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.
end-stage renal disease (ESRD); chronic kidney disease (CKD); HIV infection/AIDS; HIV/AIDS; glomerular filtration rate (GFR)
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.
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
Antiretroviral regimens (ART) changes occur frequently among HIV-infected persons. Duration and type of initial highly active antiretroviral therapy (HAART) and factors associated with regimen switching were evaluated in the Multicenter AIDS cohort Study.
Participants were classified according to the calendar period of HAART initiation: T1 (1996-2001), T2 (2002-2005) and T3 (2006-2009). Kaplan Meier curves depicted time from HAART initiation to first regimen changes within 5.5 years. Cox proportional hazards regression models were used to examine factors associated with time to switching.
Of 1009 participants, 796 changed regimen within 5.5 years after HAART initiation. The percentage of participants who switched declined from 85% during T1 to 49 % in T3., The likelihood of switching in T3 decreased by 50% (p<0.01) compared to T1 after adjustment for pre-HAART ART use, age, race and CD4 count. Incomplete HIV suppression decreased over time (p<0.01) but predicted switching across all time periods. Lower HAART adherence (≤ 95% of prescribed doses) was predictive of switching only in T1. In T2, central nervous system symptoms predicted switching (RH = 1.7, p= 0.012). Older age at HAART initiation was associated with increased switching in T1 (RH=1.03 per year increase) and decreased switching in T2 (RH = 0.97 per year increase).
During the first 15 years of the HAART era, initial HAART regimen duration lengthened and regimen discontinuation rates diminished. Both HIV RNA non-suppression and poor adherence predicted switching prior to 2001 while side effects that were possibly ART-related were more prominent during T2.
Abnormalities in the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis have been observed in HIV-infected persons and have been implicated in cardiovascular disease pathogenesis in the general population.
To determine associations of serum OPG and RANKL concentrations with HIV infection and subclinical atherosclerosis.
Cross-sectional study nested within the Multicenter AIDS Cohort Study
Four US academic medical centers
There were 578 HIV-infected and 344 HIV-uninfected men.
Main Outcome Measures
Coronary artery calcium (CAC) was measured by non-contrast cardiac computed tomography (CT), and coronary stenosis and plaque characteristics (composition, presence and extent) were measured by coronary CT angiography. All statistical models were adjusted for traditional cardiovascular risk factors.
OPG concentrations were higher and RANKL concentrations were lower among HIV-infected men compared to –uninfected men (p<0.0001 each). Among the HIV-infected men, higher OPG concentrations were associated with the presence of CAC, mixed plaque, and coronary stenosis > 50%, but not with plaque extent. In contrast, among HIV-uninfected men, higher OPG concentrations were associated with extent of both CAC and calcified plaque, but not their presence. RANKL concentrations were not associated with plaque presence or extent among HIV-infected men, but among HIV-uninfected men, lower RANKL concentrations were associated with greater extent of CAC and total plaque.
OPG and RANKL are dysregulated in HIV-infected men and their relationship to the presence and extent of subclinical atherosclerosis varies by HIV-status. The role of these biomarkers in CVD pathogenesis and risk prediction may be different in HIV-infected men.
Coronary artery disease (CAD) has been associated with HIV infection; however data are not consistent.
We performed cardiac CT to determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.
Cross-sectional study within the Multicenter AIDS Cohort Study(MACS).
HIV-infected (n=618) and –uninfected (n=383) men who have sex with men (MSM) had non-contrast and contrast enhanced cardiac CT if they were between 40–70 years, weighed <300 pounds, and had no history of coronary revascularization.
Presence and extent, for those with plaque, of coronary artery calcium (CAC) on non-contrast CT, and of any plaque, non-calcified, mixed or calcified plaque and stenosis on CT angiography.
1001 men underwent non-contrast CT of whom 759 had coronary CT angiography. After adjusting for age, race, center, and cohort, HIV-infected men had a greater prevalence of CAC [Prevalence ratio(PR)=1.21, 95% confidence interval (CI) 1.08–1.35, p=0.001], and any plaque [PR=1.14(1.05–1.24),p=0.001], including non-calcified plaque [PR=1.28(1.13–1.45),p<0.001) and mixed plaque [PR=1.35(1.10–1.65),p=0.004] than HIV-uninfected men. Associations between HIV-infection and any plaque and non-calcified plaque remained significant (p<0.005) after CAD risk factor adjustment. HIV-infected men also had a greater extent of non-calcified plaque after CAD risk factor adjustment (p=0.026). HIV-infected men had a greater prevalence of coronary artery stenosis>50% than HIV-uninfected men [PR=1.48(1.06–2.07),p=0.020), but not after CAD risk factor adjustment. Longer duration of highly active antiretroviral therapy [PR=1.09(1.02–1.17), p=0.007,per year] and lower nadir CD4+ T-cell count [PR=0.80(0.69–0.94),p=0.005, per 100 cells] were associated with coronary stenosis>50%.
Coronary artery plaque, especially non-calcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.
Cross-sectional observational study design and inclusion of only men.
Primary Funding Source
NHLBI and NIAID
Individuals with HPV infections can develop IgG antibodies to HPV proteins including the L1 capsid and E6 and E7 oncoproteins. Evidence on whether L1 antibodies reduce the risk of cervical HPV infection is mixed, but this has not been explored for oral HPV infections. Antibodies to HPV16’s E6 oncoprotein have been detected in some oropharyngeal cancer cases years prior to cancer diagnosis, but it is unknown if these antibodies are associated with oral HPV16 DNA.
Enzyme linked immunosorbent assays tested for serum antibodies to HPV16’s L1 capsid in 463 HIV-infected and 293 HIV-uninfected adults, and for antibodies to recombinantly expressed E6 and E7 oncoproteins to HPV16 in 195 HIV-infected and 69 HIV-uninfected cancer-free participants at baseline. Oral rinse samples were collected semi-annually for up to three years and tested for HPV DNA using PGMY 09/11 primers. Adjusted Poisson, logistic, and Wei-Lin-Weissfeld regression models were utilized.
HPV16 L1 seroreactivity did not reduce the subsequent risk of incident oral HPV16 infection in unadjusted (HR=1.4, 95%CI=0.59–3.3) or adjusted (aHR=1.1, 95%CI=0.41–3.0) analysis. Antibodies to HPV16 E6 and E7 oncoproteins were detected in 7.6% and 3.4% of participants respectively, but they were not associated with baseline oral HPV16 DNA prevalence or oral HPV16 persistence (each p-value>0.40).
Naturally acquired HPV16 L1 antibodies did not reduce the risk of subsequent oral HPV16 infection. HPV16 E6 and E7 seropositivity was not a marker for oral HPV16 infection in this population without HPV-related cancer.
HPV; Oropharyngeal Cancer; L1 Seropositivity; E6 Seropositivity
We characterized associations between smoking, alcohol, and recreational drug use and coronary plaque by HIV serostatus within the Multicenter AIDS Cohort Study (MACS).
MACS participants (N = 1005, 621 HIV+ and 384 HIV-) underwent non-contrast CT scanning to measure coronary artery calcium; 764 underwent coronary CT angiograms to evaluate plaque type and extent. Self-reported use of alcohol, tobacco, smoked/inhaled cocaine, methamphetamine, ecstasy, marijuana, inhaled nitrites, and erectile dysfunction drugs was obtained at semi-annual visits beginning 10 years prior to CT scanning. Multivariable logistic and linear regression models were performed, stratified by HIV serostatus.
Among HIV+ men, current smoking, former smoking, and cumulative pack years of smoking were positively associated with multiple coronary plaque measures (coronary artery calcium presence and extent, total plaque presence and extent, calcified plaque presence, and stenosis >50%). Smoking was significantly associated with fewer plaque measures of comparable effect size among HIV- men; current smoking and calcified plaque extent was the only such association. Heavy alcohol use (>14 drinks/week) was associated with stenosis >50% among HIV+ men. Among HIV- men, low/moderate (1–14 drinks/week) and heavy alcohol use were inversely associated with coronary artery calcium and calcified plaque extent. Few significant associations between other recreational drug use and plaque measures were observed.
Smoking is strongly associated with coronary plaque among HIV+ men, underscoring the value of smoking cessation for HIV+ persons. Alcohol use may protect against coronary artery calcium and calcified plaque progression in HIV- (but not HIV+) men. Few positive associations were observed between recreational drug use and coronary plaque measures.
Aging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus is not known.
HIV-infected men from the Multicenter AIDS Cohort Study (MACS), age ≥ 45 years at highly active antiretroviral therapy initiation, who had ≥ 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus.
182 HIV-infected and 267 HIV-uninfected men were included: median age 48.8 years (Interquartile range (IQR); 45.8, 53.4), median numbers of FT measurements per participant 4 (IQR; 3, 5), 65% were drawn in the AM. Mean adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples (−6.1 ng/dL (95% CI: −9.8, −2.4), p=0.001), but not in PM samples (−1.7 ng/dL (−6.0, 2.6), p=0.441). The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: −13.4, −5.0) per 10 years for HIV- infected vs. 7.9 ng/dL (95% CI: −10.2, −5.5) for HIV-uninfected men, p = 0.578.
FT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not PM, FT levels among HIV-infected men compared to HIV-uninfected men suggests a loss of diurnal variation in FT among HIV-infected men.
There is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c − expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS).
Fasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c − expected HbA1c ≤−0.5%.
Over 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (<500 cells/mm3); a regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or zidovudine; high mean corpuscular volume; and abnormal corpuscular haemoglobin.
HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to under-diagnosis and to under-treatment of established diabetes mellitus.
HbA1c; diabetes; mean corpuscular volume; glycosylated haemoglobin; HIV
Hepatitis C infection (HCV); HIV/HCV coinfection; Non-Hodgkin Lymphoma
To compare the characteristics associated with hepatitis C virus (HCV) antibody (anti-HCV) prevalence and HCV clearance between injection drug using (IDU) and non-IDU men who have sex with men (MSM).
Stored serum and plasma samples were tested for anti-HCV and HCV RNA to determine the HCV status of 6925 MSM at enrollment into the Multicenter AIDS Cohort Study (MACS). Prevalence and clearance ratios (PR and CR) were calculated to determine the characteristics associated with HCV prevalence and clearance. Multivariable analyses were performed using Poisson regression methods with robust variance estimation.
Anti-HCV prevalence was significantly higher among IDU than non-IDU MSM (42.9% vs. 4.0%) while clearance was significantly lower among IDU MSM (11.5% vs. 34.5% among non-IDU MSM). HIV infection, Black race, and older age were independently associated with higher prevalence in both groups while smoking, transfusion history, and syphilis were significantly associated with prevalence only among non-IDU MSM. The rs12979860-C/C genotype was the only characteristic independently associated with HCV clearance in both groups, but the effects of both rs12979860-C/C genotype (CR=4.16 IDUs vs. 1.71 non-IDUs; p=0.03) and HBsAg positivity (CR=5.06 IDUs vs. 1.62 non-IDUs; p=0.03) were significantly larger among IDU MSM. HIV infection was independently associated with lower HCV clearance only among non-IDU MSM (CR=0.59, 95% CI=0.40–0.87).
IDU MSM have higher anti-HCV prevalence and lower HCV clearance than non-IDU MSM. Differences in the factors associated with HCV clearance suggest that the mechanisms driving the response to HCV may differ according to the mode of acquisition.
Hepatitis C; HIV; IFNL4; IL28B; Injection Drug Use; MSM
Broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can generate the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases (GSTs) and other cytoprotective enzymes. A broccoli sprout-derived beverage providing daily doses of 600 μmol glucoraphanin and 40 μmol sulforaphane was evaluated for magnitude and duration of pharmacodynamic action in a 12-week randomized clinical trial. Two hundred and ninety-one study participants were recruited from the rural He-He Township, Qidong, in the Yangtze River delta region of China, an area characterized by exposures to substantial levels of airborne pollutants. Exposure to air pollution has been associated with lung cancer and cardiopulmonary diseases. Urinary excretion of the mercapturic acids of the pollutants, benzene, acrolein, and crotonaldehyde, were measured before and during the intervention using liquid chromatography tandem mass spectrometry. Rapid and sustained, statistically significant (p ≤ 0.01) increases in the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde were found in those receiving broccoli sprout beverage compared with placebo. Excretion of the benzene-derived mercapturic acid was higher in participants who were GSTT1-positive compared to the null genotype, irrespective of study arm assignment. Measures of sulforaphane metabolites in urine indicated that bioavailability did not decline over the 12-week daily dosing period. Thus, intervention with broccoli sprouts enhances the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.
Air pollution; broccoli; sulforaphane; benzene; chemoprevention
Previous studies demonstrated that blacks have less coronary artery calcification (CAC) than whites. We evaluated racial differences in plaque composition and stenosis in the Multicenter AIDS Cohort Study (MACS). HIV positive and negative men completed non-contrast cardiac CT if they were 40–70 years, weighed <300 pounds, and had no prior history of cardiac surgery or revascularization, and if eligible, coronary CT angiography (CTA). There were 1001 men who underwent CT scans and 759 men had CTA. We measured CAC on non-contrast CT, and total plaque, non-calcified, calcified, and mixed plaque, and identified coronary stenosis >50% on CTA. The association of presence and extent of plaque with race was determined after adjustment for HIV serostatus, cardiovascular risk factors and measures of socioeconomic status. The prevalences of any plaque on CTA and non-calcified plaque were not different between black and white men; however, black men had lower prevalences of CAC (Prevalence ratio (PR)=0.79, p=0.01), calcified plaque (PR=0.69, p=0.002), and stenosis >50% (PR=0.59, p=0.009). There were no associations between black race and extent of plaque in fully adjusted models. Using log-linear regression, black race was associated with a lower extent of any plaque on CTA in HIV positive men (estimate=−0.24, p=0.051) but not in HIV negative men (0.12, p=0.50, HIV interaction p=0.005). In conclusion, a lower prevalence of CAC in black compared to white men appears to reflect less calcification of plaque and stenosis rather than a lower overall prevalence of plaque.
Epidemiology; plaque; coronary angiography; coronary artery disease; HIV
Cytokines released by epicardial fat are implicated in the pathogenesis of atherosclerosis. HIV infection and anti-retroviral therapy have been associated with changes in body fat distribution and coronary artery disease. We sought to determine if HIV infection is associated with greater epicardial fat and if epicardial fat is associated with subclinical coronary atherosclerosis.
We studied 579 HIV-infected and 353 HIV-uninfected men age 40 to 70 years with non-contrast computed tomography (CT) to measure epicardial adipose tissue volume (EAT) and coronary artery calcium (CAC). Total plaque score (TPS), and plaque subtypes (non-calcified, calcified and mixed) were measured by coronary CT angiography in 706 men.
We evaluated the association between EAT and HIV serostatus, and the association of EAT with subclinical atherosclerosis, adjusting for age, race and serostatus and with additional cardiovascular (CV) risk factors and tested for modifying effects of HIV serostatus.
HIV-infected men had greater EAT than HIV-uninfected men (p=0.001). EAT was positively associated with duration of antiretroviral therapy (p=0.02), specifically AZT (p<0.05). EAT was associated with presence of any coronary artery plaque (p=0.006) and non-calcified plaque (p=0.001), adjusting for age, race, serostatus and CV risk factors. Among men with CAC, EAT was associated with CAC extent (p=0.006). HIV serostatus did not modify associations between EAT and either CAC extent or presence of plaque.
Greater epicardial fat volume in HIV-infected men and its association with coronary plaque and antiretroviral therapy duration suggest potential mechanisms that might lead to increased risk for cardiovascular disease in HIV.
Imaging; plaque; risk factors; HIV; ART
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
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression
Human papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown.
Free testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing.
Participants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty-four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence=17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/18 infection in unadjusted and adjusted analyses.
Higher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study.
The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi’s sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and HHV-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls.
We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a 4-fold increase of risk (OR= 4.09; 95% CI: 1.90–8.80; p= 0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI: 2.54–43.6; p=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120 Kb-long haplotype (OR=1.52; 95% CI: 1.01–2.28; p=0.047) formed by rs7029 A>G (GPANK1 3’UTR), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 readthrough) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.
To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation.
Prospective cohort study.
Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1,697 men during 8,903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984–2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV+, HAART-naïve (NAI); and HAART-exposed with HIV RNA suppressed to <50 copies/mL plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at one year.
Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (p<0.002) from NEG values: CXCL10, CRP, sCD14, sTNFR2, TNF-α, sCD27, sGP130, IL-8, CCL13, BAFF, GM-CSF, and IL-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Biomarkers of inflammation and immune activation moved toward HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Biological Markers; Inflammation; Prospective Studies; Male
To determine whether markers of systemic inflammation are associated with the presence of moderate-to-severe obstructive sleep apnea (OSA), and whether this association differs based on HIV and HIV treatment status.
HIV-uninfected men (HIV−; n=60), HIV-infected men receiving HAART (HIV+/HAART; n=58), and HIV-infected men not receiving HAART (HIV+/ No HAART; n=41) underwent polysomnograpy and measurement of plasma levels of TNF-alpha, soluble TNF-alpha receptors I and II (sTNFRI and sTNFRII) and IL-6. The relationship between moderate-severe OSA (respiratory disturbance index ≥15 apnea/hypopnea events/hour) and inflammatory markers was assessed with multivariable regression models.
Compared to the HIV− men, HIV+/HAART men and HIV+/No HAART men had higher levels of TNF-alpha, sTNFRI, and sTNFRII, independent of age, race, smoking status, obstructive lung disease (OLD), and BMI. Moderate-to-severe OSA was present in 48% of the sample (HIV−:57%; HIV+/HAART: 41%; HIV+/No HAART: 44%). Among the HIV+/No HAART men, but not in the other groups, TNF-alpha, sTNFRII, and IL-6 levels were higher in those with moderate-severe OSA compared to men with no-to-mild OSA after adjustment for age, race, smoking status, OLD, and BMI. Within this group, the association of high TNF-alpha concentrations with moderate-severe OSA was also independent of CD4 cell count and plasma HIV RNA concentration.
Compared to HIV-infected men on HAART and HIV-uninfected men, markers of systemic inflammation were higher in HIV-infected men not receiving HAART. In these men, TNF-alpha was significantly related to obstructive sleep apnea, independent of HIV-related covariates.
Diabetes and hypertension, common conditions in antiretroviral (ART) treated HIV-infected individuals, are associated with glomerular hyperfiltration, which precedes the onset of proteinuria and accelerated kidney function decline. In the Multicenter AIDS Cohort Study, we examined the extent to which hyperfiltration is present and associated with metabolic, cardiovascular, HIV and treatment risk factors among HIV-infected men.
Cross-sectional cohort using direct measurement of glomerular filtration rate (GFR) by iohexol plasma clearance for 367 HIV-infected men and 241 HIV-uninfected men who were free of CKD.
Hyperfiltration was defined as GFR >140 ml/min/1.73m2 - 1 ml/min/1.73m2 per each year over age 40. Multivariate logistic regression was used to estimate the odds ratios (OR) of prevalent hyperfiltration for metabolic, cardiovascular, HIV and cumulative ART exposure factors.
Among subjects without CKD, the prevalence of hyperfiltration was higher for HIV-infected participants (25%) compared to uninfected participants (17%; p=0.01). HIV infection was associated with hyperfiltration (OR: 1.70, 95%CI: 1.11, 2.61) and modified the association between diabetes and hyperfiltration, such that the association among HIV-uninfected men (OR: 2.56 95%CI: 1.33, 5.54) was not observed among HIV-infected men (OR: 1.19, 95%CI: 0.69, 2.05). These associations were independent of known risk factors for hyperfiltration. Indicators of hyperglycemia and hypertension were also associated with hyperfiltration as was cumulative zidovudine exposure.
Hyperfiltration, a potential modifiable predictor of kidney disease progression, is common among ART-treated HIV-infected men. HIV infection is associated with significant odds of hyperfiltration in addition to known risk factors for kidney damage.
Glomerular hyperfiltration; glomerular filtration rate; HIV; antiretroviral therapy; iohexol
Like other members of the γ-herpesvirus family, human herpes virus 8 (HHV-8), the etiologic agent of classic and HIV-related Kaposi’s sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including 7 cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84–3.92; Bonferroni-adjusted p= 9.9×10−3−2.6×10−4), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This “proof of concept” study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS
Kaposi’s sarcoma; Immunodeficiency; Herpes Virus 8; Multifactor Dimensionality Reduction; Polymorphism; Genetic association
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
In the context of HIV, the initiation of effective antiretroviral therapy (ART) has been found to increase the risk of dyslipidemia in HIV-infected individuals, and dyslipidemia has been found to be a risk factor for kidney disease in the general population. Therefore, we examined changes in lipid profiles in HIV-infected men following ART initiation and the association with future kidney dysfunction. HIV-infected men from the Multicenter AIDS Cohort Study initiating ART between December 31, 1995 and September 30, 2011 with measured lipid and serum creatinine values pre-ART and post-ART were selected. The associations between changes in total cholesterol or high-density lipoprotein following ART initiation and the estimated change in glomerular filtration rate (eGFR) over time were assessed using piecewise linear mixed effects models. There were 365 HIV-infected men who contributed to the analysis. In the adjusted models, at 3 years post-ART, those with changes in total cholesterol >50 mg/dl had an average decrease in eGFR of 2.6 ml/min/1.73 m2 per year (p<0.001) and at 5 years post-ART, the average decrease was 2.4 ml/min/1.73 m2 per year (p=0.008). This decline contrasted with the estimates for those with changes in total cholesterol ≤50 mg/dl: 1.4 ml/min/1.73 m2 decrease per year (p<0.001) and 0.1 ml/min/1.73 m2 decrease per year (p=0.594) for the same time periods, respectively. Large decreases in high-density lipoprotein (a decline of greater than 5 mg/dl) were not associated with declines in eGFR. These results indicate that large ART-related increases in total cholesterol may be a risk factor for kidney function decline in HIV-infected men. Should these results be generalizable to the broader HIV population, monitoring cholesterol changes following the initiation of ART may be important in identifying HIV-infected persons at risk for kidney disease.
Primary liver cancer (PLC) is the third leading cause of cancer mortality globally. In endemic areas of sub-Saharan Africa and Asia PLC largely arises from chronic infection with hepatitis B virus (HBV) and ingestion of aflatoxins. While synergistic interactions between these two risk factors have been observed in cohort studies in China, here we determined the impact of agricultural reforms in the 1980s leading to diminished maize consumption and implementation of subsidized universal vaccination against HBV in the 2000s on PLC primary prevention. A population-based cancer registry was used to track PLC mortality in Qidong, China and was compared to the timeline of HBV immunization. Randomly selected serum samples from archived cohort collections from the 1980s to present were analyzed for aflatoxin biomarkers. Greater than 50% reductions in PLC mortality rates occurred across birth cohorts from the 1960s to the 1980s for Qidongese less than 35 years of age although all were born before universal vaccination of newborns. Median levels of the aflatoxin biomarker decreased from 19.3 pg/mg albumin in 1989 to undetectable (<0.5 pg/mg) by 2009. A population attributable benefit of 65% for reduced PLC mortality was estimated from a government facilitated switch of dietary staple from maize to rice; 83% of this benefit was in those infected with HBV. Food policy reforms in China resulted in a dramatic decrease in aflatoxin exposure, which, independent of HBV vaccination, reduced liver cancer risk. The extensive HBV vaccine coverage now in place augurs even greater risk reductions in the future.
aflatoxin; primary prevention; liver cancer