Chronic kidney disease and HIV infection both independently increase the risk of anemia. It is not known if individuals with both HIV infection and kidney dysfunction are at greater than expected risk of anemia resulting from the combined effect of these factors. Men from the Multicenter AIDS Cohort Study with AIDS-free time after 1996 were included in the analysis if they had an initial hemoglobin value greater than 13 g/dl and available serum creatinine measurements for the estimation of glomerular filtration rate. Hemoglobin data were fit parametrically using a linear mixed effects model and effects of medication use on hemoglobin levels were removed using censoring methods. The effect of both HIV infection and glomerular filtration rate less than 60 ml/min/1.73 m2 on the mean hemoglobin value was assessed. The risk of having anemia (hemoglobin level falling below 13 g/dl) was estimated. There were 862 HIV-infected and 1,214 HIV-uninfected men who contributed to the analysis. Hemoglobin values across all 17,341 person-visits, adjusting for age, were generally lower in HIV-infected AIDS-free men with impaired kidney function by −0.22 g/dl (95% CI: −0.42, −0.03) compared to men with either HIV infection or impaired kidney function, but not both. HIV-infected AIDS-free men with impaired kidney function have a higher risk of anemia by 1.2% compared to HIV-uninfected men with normal kidney function. Comorbid conditions and medication use did not explain this increase in risk. HIV infection and impaired kidney function have a combined impact on lowering hemoglobin levels, resulting in a higher risk of anemia.
U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes.
We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU).
Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60–0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87–1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47–0.95).
We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.
Too many people with HIV have left the job market permanently and those with reduced work capacity have been unable to keep their jobs. There is a need to examine the health effects of labor force participation in people with HIV. This study presents longitudinal data from 1,415 HIV-positive men who have sex with men taking part in the Multicenter AIDS Cohort Study. Generalized Estimating Equations show that employment is associated with better physical and mental health quality of life and suggests that there may be an adaptation process to the experience of unemployment. Post-hoc analyses also suggest that people who are more physically vulnerable may undergo steeper health declines due to job loss than those who are generally healthier. However, this may also be the result of a selection effect whereby poor physical health contributes to unemployment. Policies that promote labor force participation may not only increase employment rates but also improve the health of people living with HIV.
The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. Candidate gene studies have implicated genetic susceptibility loci within immune-related genes; however, these have not been reliably validated. Here we employed genome-wide association (GWA) methods to discover novel genetic susceptibility loci associated with HAND, and validate susceptibility loci implicated in prior candidate gene studies.
Data from 1287 participants enrolled in the Multicenter AIDS Cohort Study between 1985 and 2010 were used. Genotyping was conducted with Illumina 1M, 1MDuo, or 550K platform. Linear mixed models determined subject-specific slopes for change over time in processing speed and executive functioning, considering all visits including baseline and the most recent study visit. Covariates modeled as fixed effects included: time since the first visit, depression severity, nadir CD4+ T-cell count, Hepatitis C co-infection, substance use, and antiretroviral medication regimen. Prevalence of HIV-associated dementia (HAD) and neurocognitive impairment (NCI) was also examined as neurocognitive phenotypes in a case-control analysis.
No genetic susceptibility loci were associated with decline in processing speed or executive functioning among almost 2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed. No association between the SNPs and HAD or NCI were found. Previously reported associations between specific genetic susceptibility loci, HIV-associated neurocognitive impairment and HAD were not validated.
In this first GWAS of HAND, no novel or previously identified genetic susceptibility loci were associated with any of the phenotypes examined. Due to the relatively small sample size, future collaborative efforts that incorporate this dataset may still yield important findings.
HIV; NeuroAIDS; HIV-associated neurocognitive disorder; genome-wide association; HIV-associated dementia
Alcohol Drinking; HIV Seropositivity; Men who Have Sex with Men; Prospective Studies; Sexual Behavior
Highly active antiretroviral therapy (HAART) rapidly suppresses human immunodeficiency virus (HIV) viral replication and reduces circulating viral load, but the long-term effects of HAART on viral load remain unclear.
We evaluated HIV viral load trajectories over 8 years following HAART initiation in the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study. The study included 157 HIV-infected men and 199 HIV-infected women who were antiretroviral naïve and contributed 1311 and 1837 semiannual person-visits post-HAART, respectively. To account for within-subject correlation and the high proportion of left-censored viral loads, we used a segmental Bernoulli/lognormal random effects model.
Approximately 3 months (0.30 years for men and 0.22 years for women) after HAART initiation, HIV viral loads were optimally suppressed (ie, with very low HIV RNA) for 44% (95% confidence interval = 39%–49%) of men and 43% (38%–47%) of women, whereas the other 56% of men and 57% of women had on average 2.1 (1.5–2.6) and 3.0 (2.7–3.2) log10 copies/mL, respectively.
After 8 years on HAART, 75% of men and 80% of women had optimal suppression, whereas the rest of the men and women had suboptimal suppression with a median HIV RNA of 3.1 and 3.7 log10 copies/mL, respectively.
We assessed associations of herpes simplex virus types 1 and 2 (HSV-1 and -2), cytomegalovirus (CMV), and human herpesvirus 8 (HHV-8) infection with subclinical coronary atherosclerosis in 291 HIV-infected men in the Multicenter AIDS Cohort Study. Coronary artery calcium (CAC) was measured by non-contrast coronary CT imaging. Markers for herpesviruses infection were measured in frozen specimens collected 10-12 years prior to case identification. Multivariable logistic regression models and ordinal logistic regression models were performed. HSV-2 seropositivity was associated with coronary atherosclerosis (adjusted odds ratio [AOR] =4.12, 95% confidence interval [CI] =1.58-10.85) after adjustment for age, race/ethnicity, cardiovascular risk factors, and HIV infection related factors. Infection with a greater number of herpesviruses was associated with elevated CAC levels (AOR=1.58, 95% CI=1.06-2.36). Our findings suggest HSV-2 may be a risk factor for subclinical coronary atherosclerosis in HIV-infected men. Infection with multiple herpesviruses may contribute to the increased burden of atherosclerosis.
herpesvirus; HSV-2; atherosclerosis; HIV-1/AIDS; risk factors
The BED capture enzyme immunoassay (BED-CEIA) was developed for estimating HIV incidence from cross-sectional data. This assay misclassifies some individuals with nonrecent HIV infection as recently infected, leading to overestimation of HIV incidence. We analyzed factors associated with misclassification by the BED-CEIA. We analyzed samples from 383 men who were diagnosed with HIV infection less than 1 year after a negative HIV test (Multicenter AIDS Cohort Study). Samples were collected 2–8 years after HIV seroconversion, which was defined as the midpoint between the last negative and first positive HIV test. Samples were analyzed using the BED-CEIA with a cutoff of OD-n ≤0.8 for recent infection. Logistic regression was used to identify factors associated with misclassification. Ninety-one (15.1%) of 603 samples were misclassified. In multivariate models, misclassification was independently associated with highly active antiretroviral treatment (HAART) for >2 years, HIV RNA <400 copies/ml, and CD4 cell count <50 or <200 cells/mm3; adjusted odds ratios (OR) and 95% confidence intervals (CI) were 4.72 (1.35–16.5), 3.96 (1.53–10.3), 6.85 (2.71–17.4), and 11.5 (3.64–36.0), respectively. Among 220 men with paired samples, misclassification 2–4 years after seroconversion was significantly associated with misclassification 6–8 years after seroconversion [adjusted OR: 25.8 (95% CI: 8.17–81.5), p<0.001] after adjusting for race, CD4 cell count, HIV viral load, and HAART use. Low HIV viral load, low CD4 cell count, and >2 years of HAART were significantly associated with misclassification using the BED-CEIA. Some men were persistently misclassified as recently infected up to 8 years after HIV seroconversion.
The methodology for use of cardiac CT angiography (CTA) in low risk populations is not well defined. In order to present a reference for future studies, we present CTA methodology that is being used in an epidemiology study- the Multicenter AIDS Cohort Study (MACS).
The Multicenter AIDS Cohort Study (MACS) is an on-going multicenter prospective, observational cohort study. The MACS Cardiovascular Disease substudy plans to enroll 800 men (n= 575 HIV seropositive and n= 225 HIV seronegative) age 40-75 years for coronary atherosclerosis imaging using cardiac CTA. The protocol includes heart rate (HR) optimization with beta blockers; use of proper field of view; scan length limitation; prospective ECG-gating using the lowest beam voltage possible. All scans are evaluated for presence, extent, and composition of coronary atherosclerosis, left atrial volumes, left ventricular volume and mass and non-coronary cardiac pathology.
The first 498 participants had an average radiation dose of 2.5±1.6 milliSieverts (mSv) for the cardiac CTA study. Overall quality of scans was fair to excellent in 98.6% of studies. There were three significant adverse events- two allergic reactions to contrast and one subcutaneous contrast extravasation.
Cardiac CTA was safe and afforded a low effective radiation exposure to these asymptomatic research participants and provides valuable cardiovascular endpoints for scientific analysis. The cardiac CTA methodology described here may serve as a reference for use in future epidemiology studies aiming to assess coronary atherosclerosis and cardiac anatomy in low risk populations while minimizing radiation exposure.
CT angiography; radiation dose; epidemiological study
We compared three ad hoc methods to estimate the marginal hazard of incident cancer AIDS in a highly active antiretroviral therapy (1996–2006) relative to a monotherapy/combination therapy (1990–1996) calendar period, accounting for other AIDS events and deaths as competing risks.
Study Design and Setting
Among 1911 HIV+ men from the Multicenter AIDS Cohort Study, 228 developed cancer AIDS and 745 developed competing risks in 14,202 person-years from 1990–2006. Method 1 censored competing risks at the time they occurred, method 2 excluded competing risks, and method 3 censored competing risks at the date of analysis.
The age, race and infection duration adjusted hazard ratios (HRs) for cancer AIDS were similar for all methods (HR≅0.15). We estimated bias and CI coverage of each method with Monte Carlo simulation. On average across 24 scenarios, method 1 produced less biased estimates than methods 2 or 3.
When competing risks are independent of the event of interest, only method 1 produced unbiased estimates of the marginal HR, though independence cannot be verified from the data. When competing risks are dependent, method 1 generally produced the least biased estimates of the marginal HR for the scenarios explored; however, alternative methods may be preferred.
Competing risks; epidemiology; HIV; highly active antiretroviral therapy; cancer
In a large North American cohort study, anal cancer incidence rates were substantially higher for HIV-infected men who have sex with men, other men, and women compared with HIV-uninfected individuals. Rates increased from 1996–1999 to 2000–2003 but plateaued by 2004–2007.
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 HIV-infected 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.
Plasma HIV-1 RNA was measured in 306 samples, collected from 273 highly active antiretroviral therapy (HAART)-experienced men, using both the Roche COBAS TaqMan (limit of detection [LD]=20 copies/mL) and Roche Amplicor (LD=50 copies/mL) assays. Mixtures of Gaussian distributions incorporating left-censored data were used in analyses. The more sensitive TaqMan assay estimated that 23% and 0.0003% of HIV-1 RNA values would be below 1 copy/mL and 1 copy/3L, respectively. This is in sharp contrast to the overestimation provided by the less sensitive Amplicor assay, whereby the corresponding predicted percentages were 51% and 1%. Both assays appropriately characterized sub-optimal virologic response as the rightmost peaks of both distributions provided an excellent fit to the observed data. Our results based on a widely available 20 copies/mL sensitive assay reproduce those obtained using customized assays that quantified HIV-1 RNA values as low as 1 copy/mL.
limit of detection; HIV-1 RNA; bimodal distribution; HAART
Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57+) slow progressors and B57+ rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57+ individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57.
The potential for changing HIV-1 virulence has significant implications for the AIDS epidemic, including changing HIV transmission rates, rapidity of disease progression, and timing of ART. Published data to date have provided conflicting results.
We conducted a meta-analysis of changes in baseline CD4+ T-cell counts and set point plasma viral RNA load over time in order to establish whether summary trends are consistent with changing HIV-1 virulence.
We searched PubMed for studies of trends in HIV-1 prognostic markers of disease progression and supplemented findings with publications referenced in epidemiological or virulence studies. We identified 12 studies of trends in baseline CD4+ T-cell counts (21 052 total individuals), and eight studies of trends in set point viral loads (10 785 total individuals), spanning the years 1984–2010. Using random-effects meta-analysis, we estimated summary effect sizes for trends in HIV-1 plasma viral loads and CD4+ T-cell counts.
Baseline CD4+ T-cell counts showed a summary trend of decreasing cell counts [effect=−4.93 cells/µl per year, 95% confidence interval (CI) −6.53 to −3.3]. Set point viral loads showed a summary trend of increasing plasma viral RNA loads (effect=0.013 log10 copies/ml per year, 95% CI −0.001 to 0.03). The trend rates decelerated in recent years for both prognostic markers.
Our results are consistent with increased virulence of HIV-1 over the course of the epidemic. Extrapolating over the 30 years since the first description of AIDS, this represents a CD4+ T cells loss of approximately 148 cells/µl and a gain of 0.39 log10 copies/ml of viral RNA measured during early infection. These effect sizes would predict increasing rates of disease progression, and need for ART as well as increasing transmission risk.
CD4 lymphocyte count; disease progression; HIV infections/epidemiology; HIV infections/virology; HIV pathogenicity; viral load/trends; virulence
To estimate the association of antiretroviral therapy initiation with incident acquired immunodeficiency syndrome (AIDS) or death while accounting for time-varying confounding in a cost-efficient manner, the authors combined a case-cohort study design with inverse probability-weighted estimation of a marginal structural Cox proportional hazards model. A total of 950 adults who were positive for human immunodeficiency virus type 1 were followed in 2 US cohort studies between 1995 and 2007. In the full cohort, 211 AIDS cases or deaths occurred during 4,456 person-years. In an illustrative 20% random subcohort of 190 participants, 41 AIDS cases or deaths occurred during 861 person-years. Accounting for measured confounders and determinants of dropout by inverse probability weighting, the full cohort hazard ratio was 0.41 (95% confidence interval: 0.26, 0.65) and the case-cohort hazard ratio was 0.47 (95% confidence interval: 0.26, 0.83). Standard multivariable-adjusted hazard ratios were closer to the null, regardless of study design. The precision lost with the case-cohort design was modest given the cost savings. Results from Monte Carlo simulations demonstrated that the proposed approach yields approximately unbiased estimates of the hazard ratio with appropriate confidence interval coverage. Marginal structural model analysis of case-cohort study designs provides a cost-efficient design coupled with an accurate analytic method for research settings in which there is time-varying confounding.
acquired immunodeficiency syndrome; case-cohort studies; cohort studies; confounding bias; HIV; pharmacoepidemiology; selection bias
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.
The incidence of Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) among human immunodeficiency virus (HIV)-infected individuals declined following the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s, but the cancer risk associated with HIV infection during the HAART era remains to be clarified.
We compared cancer incidence among HIV-infected and -uninfected participants in the Multicenter AIDS Cohort Study (MACS) between 1984 and 2007 to the expected incidence using US population-based data from the Surveillance, Epidemiology, and End Results (SEER) Program, and we compared age and race adjusted cancer incidence rates by HIV status and over time within the MACS. Exact statistical methods were used for all analyses.
933 incident cancers were observed during 77,320 person-years of follow-up. Compared to SEER, MACS HIV-infected men had significantly (p<0.05) elevated rates of KS (standardized incidence ratio (SIR)=139.10), NHL (SIR=36.80), Hodgkin’s lymphoma (HL) (SIR=7.30), and anal cancer (SIR=25.71). Within MACS, HIV infection was independently associated with each of these cancers across the entire follow-up period, and KS (incidence rate ratio (IRR)=54.93), NHL (IRR=11.18), and anal cancer (IRR=18.50) were each significantly elevated among HIV-infected men during the HAART era. Among these men, the incidence of KS and NHL declined (IRR=0.13 and 0.23, respectively), anal cancer incidence increased (IRR=5.84), and HL incidence remained statistically unchanged (IRR=0.75) from the pre-HAART to the HAART era.
Cancer risk remains elevated among HIV-infected men who have sex with men, highlighting the continuing need for appropriate cancer screening in this population.
HIV infection; cancer incidence; malignancy; AIDS-defining malignancy; HAART
The association between methamphetamine use and HIV seroconversion for men who have sex with men (MSM) was examined using longitudinal data from the Multicenter AIDS Cohort Study.
Seronegative (n=4003) men enrolled in 1984–85, 1987–1991 and 2001–2003 were identified. Recent methamphetamine and popper use were determined at either the current or the previous visit. Time to HIV-seroconversion was the outcome of interest. Covariates included race/ethnicity, cohort, study site, educational level, number of sexual partners, number of unprotected insertive anal sexual partners (UIAS), number of unprotected receptive anal sexual partners (URAS), insertive rimming, cocaine use at either the current or last visit, ecstasy use at either the current or last visit, any needle use since last visit, CES-D depression score > 16 since last visit, and alcohol consumption.
After adjusting for covariates, there was an approximately 1.46-fold independent increased relative hazard (HR) of HIV seroconversion for methamphetamine use. The HR associated with popper use was 2.1 [95% CI 1.63, 2.70]. The HR of HIV seroconversion increased with URAS ranging from 1.87 [95% CI 1.40, 2.51] for 1 partner to 9.32 [95% CI 6.20, 13.98] for 5+ partners. The joint HR for methamphetamine and popper use was 3.05 [95% CI 2.12, 4.37]. Most notably, there was a significant joint HR for methamphetamine use and URAS of 2.71 [95% CI 1.81, 4.04] for men with 1 unprotected receptive anal sex partner, which increased in a dose-dependent manner for >1 partners.
Further examination of the synergism of patterns of drug use and sexual risk behaviors on rates of HIV seroconversion will be necessary in order to develop new HIV prevention strategies for drug-using MSM.
Multicenter AIDS cohort study; methamphetamine; HIV seroconversion; MSM
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.
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.
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.
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.
Having a persistent frailty-like phenotype before HAART initiation predicted a worse prognosis after HAART, independent of known risk factors.
HIV; Aging; Frailty; HAART response; Survival analysis
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
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) 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 aCD4 cell count <200 cells/μL.
The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine if elevated serum levels of molecules associated with B cell activation precede the diagnosis of AIDS-associated NHL.
Serum levels of B cell activation-associated molecules, interleukin-6 (IL6), interleukin-10 (IL10), soluble CD23 (sCD23), soluble CD27 (sCD27), soluble CD30 (sCD30), C-reactive protein (CRP), and IgE were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to three time points per subject, 0–5 years prior to AIDS-NHL diagnosis.
Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared to HIV+ controls or to AIDS controls, after adjusting for CD4 T cell number. Elevated serum levels of B cell activation-associated molecules were seen to be associated with the development of systemic (non-CNS) NHL, but not with the development of primary CNS lymphoma.
Levels of certain B cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B cell activation contributes to the development of these hematologic malignancies.
Marked differences in serum levels of several molecules are seen for several years pre-diagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.
lymphoma; B cell; cytokines; AIDS; immune activation
Chronic inflammation and B-cell hyperactivation are seen in HIV infection, contributing to an increased risk for the accrual of genetic errors that may result in B-cell lymphoma. The primary objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on serum levels of molecules that are associated with immune activation and/or inflammation, including several that are associated with B-cell activation, specifically IL-6, sCD30, sCD27, IgG, IgA, CXCL13 (B lymphocyte chemoattractant, BLC), a B-lymphocyte chemokine involved in B-cell trafficking, as well as C-reactive protein, an acute-phase protein.
We used a retrospective cohort study design, measuring serum levels of these markers at each of four 1-year intervals, 2 years before and 2 years after HAART initiation, in a subgroup of 290 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS).
Serum levels of immune activation-associated molecules were measured by ELISA and multiplexed immunometric assays. Reference values were determined by the 5th to 95th percentiles from a sample of 109 HIV-uninfected MACS men.
HAART use was associated with a reduction, but not normalization, of most biomarkers tested. Serum levels of IL-6 and C-reactive protein appeared to be unaffected by HAART.
These results suggest a partial normalization of serum cytokine levels post HAART. However, a chronic state of B-cell hyperactivation continues 2–3 years after HAART initiation. These findings may explain, in part, the excess incidence of lymphoma still occurring in HIV-infected persons in the post-HAART era.
activation; AIDS; antiretroviral therapy; B lymphocytes; highly active; HIV; non-Hodgkin’s lymphoma