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Background IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984–1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval,.76–1.11]), cytomegalovirus infection (0.94 [.71–1.24]), herpes simplex virus infection (1.37 [.68–2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens. [ABSTRACT FROM AUTHOR]

Studies suggest that inflammation might be involved in the pathogenesis of depression. Individuals with human immunodeficiency virus (HIV) have a higher risk of depression and elevated inflammatory profiles. Despite this, research on the link between inflammation and depression among this high-risk population is limited. We examined a sample of men who have sex with men from the Multicenter AIDS Cohort Study in prospective analyses of the association between inflammation and clinically relevant depression symptoms, defined as scores >20 on Center for Epidemiological Studies Depression Scale. We included 1,727 participants who contributed 9,287 person-visits from 1984 to 2010 (8,218 with HIV (HIV+) and 1,069 without (HIV−)). Exploratory factor analysis (EFA) was used to characterize underlying inflammatory processes from 19 immune markers. Logistic regression with generalized estimating equations was used to evaluate associations between inflammatory processes and depressive symptoms stratified by HIV serostatus. Three EFA-identified inflammatory processes (EIPs) were identified. EIP-1 scores—described by soluble tumor necrosis factor receptor 2 (sTNF-R2), soluble interleukin-2 receptor α (sIL-2Rα), sCD27, B-cell activating factor, interferon γ-induced protein 10 (IP-10), soluble interleukin-6 receptor (sIL-6R), sCD14, and sGP130—were significantly associated with 9% higher odds of depressive symptoms in HIV+ participants (odds ratio = 1.09; 95% confidence interval: 1.03, 1.16) and 33% higher odds in HIV− participants (odds ratio = 1.33; 95% confidence interval: 1.09, 1.61). Findings suggest that immune activation might be involved in depression risk among both HIV+ and HIV− men who have sex with men. [ABSTRACT FROM AUTHOR]

Background: High-sensitivity cardiac troponin (hs-cTn) elevations are associated with incident cardiovascular disease events in primary prevention samples. However, the mechanisms underlying this association remain unclear. Methods: We studied 458 men without known cardiovascular disease who participated in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study and had cardiac CT angiography. We used multivariable linear and logistic regression models to examine the cross-sectional associations between coronary artery stenosis, coronary artery plaque, indexed left ventricular mass (LVMi), and the outcome of hs-cTnI. We also evaluated the associations between HIV serostatus or use of highly active antiretroviral therapy (HAART) and hs-cTnI. Results: The mean age was 54 years, 54% were white, and 61% were HIV infected. In multivariable-adjusted logistic models, comparing the highest quartile of LVMi with the lowest quartile, the odds ratio (OR) of hs-cTnI ≥75th percentile was 2.59 (95% CI, 1.20--5.75). There was no significant association between coronary stenosis severity or plaque type and hs-cTnI in linear models; however, in logistic regression models, coronary artery stenosis ≥70% (8% of sample) was marginally associated with a higher likelihood (OR, 2.75 [95% CI, 1.03, 7.27]) of having hs-cTnI ≥75th percentile. There were no associations between HIV serostatus or HAART use and hs-cTnI in either linear or logistic models. Conclusion: Among primary prevention men with or at risk for HIV, hs-cTnI concentrations were strongly associated with LVMi but were not associated with HIV infection or treatment status or with coronary plaque type or stenosis until the extremes of severity (≥70% stenosis). [ABSTRACT FROM AUTHOR]

Collaborative study designs (CSDs) that combine individual-level data from multiple independent contributing studies (ICSs) are becoming much more common due to their many advantages: increased statistical power through large sample sizes; increased ability to investigate effect heterogeneity due to diversity of participants; cost-efficiency through capitalizing on existing data; and ability to foster cooperative research and training of junior investigators. CSDs also present surmountable political, logistical and methodological challenges. Data harmonization may result in a reduced set of common data elements, but opportunities exist to leverage heterogeneous data across ICSs to investigate measurement error and residual confounding. Combining data from different study designs is an art, which motivates methods development. Diverse study samples, both across and within ICSs, prompt questions about the generalizability of results from CSDs. However, CSDs present unique opportunities to describe population health across person, place and time in a consistent fashion, and to explicitly generalize results to target populations of public health interest. Additional analytic challenges exist when analysing CSD data, because mechanisms by which systematic biases (e.g. information bias, confounding bias) arise may vary across ICSs, but multidisciplinary research teams are ready to tackle these challenges. CSDs are a powerful tool that, when properly harnessed, permits research that was not previously possible. [ABSTRACT FROM AUTHOR]

Background: The extent to which inflammation, immune activation/immunosenescence, and hormonal abnormalities are driven by human immunodeficiency virus (HIV) or frailty is not clear.Methods: HIV-infected frail men (n = 155) were matched to nonfrail, HIV-infected (n = 141) and HIV-uninfected (n = 150) men by age, calendar year, and antiretroviral therapy use (HIV-infected men only). Frailty was defined by ≥3 frailty-related phenotype criteria (weight loss, exhaustion, low activity, slowness) at ≥2 visits, or at 1 visit with ≥1 criteria at ≥2 visits. The following measurements were obtained: interleukin 6, high-sensitivity C-reactive protein, soluble receptors for tumor necrosis factor α 1 and 2, the percentages of CD4+CD28-, CD8+CD28-, CD4+CD38+HLA-DR+, and CD8+CD38+HLA-DR+ T cells, dehydroepiandrosterone sulfate, free testosterone, homeostatic model assessment of insulin resistance, and insulin-like growth factor 1. Log-linear regressions were adjusted for a priori selected covariates to determine differences by frailty and HIV status.Results: In multivariate analyses adjusted for covariates, frailty was associated among HIV-infected men with higher interleukin 6 and high-sensitivity C-reactive protein and lower free testosterone and dehydroepiandrosterone levels. In contrast, HIV infection but not frailty was associated with significantly greater immune senescence (percentage of CD4+CD28- or CD8+CD28- T cells) and immune activation (percentages of CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ T cells).Conclusions: Frailty among HIV-infected men was associated with increased inflammation and lower hormone levels, independent of comorbid conditions. Interventions targeting these pathways should be evaluated to determine the impact on prevention or reversal of frailty among HIV-infected men. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus (HIV)-infected individuals exhibit residual inflammation regardless of virologic suppression. We evaluated whether suboptimal adherence to combination antiretroviral therapy (cART) is associated with greater residual inflammation than optimal adherence, despite virologic suppression. Methods. Longitudinal self-reported cART adherence data and serum concentrations of 24 biomarkers of inflammation and immune activation were measured at the same study visit in HIV RNA-suppressed (<50 copies/mL) HIV-infected men in the Multicenter AIDS Cohort Study from 1998 to 2009. Associations between dichotomized 6-month (<100% vs 100%) and categorized 4-day (<85%, 85%-99%, and 100%) cART adherence with biomarker concentrations were evaluated. Results. A total of 912 men provided 2816 person-visits with documented plasma HIV RNA suppression. In adjusted models, person-visits at which <100% cART 6-month adherence was reported had higher concentrations of interleukin 2, 6, and 10, interferon γ, tumor necrosis factor α, and C-reactive protein than person-visits at which 100% cART adherence (P < .05) was reported. These same differences were observed in person-visits reporting <85% versus 100% 4-day cART adherence, but not in visits reporting 85%-99% versus 100% cART adherence. After adjustment for multiple comparisons, tumor necrosis factor α remained significantly higher (11% increase; P < .001) in person-visits at which <100% adherence was reported. Conclusions. Higher concentrations of inflammatory biomarkers were observed among HIV RNA-suppressed men who reported <100% cART adherence than among more adherent men. Residual HIV replication (ie, below the limit of detection), more likely among men with suboptimal adherence, is a plausible mechanism. Whether improving cART adherence could affect residual inflammation and associated morbidity and mortality rates should be investigated. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus (HIV)-induced inflammation and immune activation persist after initiation of combination antiretroviral therapy (cART) and HIV suppression and may contribute to mortality risks that exceed those in HIVuninfected populations, though associations are unclear. Methods. In the prospective Multicenter AIDS Cohort Study, comprising men who have sex with men from Baltimore, Chicago, Los Angeles, and Pittsburgh, concentrations of 24 biomarkers of inflammation and immune activation were measured in stored serum from HIV-positive men obtained after cART-induced HIV suppression between 1996 and 2009. The outcome was nonaccidental death, with follow-up until 2014.We used Cox proportional hazards models to test whether biomarker concentrations predict time from HIV suppression to death and adjusted for multiple tests. Exploratory factor analysis (EFA) was employed to identify groupings of biomarkers that predict mortality risk. Results. Of 670 men followed up from HIV suppression, 54 died by the end of 2013. After adjustment for age, CD4+ cell count, hepatitis B or C virus infection, and smoking, concentrations in the highest quartile of 4 biomarkers were significantly associated with mortality risk after controlling the false discovery rate at 5%: interleukin (IL) 6 (hazard ratio, 3.54; 95% confidence interval, 2.06- 6.10), soluble IL 2Rα (3.29, 1.85-5.85), soluble CD14 (2.67, 1.55-4.61), and chemokine (CXC motif ) ligand 13 (CXCL13; 2.26; 1.29- 3.95). EFA yielded 2 biomarker groupings that were independent predictors of mortality risk. Conclusions. Despite having undetectable HIV RNA levels during cART, men with higher concentrations of several biomarkers (particularly IL 6, soluble IL 2Rα, soluble CD14, and CXCL13) had higher hazards of long-term mortality. Correlations observed among biomarker concentrations may represent underlying inflammatory processes that contribute to mortality risk. [ABSTRACT FROM AUTHOR]

The association between oral human papillomavirus 16 (HPV16) DNA load and infection clearance was evaluated among 88 individuals with oral HPV16 infection who were identified within a prospective cohort of 1470 HIV-infected and uninfected individuals. Oral rinse specimens were collected semiannually for up to 5 years. The oral HPV16 load at the time of the first positive test result was significantly associated with the time to clearance of infection (continuous P trends <.01). Notably, clearance rates by 24 months were 41% and 94% in the highest and lowest HPV16 load tertiles (P = .03), respectively. High oral HPV16 load warrants consideration as a biomarker for infection persistence, the presumed precursor of HPV16-associated oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV)-infected individuals are at higher risk for chronic kidney disease than HIV-uninfected individuals. We investigated whether the inflammation present in treated HIV infection contributes to kidney dysfunction among HIV-infected men receiving highly active antiretroviral therapy. Methods: The glomerular filtration rate (GFR) was directly measured (using iohexol) along with 12 markers of inflammation in Multicenter AIDS Cohort Study participants. Exploratory factor analysis was used to identify inflammatory processes related to kidney dysfunction. The estimated levels of these inflammatory processes were used in adjusted logistic regression analyses evaluating cross-sectional associations with kidney function outcomes. Results: There were 434 HIV-infected men receiving highly active antiretroviral therapy and 200 HIV-uninfected men. HIV-infected men were younger (median age, 51 vs 53 years) and had higher urine protein-creatinine ratios (median, 98 vs 66 mg/g) but comparable GFRs (median, 109 vs 106 mL/min|1.73 m(2)). We found an inflammatory process dominated by markers: soluble tumor necrosis factor receptor 2, soluble interleukin 2 receptor α, soluble gp130, soluble CD27, and soluble CD14. An increase of 1 standard deviation in that inflammatory process was associated with significantly greater odds of GFR ≤90 mL/min/1.73 m(2) (odds ratio, 2.0) and urine protein >200 mg/g (odds ratio, 2.3). Conclusions: Higher circulating levels of immune activation markers among treated HIV-infected men may partially explain their higher burden of kidney dysfunction compared with uninfected men. [ABSTRACT FROM AUTHOR]

Background. Individuals infected with human immunodeficiency virus (HIV) live longer as a result of effective treatment, but long-term consequences of infection, treatment, and immunological dysfunction are poorly understood. Methods. We prospectively examined 1011 women (74% HIV-infected) in theWomen's Interagency HIV Study and 811 men (65% HIV-infected) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. Outcomes included changes in right common carotid artery intima-media thickness (CCA-IMT) and new focal carotid artery plaque formation (IMT >1.5 mm) over median 7 years. We assessed the association between HIV serostatus and progression of subclinical atherosclerosis, adjusting for demographic, behavioral, and cardiometabolic risk factors. Results. Unadjusted mean CCA-IMT increased (725 to 752 µm in women, 757 to 790 µm in men), but CCAIMT progression did not differ by HIV serostatus, either in combined or sex-specific analyses. Focal plaque prevalence increased from 8% to 15% in women and 25% to 34% in men over 7 years. HIV-infected individuals had 1.6-fold greater risk of new plaque formation compared with HIV-uninfected individuals (relative risk [RR] 1.61, 95% CI, 1.12-2.32), adjusting for cardiometabolic factors; the association was similar by sex. Increased plaque occurred even among persistently virologically suppressed HIV-infected individuals compared with uninfected individuals (RR 1.56, 95% CI, 1.07-2.27). HIV-infected individuals with baseline CD4+ ≥500 cells/μL had plaque risk not statistically different from uninfected individuals. Conclusions. HIV infection is associated with greater increases in focal plaque among women and men, potentially mediated by factors associated with immunodeficiency or HIV replication at levels below current limits of detection. [ABSTRACT FROM AUTHOR]

Background. Heightened immune activation among human immunodeficiency virus (HIV)-infected persons may contribute to atherosclerosis. We assessed associations of serologic markers of monocyte activation, soluble CD163 (sCD163) and soluble CD14 (sCD14), and monocyte chemoattractant protein 1 (CCL2) with subclinical atherosclerosis among men with and those without HIV infection in the Multicenter AIDS Cohort Study. Methods. We performed noncontrast computed tomography on 906 men (566 HIV-infected men and 340 HIVuninfected men), 709 of whom also underwent coronary computed tomographic angiography. Associations between each biomarker and the prevalence of coronary plaque, the prevalence of stenosis of =50%, and the extent of plaque were assessed by logistic and linear regression, adjusting for age, race, HIV serostatus, and cardiovascular risk factors. Results. Levels of all biomarkers were higher among HIV-infected men, of whom 81% had undetectable HIV RNA, and were associated with lower CD4+ T-cell counts. In the entire population and among HIV-infected men, higher biomarker levels were associated with a greater prevalence of coronary artery stenosis of =50%. Higher sCD163 levels were also associated with greater prevalences of coronary artery calcium, mixed plaque, and calcified plaque; higher CCL2 levels were associated with a greater extent of noncalcified plaque. Conclusions. sCD163, sCD14, and CCL2 levels were elevated in treated HIV-infected men and associated with atherosclerosis. Monocyte activation may increase the risk for cardiovascular disease in individuals with HIV infection. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus-infected individuals have benefited from improved viral suppression, but a discrepancy in end-stage renal disease risk between black and nonblack HIV-infected persons remains, in part due to continued disparities in antiretroviral use and viral suppression, and higher rates of comorbidities.Background. Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks.Methods. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18–80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD.Results. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8–3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9–5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection.Conclusions. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility. [ABSTRACT FROM PUBLISHER]

Background. Adults aging with HIV infection are at risk for age-related comorbidities and syndromes, such as frailty. The objective of this study was to evaluate the expression and predictors of the frailty phenotype (FP) among HIV-infected (HIV+) and HIV-uninfected (HIV−) men who have sex with men. Methods. A prospective, observational cohort study was nested in the Multicenter AIDS Cohort Study from October 2007–September 2011. FP conversion was defined as the onset of FP over two consecutive study visits. Adjusted odds ratios and 95% confidence intervals ([,]) for FP conversion were estimated using logistic regression models with generalized estimating equations. Results. Of 10,571 completed study visits from 1,946 men who have sex with men, 12% and 9% were FP+ among HIV+ and HIV− men, respectively (p = .002). The proportion of FP+ visits increased with age regardless of HIV status, but was significantly greater in HIV+ compared to HIV− men aged 50–64 years. Of the 10,276 consecutive visit pairs contributed by participants, 5% (537) were classified as FP conversion, and 45% of the men with FP conversion had only one FP+ study visit. FP conversion was significantly associated with a history of AIDS (adjusted odds ratios = 2.26 [1.50, 3.39], but not with HIV+ alone (adjusted odds ratios = 1.26 [0.98, 1.64]). Among men who had one or more FP+ visits, 34% of HIV+ and 38% of HIV− men had less than two comorbidities. Conclusions. These findings suggest that expression of the FP can be measured in men who have sex with men with and without HIV infection and reflects multisystem dysfunction in this population; further investigations are needed to better understand clinical utility. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Parametric and semiparametric competing risks methods were used to estimate proportions, timing, and predictors of acquired immune deficiency syndrome (AIDS)-related and non-AIDS-related mortality among individuals both positive and negative for the human immunodeficiency syndrome (HIV) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) from 1984 to 2008 and 1996 to 2008, respectively. Among HIV-positive MACS participants, the proportion of deaths unrelated to AIDS increased from 6% before the introduction of highly active antiretroviral therapy (HAART) (before 1996) to 53% in the HAART era (P < 0.01); the median age of persons who died from non-AIDS-related causes after age 35 years increased from 49.0 to 66.0 years (P < 0.01). In both cohorts during the HAART era, median ages at time of non-AIDS-related death were younger for HIV-positive individuals than for comparable HIV-negative individuals (8.7 years younger in MACS (P < 0.01) and 7.6 years younger in WIHS (P < 0.01)). In a multivariate proportional cause-specific hazards model, unemployment (for non-AIDS death, hazard ratio (HR) = 1.8; for AIDS death, HR = 2.3), depression (for non-AIDS death, HR = 1.4; for AIDS death, HR = 1.4), and hepatitis B or C infection (for non-AIDS death, HR = 1.8, for AIDS death; HR = 1.4) were significantly (P < 0.05) associated with higher hazards of both non-AIDS and AIDS mortality among HIV-positive individuals in the HAART era, independent of study cohort. The results illuminate the changing face of mortality among the growing population infected with HIV. [ABSTRACT FROM AUTHOR]

Background. Accurate testing algorithms are needed for estimating human immunodeficiency virus (HIV) incidence from cross-sectional surveys.Methods. We developed a multiassay algorithm (MAA) for HIV incidence that includes the BED capture enzyme immunoassay (BED-CEIA), an antibody avidity assay, HIV load, and CD4+ T-cell count. We analyzed 1782 samples from 709 individuals in the United States who had a known duration of HIV infection (range, 0 to >8 years). Logistic regression with cubic splines was used to compare the performance of the MAA to the BED-CEIA and to determine the window period of the MAA. We compared the annual incidence estimated with the MAA to the annual incidence based on HIV seroconversion in a longitudinal cohort.Results. The MAA had a window period of 141 days (95% confidence interval [CI], 94–150) and a very low false-recent misclassification rate (only 0.4% of 1474 samples from subjects infected for >1 year were misclassified as indicative of recent infection). In a cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI, .70%–1.55%). The incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI, .51%–1.71%).Conclusions. The MAA is as sensitive for detecting recent HIV infection as the BED-CEIA and has a very low rate of false-recent misclassification. It provides a powerful tool for cross-sectional HIV incidence determination. [ABSTRACT FROM AUTHOR]

Background. Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends. Methods. In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men). Results. Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIVinfected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7-151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5-61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8-6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5-2.2). In comparison with the period 2000-2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3-.9) in 1996-1999 and 0.9 (95% CI, .6-1.2) in 2004-2007. Conclusions. Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued. [ABSTRACT FROM AUTHOR]

Epidemiological evidence has suggested that consumption of a diet rich in cruciferous vegetables reduces the risk of several types of cancers and chronic degenerative diseases. In particular, broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can release the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases. Two broccoli sprout-derived beverages, one sulforaphane-rich (SFR) and the other glucoraphanin-rich (GRR), were evaluated for pharmacodynamic action in a crossover clinical trial design. Study participants were recruited from the farming community of He Zuo Township, Qidong, China, previously documented to have a high incidence of hepatocellular carcinoma with concomitant exposures to aflatoxin and more recently characterized with exposures to substantive levels of airborne pollutants. Fifty healthy participants were randomized into two treatment arms. The study protocol was as follows: a 5 days run-in period, a 7 days administration of beverage, a 5 days washout period and a 7 days administration of the opposite beverage. Urinary excretion of the mercapturic acids of acrolein, crotonaldehyde, ethylene oxide and benzene were measured both pre- and postinterventions using liquid chromatography tandem mass spectrometry. Statistically significant increases of 20–50% in the levels of excretion of glutathione-derived conjugates of acrolein, crotonaldehyde and benzene were seen in individuals receiving SFR, GRR or both compared with their preintervention baseline values. No significant differences were seen between the effects of SFR versus GRR. Intervention with broccoli sprouts may enhance detoxication of airborne pollutants and attenuate their associated health risks. [ABSTRACT FROM AUTHOR]

Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts. Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995-August 2009. Parametric survival models identified factors associated with tuberculosis occurrence. Results. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131-333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk. Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm³ or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex. [ABSTRACT FROM AUTHOR]

Background. In the general population, frailty, a late stage of the aging process, predicts mortality. We investigated whether manifesting a previously defined frailty-related phenotype (FRP) before initiating highly active antiretroviral therapy (HAART) affects the likelihood of developing clinical AIDS or mortality after HAART initiation. Methods. Among 596 HIV-infected men in the Multicenter AIDS Cohort Study whose date of HAART initiation was known within ±6 months and who had an assessable FRP status within 3 years before HAART, survival analyses were performed to assess the effect of FRP manifestation on clinical AIDS or death after HAART. Results. In men free of AIDS before HAART, AIDS or death after HAART occurred in 13/36 (36%) men who exhibited the FRP before HAART but only in 69/436 (16%) men who did not (hazard ratio = 2.6; 95% confidence interval = 1.4–4.6; p < .01). After adjusting for age, ethnicity, education, nadir CD4+ T-cell count, peak HIV viral load, and hemoglobin in the 3 years before HAART, having the FRP at >25% of visits in the 3 years before HAART significantly predicted AIDS or death (adjusted hazard ratio = 3.8; 95% confidence interval = 1.9–7.9; p < .01). Results were unchanged when the analysis was restricted to the 335 AIDS-free men who were HAART responders, to the 124 men who had AIDS at HAART initiation, or to the subsets of men for whom indices of liver and kidney function could be taken into account. Conclusion. Having a persistent frailty-like phenotype before HAART initiation predicted a worse prognosis after HAART, independent of known risk factors. [ABSTRACT FROM PUBLISHER]

Typical applications of marginal structural time-to-event (e.g., Cox) models have used time on study as the time scale. Here, the authors illustrate use of time on treatment as an alternative time scale. In addition, a method is provided for estimating Kaplan-Meier–type survival curves for marginal structural models. For illustration, the authors estimate the total effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome (AIDS) or death in 1,498 US men and women infected with human immunodeficiency virus and followed for 6,556 person-years between 1995 and 2002; 323 incident cases of clinical AIDS and 59 deaths occurred. Of the remaining 1,116 participants, 77% were still under observation at the end of follow-up. By using time on study, the hazard ratio for AIDS or death comparing always with never using highly active antiretroviral therapy from the marginal structural model was 0.52 (95% confidence interval: 0.35, 0.76). By using time on treatment, the analogous hazard ratio was 0.44 (95% confidence interval: 0.32, 0.60). In time-to-event analyses, the choice of time scale may have a meaningful impact on estimates of association and precision. In the present example, use of time on treatment yielded a hazard ratio further from the null and more precise than use of time on study as the time scale. [ABSTRACT FROM PUBLISHER]

Background. A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study. Methods. The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters. Results. Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P=6.23×10-7). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P=1.63×10-6). Conclusions. This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-γ expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis. [ABSTRACT FROM AUTHOR]

To estimate the net effect of imperfectly measured highly active antiretroviral therapy on incident acquired immunodeficiency syndrome or death, the authors combined inverse probability-of-treatment-and-censoring weighted estimation of a marginal structural Cox model with regression-calibration methods. Between 1995 and 2007, 950 human immunodeficiency virus–positive men and women were followed in 2 US cohort studies. During 4,054 person-years, 374 initiated highly active antiretroviral therapy, 211 developed acquired immunodeficiency syndrome or died, and 173 dropped out. Accounting for measured confounders and determinants of dropout, the weighted hazard ratio for acquired immunodeficiency syndrome or death comparing use of highly active antiretroviral therapy in the prior 2 years with no therapy was 0.36 (95% confidence limits: 0.21, 0.61). This association was relatively constant over follow-up (P = 0.19) and stronger than crude or adjusted hazard ratios of 0.75 and 0.95, respectively. Accounting for measurement error in reported exposure using external validation data on 331 men and women provided a hazard ratio of 0.17, with bias shifted from the hazard ratio to the estimate of precision as seen by the 2.5-fold wider confidence limits (95% confidence limits: 0.06, 0.43). Marginal structural measurement-error models can simultaneously account for 3 major sources of bias in epidemiologic research: validated exposure measurement error, measured selection bias, and measured time-fixed and time-varying confounding. [ABSTRACT FROM PUBLISHER]

Background. Although combination antiretroviral therapy continues to evolve, with potentially more effective options emerging each year, the ability of therapy to prevent multiple regimen failure and mortality in clinical practice remains poorly defined. Methods. Sixteen cohorts representing over 60 sites contributed data on all individuals who initiated combination antiretroviral therapy. We identified those individuals who experienced virologic failure (defined as a human immunodeficiency virus [HIV] RNA level 11000 copies/mL), received modified therapy, and subsequently had a second episode of virologic failure. Multivariate Cox regression was used to assess factors associated with time to second regimen failure and the time to death after the onset of second regimen failure. Results. Of the 42,790 individuals who received therapy, 7159 experienced a second virologic failure. The risk of second virologic failure decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; P < .001). The cumulative mortality after onset of second virologic failure was 26% at 5 years and decreased over time. A history of AIDS, a lower CD4+ T cell count, and a higher plasma HIV RNA level were each independently associated with mortality. Similar trends were observed when analysis was limited to the subset of previously treatment-naive patients Conclusions. Although the rates of multiple regimen failure have decreased dramatically over the past decade, mortality rates for those who have experienced failure of at least 2 regimens have remained high. Plasma HIV RNA levels, CD4+ T cell counts at time of treatment failure, and a history of AIDS remain independent risk factors for death, which emphasizes that these factors remain important targets for those in need of more-aggressive therapeutic interventions. [ABSTRACT FROM AUTHOR]

We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS Cohort Study (MACS) who were selected to reflect the full spectrum of rates of HIV-1 disease progression. A mean of 10 serial samples per donor were evaluated by a laboratory-validated, commercially available assay to determine phenotypic coreceptor use.Atotal of52%ofmen had dual- or mixed-tropic HIV-1 detected at 1 or more of the time points tested. Use of X4 by HIV-1 was detected more frequently among men who developed AIDS (defined as a CD4+ T cell count of <200 cells/μL and/or an AIDS-defining illness)⩽11 years after seroconversion thanamongthosewhodid not (P = .005), as well asamong men who exhibited a total T cell count decline (i.e., a CD3+ inflection point), compared with those who did not (P = .03). Formen in whom both X4 virus and an inflection point were detected, emergence of X4 virus preceded the inflection point by a median of 0.83 years. The median CD4+ T cell count at first detection of X4 viruses before the onset of AIDS was 475 cells/μL. We conclude that HIV-1 variants that used X4 frequently emerged at high CD4+ T cell counts and may contribute to the decrease in T cell numbers during late HIV-1 infection. [ABSTRACT FROM AUTHOR]

Understanding the characteristics of human immunodeficiency virus (HIV) necessary for infection in a new host is a critical goal for acquired immunodeficiency syndrome (AIDS) research. We studied the characteristics of HIV-1 envelope genes in 38 men in the Multicenter AIDS Cohort Study cohort before seroconversion. We found a range of diversity (0.2%- 5.6% [median, 0.86%]), V1-V2 loop length (58-93 aa), and potential N-linked glycosylation sites (n = 2-9). However, at least 46% of the men had replicating virus that appeared to have been derived from a single viral variant. Nearly all variants were predicted to be CCR5 tropic. We found no correlation between these viral characteristics and the HIV outcomes of time to clinical AIDS or death and/or aCD4cell count<200 cells/μL. [ABSTRACT FROM AUTHOR]

Background. Adherence to therapy is a dynamic behavior. However, few studies have identified factors associated with changes in adherence to highly active antiretroviral therapy (HAART) among men and women. Methods. From 1999 through 2004, self-reported adherence to HAART was recorded twice yearly as part of 2 prospective cohort studies. At each study visit, participants were categorized as being 100% adherent if they reported full adherence with their HAART regimen over the past 4 days (for men) and 3 days (for women). Repeated-measures logistic regression models were used to identify predictors for changes in adherence between consecutive visits. Results. Of the participants, 640 men and 1304 women contributed 2803 and 5972 visit-pairs, respectively. Among white men, the prevalence of 100% adherence decreased from 91% in 1998 to 80% in 2003. Among women and African American men, the prevalence of full adherence was lower (75% and 77% on average, respectively) and stable over time (P> .6 ). In both cohorts, the presence of clinical symptoms was independently P 1 .6 associated with decreasing adherence (odds ratio [OR], 1.38 in men and 1.48 in women). Depression in men (OR, 1.44) and use of alcohol in women (OR, 1.81, 1.52, and 1.29, for binge drinking, moderate-to-heavy drinking, and low consumption, respectively) also predicted decreasing adherence. In addition, the use of drugs by men and women (OR, 0.61 and 0.58, respectively) and alcohol binging by women (OR, 0.41) were negatively associated with improving adherence. Conclusions. Adherence to antiretroviral treatment is a dynamic process; modifiable risk factors are associated with increasing and decreasing adherence, suggesting specific interventions. Moreover, the association of these risk factors with changes in adherence may differ by sex. [ABSTRACT FROM AUTHOR]

Background. Older healthy and HIV-infected adults exhibit physiological similarities. Frailty is a clinical syndrome associated with aging that identifies a subset of older adults at high risk of mortality and other outcomes. We investigated whether HIV infection increases the prevalence of a frailty-related phenotype (FRP) that approximates a clinical definition of frailty. Methods. We first defined the FRP and assessed its prevalence among HIV-uninfected men followed in the Multicenter AIDS Cohort Study (MACS) between 1994 and 2004. Using repeated measurements logistic regression models, we then assessed the association between FRP and HIV infection before the era of highly active antiretroviral therapies, adjusting for covariates among HIV-uninfected (N = 1905) and incident H1V cases (N = 245). Results. HIV infection was strongly associated with FRP prevalence. Compared to HIV-uninfected men of similar age, ethnicity and education, HIV-infected men were more likely to have the FRP for all durations of infection: for ≤4 years, the adjusted odds ratio (OR) was 3.38, with 95% confidence interval (CI), 1.25-9.11, and for 4.01-8 years and 8.01-12 years the corresponding figures were (OR = 12.95, 95% CI, 6.60-25.40) and (OR = 14.68, 95% CI, 7.60-28.35), respectively. The FRP prevalence for 55-year-old men infected with HIV for ≤4 years (3.4%; 95% CI, 1.3-8.6) was similar to that of uninfected men ≥65 years old (3.4%; 95% CI, 1.5-7.6). Conclusion. In this cohort, HIV infection was associated with an earlier occurrence of a phenotype that resembles the phenotype of frailty in older adults without HIV infection. Studies of frailty in the setting of HIV infection may help to clarify the biological mechanism of frailty. [ABSTRACT FROM AUTHOR]

Vaccines designed to induce cell-mediated immune responses against human immunodeficiency virus (HIV)-1 are being developed. Such vaccines are unlikely to provide sterilizing immunity but may be associated with reduced viral set points-after infection. We modeled the potential impact of a vaccine that reduces viral set point after infection, using natural history data from 311 HIV-1 seroconverters. Log-normal parametric regression models were used to estimate the log median time to events of interest. Relative times were estimated for those with viral load set points of 30,000 copies/mL (reference group) versus those with lower viral set points. The time to key clinical events in the course of HIV-1 disease progression was significantly extended for those with viral set points 0.5-1.25 log10 copies/mL lower than the reference group. By quantifying the anticipated clinical benefits associated with a reduction in viral set point, these findings support the use of virologic end points in HIV-1 vaccine trials. [ABSTRACT FROM AUTHOR]

The authors evaluated population- and individual-level CD4-positive T-lymphocyte (CD4 cell) count trajectories over a 7-year period (July 1995–March 2004) following initiation of highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. The study population included 404 human immunodeficiency virus (HIV)-infected men and 609 HIV-infected women who 1) had a CD4 cell count measurement available from their last pre-HAART study visit, 2) provided at least four post-HAART CD4 cell count measurements, and 3) reported HAART usage for at least 80% of the post-HAART visits. The CD4 cell count trajectory was analyzed by means of a Bayesian random change-point model. The results indicated that CD4 cell count trajectories for long-term frequent HAART users can be well modeled with change points at both the population and individual levels. At the population level, regardless of CD4 cell count before HAART initiation, the gains in CD4 cell count ended approximately 2 years after HAART initiation in both men and women. At the individual level, 35% of men in the Multicenter AIDS Cohort Study versus 25% of women in the Women's Interagency HIV Study had a statistically significant change in CD4 cell count trajectory within 7 years after HAART initiation. [ABSTRACT FROM AUTHOR]

Background. Human herpesvirus 8 (HHV-8) is associated with Kaposi sarcoma (KS) in patients with acquired immunodeficiency syndrome (AIDS) and KS, classical KS, or endemic KS. Because human immunodeficiency virus (HIV) infections and HIV/AIDS are common in Thailand but KS is very rare (only 0.2% of reported patients with AIDS in Thailand had KS), we determined the HHV-8 seroprevalence among populations who were HIV positive or at risk of HIV infection. Methods. A total of 992 persons from 2 populations underwent testing for lytic antibodies to HHV-8 using an immunofluorescence assay involving a BCBL-1 cell line at serum dilutions of 1:50 and 1:100. Serum specimens with positive results were titered to end points. Subjects included ∼400 married couples in which the husband was HIV positive and the wife was HIV positive (200 couples) or HIV negative (200 couples). In addition, 200 HIV-negative men from a sexually transmitted diseases (STD) clinic were studied. Results. The antibody prevalence was 24.2% in the total population. The prevalence was higher among HIV negative men (13.0%) but was similar among HIV-positive women (27.9%) and HIV-negative women (23.8%). The HHV-8 seroprevalence among wives whose husbands were HIV-1 positive did not differ according to their husband's HHV-8 status. There was no association between HHV-8 seroprevalence and reported sexual behavior or STD history. Conclusion. Despite the rarity of KS among patients with AIDS in Thailand, HHV-8 infections are common and do not appear to be frequently transmitted sexually in these populations. [ABSTRACT FROM AUTHOR]

Examines the relationship of human leukocyte antigen (HLA) class I and transporter associated with antigen processing genes with resistance to HIV-1 infection. Effect of the presence of the subgroup alleles; Possibility for the differential preferences for amino acids at the C terminus to influence peptide-binding capacity.

The authors examined the impact of potent antiretroviral therapy (ART) on the diagnosis of wasting syndrome in the Multicenter AIDS Cohort Study. Study time was divided into the periods 1988–1990, 1991–1993, 1994–1995, and 1996–1999 to correspond to different treatment eras. The proportion of acquired immunodeficiency syndrome diagnoses in which wasting was present increased from 5% in 1988–1990 to 7.1% in 1991–1993, 7.7% in 1994–1995, and 18.9% in 1996–1999. The incidence of wasting per 1,000 person-years increased from 7.5 in 1988–1990 to 14.4 in 1991–1993 and 22.1 in 1994–1995; it decreased to 13.4 in 1996–1999. Fewer patients with wasting had low hemoglobin and hematocrit levels and reported oral thrush in 1996–1999 than in any other period. Analysis of change in body mass index (weight (kg)/height (m)2) after wasting showed a faster return to prewasting levels in 1994–1995 and 1996–1999 than in earlier periods. Case-control analysis showed that wasting prior to 1996 was weakly associated with fatigue (p = 0.10), low hemoglobin (p = 0.11), and CD4-positive T-lymphocyte count (p = 0.04). During 1996–1999, wasting was weakly associated with diarrhea (p = 0.05) and potent ART (p = 0.097). Predictors of wasting have changed with potent ART. Further research is needed to determine whether lipodystrophy may be misdiagnosed as wasting syndrome. Am J Epidemiol 2002;156:211–18. [ABSTRACT FROM PUBLISHER]

Deals with a study on human herpesvirus 8 (HHV-8) infection among HIV-infected and high-risk HIV-uninfected women. Participants and methods; Univariate analysis of factors associated with HHV-8 infection; Multivariate analysis of factors associated with HHV-8 infection; Association of HHV-8 serologic reactivity with Kaposi's sarcoma.

Characterizes cytotoxic T lymphocytes (CTL) responses to lytic proteins of human herpes virus 8 (HHV-8) in HIV type 1-infected or -uninfected individuals. Inverse correlation between HIV-1 load and glycoprotein H-specific CTL lysis in the study subjects infected with both viruses; Possible involvement of CTL reactivity to HHV-8 lytic proteins in host control of HHV-8-related diseases.

Background: Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of foods contaminated with aflatoxins, which require metabolic activation to become carcinogenic. In a randomized, placebo-controlled, double-blind phase IIa chemoprevention trial, we tested oltipraz, an antischistosomal drug that has been shown to be a potent and effective inhibitor of aflatoxin-induced hepatocarcinogenesis in animal models.Methods: In 1995, 234 adults from Qidong were enrolled. Healthy eligible individuals were randomly assigned to receive by mouth 125 mg oltipraz daily, 500 mg oltipraz weekly, or a placebo. Sequential immunoaffinity chromatography and liquid chromatography coupled to mass spectrometry or to fluorescence detection were used to identify and quantify phase 1 and phase 2 metabolites of aflatoxin B1 in the urine of study participants. Reported P values are two-sided.Results: One month of weekly administration of 500 mg oltipraz led to a 51% decrease in median levels of the phase 1 metabolite aflatoxin M1 excreted in urine compared with administration of a placebo (P = .030), but it had no effect on levels of a phase 2 metabolite, aflatoxin-mercapturic acid (P = .871). By contrast, daily intervention with 125 mg oltipraz led to a 2.6-fold increase in median aflatoxin-mercapturic acid excretion (P = .017) but had no effect on excreted aflatoxin M1 levels (P = .682).Conclusions: Intermittent, high-dose oltipraz inhibited phase 1 activation of aflatoxins, and sustained low-dose oltipraz increased phase 2 conjugation of aflatoxin, yielding higher levels of aflatoxin-mercapturic acid. While both mechanisms can contribute to protection, this study highlights the feasibility of inducing phase 2 enzymes as a chemopreventive strategy in humans. [ABSTRACT FROM AUTHOR]

Despite much investigation of zidovudine, little has been reported regarding its effect on the development of most individual AIDS-defining illnesses, including Kaposi's sarcoma (KS). We used observational data from the Multicenter AIDS Cohort Study (MACS) to estimate the effect of zidovudine use on the subsequent incidence of KS. To do this, we examined and adjusted for predictors of zidovudine use. CD4 lymphocyte counts, the development of HIV-related symptoms and AIDS, and changes in these factors were important predictors of zidovudine use. We used these associations to control for confounding by these and other factors with the G-estimation approach. We found no evidence that zidovudine use affected the time to KS in the MACS; the point estimate (95% confidence interval [CI]) for increase in time to KS was zero (−28%–68%). The relative risk was 1.0 (95% CI, 0.54–1.84). Randomized trials suggest that zidovudine may prevent KS. We discuss possible explanations for differences between results. [ABSTRACT FROM PUBLISHER]

Changes in the use of antiretroviral drugs and factors associated with changes from monotherapy with zidovudine (ZDV) to other regimens were quantified in the Multicenter AIDS Cohort Study. Participants who had been receiving monotherapy with ZDV were categorized as (1) discontinuing ZDV monotherapy; (2) switching to didanosine (ddI), zalcitabine (ddC), or stavudine (d4T) monotherapy; (3) switching to combination therapy (ZDV with ddI, ddC, or d4T); or (4) continuing ZDV monotherapy. From 1990 to 1994, the percentage of participants using ZDV monotherapy decreased from 27% to 17% (among participants without AIDS) and from 60% to 17% (among those with AIDS). At the same time, the proportion of participants using combination therapy increased from zero to 11% (no AIDS) and from 2% to 21% (AIDS), and the proportion switching to a different monotherapy increased from zero to 8% (no AIDS) and from 8% to 26% (AIDS). Polychotomous logistic regression methods were used to identify the factors predicting changes from ZDV monotherapy. Among participants without AIDS, indicators of drug failure (such as a lower CD4 lymphocyte count or symptoms of human immunodeficiency virus type 1 infection) were predictive of the initiation of combination therapy, while among patients with AIDS they were predictive of a switch to an alternative monotherapy. A decrease in hemoglobin levels, a marker of ZDV toxicity, was predictive for all patients of a switch to other monotherapy. In addition, private health insurance coverage was associated with reduced odds of the discontinuation of antiretroviral therapy. These data show that clinicians and patients are opting for more aggressive antiretroviral regimens and that changes in CD4 lymphocyte count and in the status of symptoms remain the primary guides for changes in therapy. [ABSTRACT FROM PUBLISHER]

Early (pre-seroconversion) infection with human immunodeficiency virus type 1 (HIV-1) was identified in 50 of 267 participants in the Multicenter AIDS Cohort Study. These 50 men had a positive EIA result, which detected IgM antibody (n = 35), p24 antigen, or serum HIV RNA (n = 15) at their last “seronegative” visit. At that visit, the mean CD4 lymphocyte number (890/mm3 vs. 1038/mm3) was significantly lower than in men who subsequently seroconverted but had no evidence of early infection. The decline in CD4 cells was slower and the duration of AIDS-free time longer in the 19 men who were symptomatic in comparison to the 31 asymptomatic men with early infection, but differences were not significant. [ABSTRACT FROM PUBLISHER]

Background The objective of this study was to investigate whether 100% antiretroviral therapy (ART) adherence in men with HIV (MWH) is associated with normalization of concentrations of biomarkers of inflammation and immune activation compared with HIV-uninfected men. Methods We analyzed person-visits with available biomarker data from the Multicenter AIDS Cohort Study (MACS) among MWH receiving ART with HIV RNA <50 copies/mL and among HIV-uninfected men. Self-reported adherence was classified as 100% if no missed ART doses in the past 4 days were reported. We evaluated associations between ART adherence and concentrations of 24 serum biomarkers compared with HIV-uninfected visits using a generalized gamma model, adjusting for potential confounders. Results Person-visits (2565 from MWH reporting 100% ART adherence and 1588 from HIV-uninfected men) from a total of 1469 men were included in the analysis. Serum concentrations of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), IL-1β, interferon-γ (IFN-γ), chemokine C-C motif ligand 2 (CCL2), and CCL14 from person-visits among MWH who reported 100% adherence were similar to HIV-uninfected person-visits. Comparatively higher concentrations of 11 biomarkers and lower concentrations of 7 biomarkers were observed in person-visits from MWH who reported 100% ART adherence, compared with HIV-uninfected person-visits. Conclusions Although MWH with virologic suppression who reported 100% ART adherence exhibited overall higher concentrations of biomarkers of inflammation and immune activation compared with HIV-uninfected men, some biomarker concentrations were similar in both groups. These findings suggest that optimal ART adherence could have clinical implications beyond achieving and sustaining viral suppression. [ABSTRACT FROM AUTHOR]

Objective We evaluated trends and population effectiveness (tolerability, HIV suppression) of current combination antiretroviral therapy (cART) regimens mindful of treatment guidelines. Method Trend analyses included 18 017 person-visits (1457 men) on cART during 2008–2017 in the Multicenter AIDS Cohort Study. Effectiveness analyses of current regimens used 3598 person-visit–pairs (745 men) on cART in 2014–2017. Inverse-probability-of-treatment-and-censoring weighted Poisson regression with robust variances was used to evaluate the association between regimens and switching, adherence and HIV RNA <20 copies/mL. Results Integrase strand transfer inhibitor (INSTI)-based regimen usage has increased since 2008. Almost 90% of cART initiators started with INSTI-cART in 2016–2017; cART adherence was stable around 90% and 83%–85% suppressed virus (<20 cp/mL). Commonly used regimens in 2014–2017 contained disoproxil fumarate/emtricitabine (TDF/FTC) backbone with efavirenz (EFV, n = 1161 person-visits), elvitegravir/cobicistat (EVG/c, n = 551), rilpivirine (RPV, n = 492), darunavir/ritonavir (DRV/r, n = 351), or atazanavir (ATV)/r (n = 333). Others were dolutegravir/abacavir/lamivudine (DTG/ABC/3TC, n = 401) and EVG/c/tenofovir alafenamide/FTC (EVG/c/TAF/FTC, n = 309). Compared to EFV/TDF/FTC users, ATV/r+TDF/FTC users switched more (rate ratio [RR] = 1.80, 95% confidence interval (CI), 1.17–2.76), while those on DTG/ABC/3TC (RR [95% CI] = 0.16 [0.08–0.31]) or EVG/c/TAF/FTC (RR [95% CI] = 0.12 [0.06–0.27]) switched less. The rate of suppressed HIV RNA was 15% (95% CI, 2%–26%) lower among younger EVG/c/TDF/FTC users and 18% (95% CI, 3%–34%) higher in older DRV/r+TDF/FTC users; adherence did not differ by regimen. Conclusions Consistent with guidelines, recent cART initiators started with INSTI-cART, which was associated with less switching early after initiation. Factors beyond those studied here, such as need for salvage therapy, unique personal characteristics, drug interactions, and cost may influence treatment decisions. [ABSTRACT FROM AUTHOR]

A response by Nikolas Wada and colleagues to an invited commentary on their article "AIDS and Depressive Symptoms," in the June 28, 2012 issue is presented.

Presents several medical evidences on HIV-1 infections. Development of Kaposi's sarcoma in human herpesvirus 8 infection; Enhancement of KS expression with HIV-induced immunosuppression; Prevalence of mucosal immune response in seronegative sex partners of HIV-infected persons.

Examines the association of survival in advanced HIV type 1 infection with the T lymphocyte activation and virus chemokine coreceptor usage. Determinants of HIV-1 disease progression; Cause of T cell immune dysfunction; Measurement of the immune activation of CD4 and CD8 T cells.