia on therapy was identified in 1 of 3 main patterns. Suboptimal adherence was associated with detectable HBV DNA during therapy, even when HIV was undetectable.
doi:10.1093/cid/cit002
PMCID: PMC3693490  PMID: 23315316
HIV; hepatitis B; antiretroviral therapy; adherence
19.  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
20.  Factors Affecting the Prevalence of Strongly and Weakly Carcinogenic and Lower-Risk Human Papillomaviruses in Anal Specimens in a Cohort of Men Who Have Sex with Men (MSM) 
PLoS ONE  2013;8(11):e79492.
Background
MSM are at higher risk for invasive anal cancer. Twelve human papillomaviruses (HPVs) cause cervical cancer in women (Group 1 high-risk HPVs (hrHPVs)) and 13 HPVs are probable/possible causes (Group 2 hrHPVs) of cervical malignancy. HPVs rarely associated with malignancy are classified as lower-risk HPVs (lrHPVs).
Materials and Methods
Dacron-swab anal-cytology specimens were collected from and data complete for 97% (1262/1296) of Multicenter AIDS Cohort Study (MACS) men tested for HPVs using the Linear Array assay. Multivariate Poisson regression analyses estimated adjusted prevalence ratios for Group 1/2 hrHPVs and lrHPVs, controlling for the effects of age, race, ethnicity, sexual partnerships, smoking; HIV-infection characteristics, treatment, and immune status among HIV-infected men.
Results
HIV-infected men showed 35–90% higher prevalence of Group 1/2 hrHPVs and lrHPVs than HIV-uninfected men, and higher prevalence of multi-Type, and multiple risk-group infections. CD4+ T-cell count was inversely associated with HPV Group 2 prevalence (p<0.0001). The number of receptive anal intercourse (RAI) partners reported in the 24 months preceding HPV testing predicted higher prevalence of Group 1/2 hrHPVs. Men reporting ≥30 lifetime male sex partners before their first MACS visit and men reporting ≥1 RAI partners during the 24 months before HPV testing showed 17–24% and 13–17% higher prevalence of lrHPVs (p-values ≤0.05). Men reporting smoking between MACS visit 1 and 24 months before HPV testing showed 1.2-fold higher prevalence of Group 2 hrHPVs (p = 0.03). Both complete adherence to CART (p = 0.02) and HIV load <50 copies/mL (p = 0.04) were protective for Group 1 hrHPVs among HIV-infected men.
Conclusions
HIV-infected men more often show multi-type and multi-group HPV infections HIV-uninfected men. Long-term mutual monogamy and smoking cessation, generally, and CART-adherence that promotes (HIV) viremia control and prevents immunosuppression, specifically among HIV-infected MSM, are important prevention strategies for HPV infections that are relevant to anal cancer.
doi:10.1371/journal.pone.0079492
PMCID: PMC3835810  PMID: 24278140
21.  Comparative Risk of Liver-Related Mortality From Chronic Hepatitis B Versus Chronic Hepatitis C Virus Infection 
In a cohort of men who have sex with men, most of whom were infected with human immunodeficiency virus, men chronically infected with hepatitis B were 2-fold more likely to die a liver-related death than those chronically infected with hepatitis C.
Background. It is not known whether chronic hepatitis B (CH-B) or chronic hepatitis C (CH-C) carries a greater risk of liver-related mortality. This study compared rates of liver-related mortality between these 2 groups in the Multicenter AIDS Cohort Study (MACS).
Methods. Six hundred eighty men with CH-B (n = 337) or CH-C (n = 343) at study entry into the MACS were prospectively followed to death, last follow-up visit, or 30 March 2010, whichever came first. Four hundred seventy-two (69.4%) of these men were infected with human immunodeficiency virus type 1 (HIV-1). Causes of death were obtained from death registry matching and death certificates. Liver-related and all-cause mortality rates (MRs) were compared between groups using Poisson regression and adjusted for potential confounders and competing risks.
Results. In 6728 person-years (PYs) of follow-up, there were 293 deaths from all causes (43.5 per 1000 PYs), of which 51 were liver-related (7.6 per 1000 PYs). The all-cause MR was similar between those with CH-B and CH-C; however, the liver-related MR was significantly higher in those with CH-B (9.6 per 1000 PYs; 95% confidence interval [CI], 6.9–13.2) than those with CH-C (5.0 per 1000 PYs; 95% CI, 3.0–8.4). In the HIV-infected subgroup, which had 46 (90.2%) of the liver-related deaths, the liver-related MR remained higher from CH-B after adjusting for potential confounders (incidence rate ratio, 2.2; P = .03) and competing risks (subhazard rate ratio, 2.4; P = .02). Furthermore, among HIV-infected subjects, CD4 cell counts <200 cells/mm3 were associated with a 16.2-fold (95% CI, 6.1–42.8) increased risk of liver-related death compared with CD4 cell counts >350 cell/mm3.
Conclusions. Chronic hepatitis B carries a higher risk of death from liver disease than does CH-C, especially in HIV-infected men with greater immunosuppression.
doi:10.1093/cid/cis432
PMCID: PMC3520384  PMID: 22523269
22.  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
24.  PRE-EXISTING ALBUMINURIA PREDICTS AIDS AND NON-AIDS MORTALITY IN WOMEN INITIATING ANTIRETROVIRAL THERAPY 
Antiviral therapy  2011;16(4):591-596.
Background
We previously reported an increased risk of all-cause and AIDS mortality among HIV-infected women with albuminuria (proteinuria or microalbuminuria) enrolled in the Women’s Interagency HIV Study (WIHS) prior to the introduction of highly active antiretroviral therapy (HAART).
Methods
The current analysis includes 1,073 WIHS participants who subsequently initiated HAART. Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria from two consecutive study visits prior to HAART initiation were categorized as follows: confirmed proteinuria (both specimens positive for protein), confirmed microalbuminuria (both specimens positive with at least one microalbuminuria), unconfirmed albuminuria (one specimen positive for proteinuria or microalbuminuria), or negative (both specimens negative). Time from HAART initiation to death was modeled using proportional hazards analysis.
Results
Compared to the reference group of women with two negative specimens, the hazard ratio (HR) for all-cause mortality was significantly elevated for women with confirmed microalbuminuria (HR 1.9; 95% CI 1.2–2.9). Confirmed microalbuminuria was also independently associated with AIDS death (HR 2.3; 95% CI 1.3–4.3), while women with confirmed proteinuria were at increased risk for non-AIDS death (HR 2.4; 95% CI 1.2–4.6).
Conclusions
In women initiating HAART, pre-existing microalbuminuria independently predicted increased AIDS mortality, while pre-existing proteinuria predicted increased risk of non-AIDS death. Urine testing may identify HIV-infected individuals at increased risk for mortality even after the initiation of HAART. Future studies should consider whether these widely available tests can identify individuals who would benefit from more aggressive management of HIV infection and comorbid conditions associated with mortality in this population.
doi:10.3851/IMP1766
PMCID: PMC3119869  PMID: 21685547
HIV; microalbuminuria; proteinuria; mortality; non-AIDS death
25.  Factors Associated with Elevated ALT in an International HIV/HBV Co-Infected Cohort on Long-Term HAART 
PLoS ONE  2011;6(11):e26482.
Background
Previous studies have demonstrated that hepatitis B virus (HBV) infection increases the risk for ALT elevations in HIV-HBV co-infected patients during the first year of HAART; however, there is limited data on the prevalence of ALT elevations with prolonged HAART in this patient group.
Methods/Principal findings
To identify factors associated with ALT elevations in an HIV-HBV co-infected cohort receiving prolonged HAART, data from 143 co-infected patients on HAART enrolled in an international HIV-HBV co-infected cohort where ALT measurements were obtained every 6 months was analysed. A person-visit analysis was used to determine frequency of ALT elevation (≥2.5×ULN) at each visit. Factors associated with ALT elevation were determined using multivariate logistic regression with generalized estimating equations to account for correlated data. The median time on HAART at the end of follow-up was 5.6 years (range 0.4–13.3) years. During follow-up, median ALT was 36 U/L with 10.6% of person-visits classified as having ALT elevation. Most ALT elevations were grade 2 (86.5%), with only 13.5% of all ALT elevations grade 3 or higher. Univariate associations with ALT elevation (p<0.05) included history of AIDS, HBV DNA ≥2,000 IU/ml, HBeAg positive, study visit CD4 <200 cells/ml and nadir CD4 <200 cells/ml. In the multivariate analysis, only study visit CD4 <200 cells/ml (OR 2.07, 95%CI 1.04–4.11, p = 0.04) and HBeAg positive status (OR 2.22, 95%CI 1.03–4.79, p = 0.04) were independently associated with ALT elevation.
Conclusions
In this HIV-HBV co-infected cohort, elevated ALT after >1 year of HAART was uncommon, and severe ALT elevations were rare. HIV-HBV co-infected patients on long-term HAART who are either HBeAg positive or have a CD4 count of <200 cells/ml are at increased risk for ALT elevations.
doi:10.1371/journal.pone.0026482
PMCID: PMC3206023  PMID: 22069454

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