HIV-specific Factors Research Articles

Traditional and HIV-Specific Risk Factors for Cardiovascular Morbidity and Mortality Among HIV-Infected Adults in Brazil

Author(s): Diaz, Chanelle; Segura, Eddy; Luz, Paula M; Ribeiro, Sayonara; Eksterman, Leonardo; Boni, Raquel De; Clark, Jesse L; Veloso, Valdilea; Grinsztejn, Beatriz; Lake, Jordan

Abstract 11139: Prevalence, Characteristics and Prognostic Associations of Carotid Plaque Among HIV-infected Subjects Free of Known Cerebrovascular Disease

Introduction: The risk of cerebrovascular events is increased among HIV-infected subjects; this risk is independent of conventional cardiovascular (CV) risk factors and may be related to persistent inflammation leading to accelerated carotid atherosclerosis. However, there are no data characterizing the prevalence, characteristics and prognostic associations of carotid plaque among subjects with HIV. Methods: From a clinical registry, we identified all HIV-infected subjects with a CT neck from 2005-2014. Data collection and CT analysis were performed by blinded independent teams and included CV and HIV specific risk factors. CT variables included presence of carotid plaque, plaque composition (calcified/non-calcified/mixed), degree of stenosis [≥ 50%] and high-risk plaque (HRP) features [low attenuation, spotty calcification]. The outcome was a cerebrovascular event (stroke, transient ischemic event) defined by ICD codes and independently adjudicated by a board certified physician. Association between plaque presence, characteristics and HRP with events was tested by Cox proportional hazard models. Results: Of 231 HIV-infected subjects, 32 had prior cerebrovascular disease,15 had poor image quality leaving an n=184 (46±10 yrs, 21% female,12% diabetics, 19% HTN, smoking in 31%, 14% on statins, average LDL of 90±39mg/dl). On CT, 36% had any carotid plaque and 23% had bilateral plaque. Of those with plaque,15% had a stenosis of ≥50% and 70% had any HRP feature. Both plaque and HRP were increased with age, duration of HIV and anti-retroviral therapy. Over a median of 4 yrs,13 (7%) cerebrovascular events occurred. After adjusting for the number of CV risk factors, a carotid plaque [HR: 3.5 (1.1-11) P =0.03, Fig 1A] and any HRP feature [HR: 3.2 (1.0-10) P =0.04, Fig 1B] were associated with incident cerebrovascular events. Conclusions: Among HIV-infected subjects, free of known cerebrovascular disease, carotid plaque and/or HRP predict cerebrovascular events.

Geographical variations in risk factors associated with HIV infection among drug users in a prefecture in Southwest China.

BackgroundPrevious studies have shown inconsistent or even contradictory results for some risk factors associated with HIV infection among drug users, and these may be partially explained by geographical variations.MethodsData were collected from 11 methadone clinics in the Liangshan Yi Autonomous Prefecture from 2004 to 2012. A non-spatial logistical regression model and a geographically weighted logistic regression model were fitted to analyze the association between HIV infection and specific factors at the individual level.ResultsThis study enrolled 6,458 patients. The prevalence of HIV infection was 25.1 %. The non-spatial model indicated that being divorced was positively associated with HIV infection. The spatial model also showed that being divorced was positively associated with HIV infection, but only for 49.4 % of individuals residing in some northern counties. The non-spatial model suggested that service sector work was negatively associated with HIV infection. However, the spatial model indicated that service work was associated with HIV infection, but only for 23.0 % of patients living in some western counties. The non-spatial model did not show that being married was associated with HIV infection in our study field, but the spatial model indicated that being married was negatively associated with HIV infection for 12.0 % of individuals living in some western counties. For other factors, the non-spatial and spatial models showed similar results.ConclusionThe spatial model may be useful for improving understanding of geographical heterogeneity in the relationship between HIV infection and individual factors. Spatial heterogeneity may be useful for tailoring intervention strategies for local regions, which can consequently result in a more efficient allocation of limited resources toward the control of HIV transmission.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-015-0073-x) contains supplementary material, which is available to authorized users.

PP.30.02

Objective: To assess the prevalence of microalbuminuria and its relationship with other cardiovascular risk factors in infected subjects HIV-1(+) controlled in our institution. Design and method: Cross-sectional study. Hypertension was defined as a blood pressure greater or equal than 140/90 mmHg or being on antihypertensive treatment, diabetes mellitus (DM) as a fasting glycaemia greater or equal 126 mg/dL or antidiabetic treatment, and hypercholesterolemia as a fasting LDL cholesterol (LDLc) greater or equal than 130 mg/mL or being on treatment. Microalbuminuria was defined as an increase urinary excretion of albumin: urine albumin-to-creatinine ratio (UACR) more or equal than 30 mg/g in a spot urine (average of 2 determinations). High-normal albuminuria was defined as a UACR between 10–29 mg/g. Results: Three hundred and fifty-nine subjects are usually controlled in our unit. Two hundred and thirty three of them with UACR determinations, aged 44.7 ± 8.6 years old, 71.2% (166/233) males, were included. The prevalence of hypertension, DM, hypercholesterolemia and current smoking were 26.2% (61/233), 7.7% (18/233), 33.0% (77/233) and 45.7% (106/233) respectively. The prevalence of microalbuminuria was 5.6% (13/233). In the univariate analysis the factors associated with microalbuminuria were age higher than 50 years old (1.7% vs 17.2% p < 0.001), hypertension (2.9% vs 13.1 p < 0.005), DM (3.7% vs 27.7% p < 0.001) and hypercholesterolemia (3.2% vs 10.4% p < 0.05), but not smoking and others HIV specific factors (combination antiretroviral therapy, current HIV-1 RNA, current CD4(+) cells count, duration of HIV infection and risk behaviour of HIV aquisition). The prevalence of high-normal albuminuria was also significantly higher in subjects with hypertension, DM or hypercholesterolemia. After adjusting by age, the differences were still significant. When an analysis were performed as a continuous variable, there were a positive correlation between urinary albumin excretion and systolic blood pressure (BP) (r2 = 0.13 p < 0.001) as well as diastolic BP (r2 = 0.07 p < 0.001) and a weak negative correlation with nadir CD4(+) count (r2 = 0.02 p < 0.05).Conclusions: Hypertension, DM and hypercholesterolemia were associated with microalbuminuria and high-normal albuminuria in HIV-1(+) patients. A positive correlation was observed among albumin urinary excretion and systolic and diastolic blood pressure in these subjects.

Randomized, Double-Blind, Placebo-Controlled Study on Decolonization Procedures for Methicillin-Resistant Staphylococcus aureus (MRSA) among HIV-Infected Adults.

BackgroundHIV-infected persons have increased risk of MRSA colonization and skin and soft-tissue infections (SSTI). However, no large clinical trial has examined the utility of decolonization procedures in reducing MRSA colonization or infection among community-dwelling HIV-infected persons.Methods550 HIV-infected adults at four geographically diverse US military HIV clinics were prospectively screened for MRSA colonization at five body locations every 6 months during a 2-year period. Those colonized were randomized in a double-blind fashion to nasal mupirocin (Bactroban) twice daily and hexachlorophene (pHisoHex) soaps daily for 7 days compared to placeboes similar in appearance but without specific antibacterial activity. The primary endpoint was MRSA colonization at 6-months post-randomization; secondary endpoints were time to MRSA clearance, subsequent MRSA infections/SSTI, and predictors for MRSA clearance at the 6-month time point.ResultsForty-nine (9%) HIV-infected persons were MRSA colonized and randomized. Among those with 6-month colonization data (80% of those randomized), 67% were negative for MRSA colonization in both groups (p = 1.0). Analyses accounting for missing 6-month data showed no significant differences could have been achieved. In the multivariate adjusted models, randomization group was not associated with 6-month MRSA clearance. The median time to MRSA clearance was similar in the treatment vs. placebo groups (1.4 vs. 1.8 months, p = 0.35). There was no difference on subsequent development of MRSA infections/SSTI (p = 0.89). In a multivariable model, treatment group, demographics, and HIV-specific factors were not predictive of MRSA clearance at the 6-month time point.ConclusionA one-week decolonization procedure had no effect on MRSA colonization at the 6-month time point or subsequent infection rates among community-dwelling HIV-infected persons. More aggressive or novel interventions may be needed to reduce the burden of MRSA in this population.Trial RegistrationClinicalTrials.gov NCT00631566

Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma

We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989-1995), early cART (1996-2000), recent cART (2001-2004), and contemporary cART era (2005-2010). Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P < 0.001). While the age-adjusted IPI was a significant predictor of outcome in all time periods, the influence of other factors waxed and waned. Individual HIV-related factors such as low CD4 counts (<50/mm(3)) and prior history of AIDS were no longer associated with poor outcomes in the contemporary era. Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

Human immunodeficiency virus (HIV) modulates the associations between insulin resistance and cognition in the current combination antiretroviral therapy (cART) era: a study of the Women's Interagency HIV Study (WIHS).

Cognitive impairment (CI) remains common despite access to combination antiretroviral therapy (cART); it has been linked to HIV-specific, HIV-related, and HIV-unrelated factors. Insulin resistance (IR) was associated with CI in the early cART era, when antiretroviral medications had greater mitochondrial and metabolic toxicity. We sought to examine these relationships in the current cART era of reduced antiretroviral toxicities. This study examined IR among non-diabetics in relation to a 1-h neuropsychological test battery among 994 women (659 HIV-infected and 335 HIV-uninfected controls) assessed between 2009 and 2011. The mean (standard deviation (SD)) age of the sample was 45.1 (9.3) years. The HIV-infected sample had a median interquartile range (IQR) cluster of differentiation 4 (CD4) T-lymphocyte count of 502 (310-727) cells/μL, and 54 % had undetectable plasma HIV RNA levels. Among all, the homeostasis model assessment (HOMA) of IR ranged from 0.25 to 37.14. In adjusted models, increasing HOMA was significantly associated with reduced performance on Letter-Number Sequencing (LNS) attention task (β = -0.10, p < 0.01) and on Hopkins Verbal Learning Test (HVLT) recognition (β = -0.10, p < 0.01) with weaker but statistically significant associations on phonemic fluency (β = -0.09, p = 0.01). An HIV*HOMA interaction effect was identified on the LNS attention task and Stroop trials 1 and 2, with worse performance in HIV-infected vs. HIV-uninfected women. In separate analyses, cohort members who had diabetes mellitus (DM) performed worse on the grooved pegboard test of psychomotor speed and manual dexterity. These findings confirm associations between both IR and DM on some neuropsychological tests and identify an interaction between HIV status and IR.

Assessment of arterial elasticity among HIV-positive participants with high CD4 cell counts: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Analysis of baseline data demonstrates that small artery elasticity is impaired (lower) with older age and differs by race and between geographical regions. No HIV-specific factors studied remained significantly associated with arterial elasticity in multivariate models. Longitudinal analyses in this substudy will provide essential randomized data with which to study the effects of early ART initiation on the progression of vascular disease among a diverse global population. When combined with future biomarker analyses and clinical outcomes in START, these findings will expand our understanding of the pathogenesis of HIV-related CVD.

Adiponectin and interleukin-6, but not adipose tissue, are associated with worse neurocognitive function in HIV-infected men.

Generalized obesity has been associated with cognitive decline, a process potentially mediated by adipocytokines. The effects of regional adipose tissue (AT) on cognition, however, are not well understood. We explored cross-sectional relationships between regional AT, adipocytokines, inflammatory markers and neuropsychological (NP) test scores among HIV+ and HIV- men enrolled in the Multicenter AIDS Cohort Study. Visceral, subcutaneous abdominal and subcutaneous thigh AT areas were quantified by computed tomography (CT). NP tests (Trail Making Test parts A and B, and Symbol-Digit Modalities) obtained within 2 years of CT screened for psychomotor speed and executive function. Adiponectin, leptin, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were measured. Of 509 HIV+ and 271 HIV- participants, HIV+ men (98% on antiretroviral therapy, 81% HIV-1 RNA<50 copies/ml) had lower median subcutaneous AT and adiponectin levels and higher hs-CRP levels, but visceral AT, body mass index, IL-6 and NP scores did not vary by HIV serostatus. In multivariable analysis, older age, ≤ high school education and African American race, but not AT area or site, were associated with worse NP test scores among all participants. In HIV+ only, higher adiponectin and IL-6 were associated with worse cognitive function independent of AT area. No HIV-specific factors were associated with NP test scores. Demographic factors were associated with NP test performance, but regional adiposity was not. In HIV+ only, higher adiponectin and IL-6 were associated with worse NP test scores, supporting a role for chronic inflammation and adipocytokine imbalance in neurocognitive decline in HIV+ persons.

An Adverse Drug Reaction to Trimethoprim-Sulfamethoxazole Revealing Primary HIV: A Case Report and Literature Review.

Adverse drug reactions (ADRs) to antibiotics complicate the management of any infection, particularly opportunistic infections in advanced HIV as some ADRs are potentiated by HIV. Trimethoprim-sulfamethoxazole (TMP-SMX) causes ADRs in 40–80% of HIV infected individuals, compared to 3–5% in the general population. The incidence and severity of ADRs among HIV infected individuals appear to increase as they progress from latent infection to AIDS. We present a single case report of a 55-year-old African American male found to have an otherwise asymptomatic acute HIV infection who developed an ADR to TMP-SMX, despite having previously tolerating the medication. The proposed mechanisms for the increased incidence of sulfa hypersensitivity reactions among HIV infected individuals focus on either (1) HIV-induced changes in the immune function driven by falling levels of CD4 cells or (2) other HIV-specific factors correlated with rising viral load. To our knowledge this is the first reported case of new sulfa hypersensitivity in primary HIV and may provide clinical evidence to support the correlation between viral load and ADRs to TMP-SMX without a severely diminished CD4 count, though further research is necessary. This case also demonstrates a rare and easily overlooked presentation of HIV that may aid in early diagnosis.

Effect of CD4+ cell count and viral suppression on risk of ischemic stroke in HIV infection.

Evidence from the current era of combination antiretroviral therapy supports an association between HIV and cerebrovascular disease. In addition to traditional vascular risk factors, HIV-specific factors including immunodeficiency and viral replication may also predict stroke risk. The aim of this study was to determine the relationship between CD4(+) cell count, viral suppression and validated ischemic stroke outcomes. A single-centre, case-control study. We identified ischemic stroke cases in HIV-infected adults from an HIV clinic using International Classification of Diseases codes for cerebrovascular disease followed by validation of each case. Controls from the same HIV clinic were selected by incidence density sampling. Demographic and clinical data, including the most recent CD4(+) cell count and plasma HIV RNA concentration, were abstracted from hospital and HIV clinic electronic medical records. Matched conditional logistic regression models were used to evaluate the association between CD4(+) cell count, viral suppression and ischemic stroke. In an adjusted model, viral suppression decreased the odds of ischemic stroke by a factor of 0.16 [95% confidence interval (95% CI) 0.05-0.50, P = 0.002]. This association, although attenuated [odds ratio (OR) 0.31, 95% CI 0.09-1.06, P = 0.062], remained after restricting the analysis to ischemic strokes due to true atherosclerotic mechanisms (i.e. excluding infection and malignancy-related strokes). Achieving viral suppression may reduce ischemic stroke risk, including risk of atherosclerotic strokes, in HIV-infected individuals.

OI0345 Oral squamous cell carcinoma and epithelial dysplasia in HIV-infected individuals

HIV-infected individuals are at increased risk of oral cavity Kaposi sarcoma and non-Hodgkin lymphoma. However, it is suggested this patient population may also be at increased risk of oral cavity squamous cell carcinoma (OSCC). It remains unclear whether this is secondary to known risk factors (such as smoking and alcohol) or relates to HIV-specific factors, such as coinfection with human papillomavirus or Candida species, or the use of highly active antiretroviral therapy (HAART).

Heart failure in HIV infection

Since the advent of highly active antiretroviral treatment, accelerated atherosclerosis resulting in coronary artery disease (CAD) has become an area of increasing concern among patients infected with HIV. As CAD has replaced myocarditis and opportunistic infection as the most common cause of heart failure in this population, it is necessary to re-evaluate the specific risks of cardiovascular disease in HIV-infected patients taking into consideration the processes driving atherogenesis. Recent data illustrating that atazanavir is not associated with an increased risk of CAD argue against a class-wide association of protease inhibitors in HIV treatment and adverse cardiovascular outcomes. C-C chemokine receptor-type 5 has been identified as a potential target for pharmacological therapy to manage the process of atherosclerosis while simultaneously having an antiretroviral effect. Additionally, as the use of statins has recently been associated with new-onset diabetes in the general population, further investigation of this risk in HIV-infected patients is necessary. HIV-infected patients have an increased risk of CAD and subsequently heart failure. This is likely because of a confluence of several factors including: conventional risk factors, HIV-specific processes driving inflammation, coagulatory pathway and endothelial dysfunction. The benefits of antiretroviral drugs in terms of overall survival rates outweigh the risks of dyslipidemia. The focus of the management of cardiovascular risk remains in the domains of primary and secondary prevention. More accurate risk stratification, which accounts for HIV-specific risk factors, is now increasingly warranted.

Promoting a combination approach to paediatric HIV psychosocial support.

Ninety percent of the 3.4 million HIV-infected children live in sub-Saharan Africa. Their psychosocial well being is fundamental to establishing and maintaining successful treatment outcomes and overall quality of life. With the increased roll-out of antiretroviral treatment, HIV infection is shifting from a life-threatening to a chronic disease. However, even for paediatric patients enrolled in care and treatment, HIV can still be devastating due to the interaction of complex factors, particularly in the context of other household illness and overextended healthcare systems in sub-Saharan Africa.This article explores the negative effect of several interrelated HIV-specific factors on the psychosocial well being of HIV-infected children: disclosure, stigma and discrimination, and bereavement. However, drawing on clinical studies of resilience, it stresses the need to move beyond a focus on the individual as a full response to the needs of a sick child requires support for the individual child, caregiver-child dyads, extended families, communities, and institutions. This means providing early and progressive age appropriate interventions aimed at increasing the self-reliance and self-acceptance in children and their caregivers and promoting timely health-seeking behaviours. Critical barriers that cause poorer biomedical and psychosocial outcomes among children and caregiver must also be addressed as should the causes and consequences of stigma and associated gender and social norms.This article reviews interventions at different levels of the ecological model: individual-centred programs, family-centred interventions, programs that support or train healthcare providers, community interventions for HIV-infected children, and initiatives that improve the capacity of schools to provide more supportive environments for HIV-infected children. Although experience is increasing in approaches that address the psychosocial needs of vulnerable and HIV-infected children, there is still limited evidence demonstrating which interventions have positive effects on the well being of HIV-infected children. Interventions that improve the psychosocial well being of children living with HIV must be replicable in resource-limited settings, avoiding dependence on specialized staff for implementation.This paper advocates for combination approaches that strengthen the capacity of service providers, expand the availability of age appropriate and family-centred support and equip schools to be more protective and supportive of children living with HIV. The coordination of care with other community-based interventions is also needed to foster more supportive and less stigmatizing environments. To ensure effective, feasible, and scalable interventions, improving the evidence base to document improved outcomes and longer term impact as well as implementation of operational studies to document delivery approaches are needed.

Inverse Correlation Between Vascular Calcification and Bone Mineral Density in Human Immunodeficiency Virus-Infected Patients

HIV-infected individuals suffer from accelerated aging, which manifests as premature cardiovascular and bone disease. However, little is known of the association of these two disorders in the HIV population. Our objective was to investigate the association between a marker of atherosclerosis (coronary artery calcium [CAC]) and low bone mineral density (BMD) in a cross-sectional cohort of HIV-infected patients. The study was conducted at the University of Modena and Reggio Emilia, Italy. A total of 636 consecutive middle-aged, HIV-infected subjects were recruited between January 2006 and December 2010. All patients underwent CAC and BMD assessment. Patients were categorized according to a CAC score <100 or >100 units based on previous literature that identified this cut-point as a marker of increased risk. Low femoral and lumbar spine BMD was defined as <25th percentile value for the study cohort. Logistic regression and bootstrap analysis were used to assess the independent association between CAC and BMD. The main outcome measure was a CAC score >100. Patients with CAC > 100 were older and more likely to be men, diabetic, and overweight. Patients with CAC < 100 had better renal function and a lower cardiovascular risk profile. After adjusting for age, sex, traditional and HIV-specific risk factors, vitamin D level, and PTH level, there was a significant association between CAC > 100 and low BMD for the femur (OR = 2.33, 95 % CI 1.09-4.99; p = 0.02) but not for the spine. Bootstrap analyses confirmed these findings. In summary, CAC was independently associated with low femoral BMD in HIV-infected patients. Future studies should test whether therapies that attenuate cardiovascular risk in HIV favorably impact bone health.

GW24-e3755 Acquired QTc prolongation in HIV-infected patients: the prevalence, risk factors, and clinical significance

ObjectivesRecent study showed that corrected QT (QTc) prolongation is an independent risk factor for sudden cardiac death, which is predictive of cardiovascular mortality in human immunodeficiency virus (HIV) populations.To assess...

Correlates of hypertension in patients with AIDS in the era of highly active antiretroviral therapy.

It is unclear whether HIV-related factors modify risk of hypertension (HTN). In a cohort of patients with AIDS, the authors determined HTN incidence and prevalence and assessed associated traditional, HIV-specific, and retinal vasculature factors. Prospective observational cohort included 2390 patients with AIDS (1998-2011). Univariate analysis was used to assess the impact of traditional- and AIDS-related risk factors for HTN prevalence and incidence. Multivariate regression analyses were used to evaluate the adjusted impact of these factors. Hypertension prevalence was 22%(95% confidence interval [CI] 21%-24%) and was associated with traditional HTN risk factors (age, black race, and higher weight) as well as diabetes, hyperlipidemia, time since AIDS diagnosis, and higher CD4 counts. Hypertension incidence was 64.1 per 1000 person-years (95% CI 58.7/1000-69.9/1000). Age, race, weight, and diabetes were associated with incident HTN but HIV-specific factors were not. Hypertension, a prevalent cardiovascular risk factor in patients with AIDS, is associated with traditional and metabolic risk factors.

Elevated levels of asymmetric dimethylarginine are associated with lower CD4+ count and higher viral load in HIV-infected individuals

ObjectivesTo compare asymmetric dimethylarginine (ADMA) among HIV-infected and uninfected individuals and to evaluate predictors of ADMA in HIV infection. BackgroundHIV-infected individuals have high rates of atherosclerosis. Endothelial dysfunction is central to atherogenesis and is one possible mechanism underlying this increased cardiovascular risk. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, higher ADMA levels predict cardiovascular events and mortality. The association between HIV infection, HIV-related factors, and ADMA has not been well described. MethodsWe compared ADMA in 248 HIV-infected individuals and 50 uninfected controls. We performed multivariable analysis using traditional cardiovascular and HIV-specific factors as covariates to identify factors associated with ADMA. ResultsHIV-infected men were older, less often Caucasian, more hypertensive, and had lower HDL than uninfected men. The median duration of HIV infection was 13 years, median CD4+ count was 592 cells/μL, 76% had an undetectable viral load, and 76% were on antiretroviral therapy. ADMA levels were modestly higher in HIV-infected individuals than controls [median (IQR): 0.46 μM (0.41–0.52) vs. 0.44 μM (0.38–0.46), p = 0.019], but the association lost statistical significance after controlling for cardiovascular risk factors (+0.028 μM, p = 0.054). Lower CD4+ count and both detectable and higher viral load were independently associated with increased ADMA. ConclusionsADMA levels were modestly elevated in the setting of HIV infection. Notably, a greater HIV-associated inflammatory burden, as evidenced by lower CD4+ counts and higher viral loads, was associated with increased ADMA levels. Our findings suggest that HIV infection impairs endothelial function and predisposes to atherosclerosis through chronic inflammation and subsequent accumulation of ADMA.

A Nonparametric Procedure for Defining a New Humoral Immunologic Profile in a Pilot Study on HIV Infected Patients

This work aims at identifying a set of humoral immunologic parameters that improve prediction of the activation process in HIV patients. Starting from the well-known impact of humoral immunity in HIV infection, there is still a lack of knowledge in defining the role of the modulation of functional activity and titers of serum antibodies from early stage of infection to the development of AIDS. We propose an integrated approach that combines humoral and clinical parameters in defining the host immunity, implementing algorithms associated with virus control. A number of humoral parameters were simultaneously evaluated in a whole range of serum samples from HIV-positive patients. This issue has been afforded accounting for estimation problems typically related to “feasibility” studies where small sample size in each group and large number of parameters are jointly estimated. We used nonparametric statistical procedures to identify biomarkers in our study which included 42 subjects stratified on five different stages of HIV infection, i.e., Elite Controllers (EC), Long Term Non Progressors (LTNP), HAART, AIDS and Acute Infection (AI). The main goal of the paper is to illustrate a novel profiling method for helping to design a further confirmatory study. A set of seventeen different HIV-specific blood humoral factors were analyzed in all subjects, i.e. IgG and IgA to gp120IIIB, to gp120Bal, to whole gp41, to P1 and T20 gp41 epitopes of the MPER-HR2 region, to QARILAV gp41 epitope of the HR1 region and to CCR5; neutralization activity against five different virus strains and ADCC were also evaluated. Patients were selected on the basis of CD4 cell counts, HIV/RNA and clinical status. The Classification and Regression Trees (CART) approach has been used to uncover specific patterns of humoral parameters in different stages of HIV disease. Virus neutralization of primary virus strains and antibodies to gp41 were required to classify patients, suggesting that clinical profiles strongly rely on functional activity against HIV.

ARL-IPI - A New Prognostic Score for AIDS-Related Lymphomas in the Rituximab Era

Abstract 1564 INTRODUCTION:The International Prognostic Index (IPI) and the age-adjusted IPI (aaIPI) are commonly used to predict outcomes in immunocompetent patients with aggressive B-cell Non-Hodgkin Lymphomas (NHL). Although the IPI has also been validated for AIDS-related lymphomas (ARL), HIV-infection is an important competing risk that has not been adequately evaluated as a factor contributing to prognosis in the context of contemporary rituximab-containing chemoimmunotherapy. Here, we assessed whether HIV-specific factors in addition to the IPI provided more accurate prediction of clinical outcomes than IPI alone. METHODS:We obtained patient-level data for 487 patients from 8 prospective phase 2 or 3 clinical trials including patients with HIV-associated aggressive B-cell NHL receiving initial therapy with rituximab containing chemoimmunotherapy identified by systematic literature review, and randomly divided the population in a training (N=244) and validation set (N=243). We defined an HIV-score by combining individual HIV risk-factors: (1) baseline CD4 count (cells/ul): <50 =3, 50–199=2, 200–499=1, 500 or more =0; (2) HIV viral load (copies/ml): <400=0; 400-9, 999=1,10,000 or more =2; (3) prior history of AIDS=1, thereby yielding an HIV-score that could range from 0–6. We examined the association of HIV-score in addition to patient-, and lymphoma-specific factors with overall survival (OS) using a Cox-PH-model in the training and validation set independently by comparing 4 different multivariate models by a LR-chi2 test: model 1 (included age, sex, & histology), model 2 (model 1 + aaIPI), model 3 (model 2 + number of involved extranodal disease sites [ENS]) and model 4 (model 3 + HIV-score). Next, we defined a new score (ARL-IPI) by assigning appropriate weights to each significant predictor depending on the strength of association in the multivariate model in the training set: 2 for aaIPI score (0,1,2 or 3); 1 for ENS: no ENS=0, 1 ENS=1, 2 ENS=2, 3 or more ENS=3; and 1 for HIV-score. We examined the difference in OS for 3 risk groups: low (LR), intermediate (IR) and high risk (HR) based on the ARL-IPI in the validation set. We compared the discrimination power of the ARL-IPI with the aaIPI by comparing the difference in OS across the 3 groups defined by each score. RESULTS:487 patients were included in the analysis with a median follow-up of 2.3 years (0.1–12.1). There were no significant differences in patient characteristics between training and validation set. Considering the entire population, 77% were male, median age was 42 years (20–74), median CD4 count 174 cells/ul (0–2,457), and median HIV viral load 23,802 copies/ml (0–6×106). The histologies included DLBCL (69%), BL or BLL (29%), and other histologies (3%). All patients received rituximab plus either CHOP (49%), EPOCH (19%), CDE (15%), or other multi-agent intensive regimens (16%). In the training set, only aaIPI, ENS and HIV-score were significantly associated with OS, but not age, sex, extranodal sites as defined in the IPI (<2 or 2 or more), or histology. When tested in the validation set, the addition of the HIV-score (model 4; ARL-IPI) showed a significant improvement in predictive power for OS over all other models (p-value=0.009). When we compared the risk groups defined by the aaIPI (LR: <1, IR: 1–2, HR: 3) versus the ARL-IPI (aaIPI + ENS + HIV-score: LR: <7, IR: 7–10, HR: >10) in the validation set, the ARL-IPI was able to more clearly define prognosis based on the 3 risk groups in regards to OS (p=0.013; Table 1), which was confirmed by KM survival analysis (Figure 1). The ARL-IPI also compared favorably to a score defined by aaIPI and ENS (LR: <4, IR: 4–6, HR: >6), demonstrating the significant impact of the HIV-score on prediction power. In our dataset, the ARL-IPI could not significantly improve prediction power for CR rate or PFS compared with the two other scores. CONCLUSION:By combining HIV-associated factors with known prognostic patient- and lymphoma factors into a composite prognostic risk score (ARL-IPI) we were able to more accurately define prognosis for patients with ARL treated with chemoimmunotherapy. [Display omitted] Table 1.Median OS as per risk group adjusted for age, sex & histology in the validation set.Risk Group2-year OS % (95%CI)aaIPIaaIPI+ENSARL-IPILow0.83 (0.61–0.93)0.75 (0.58–0.85)0.87 (0.57–0.97)Intermediate0.64 (0.55–0.71)0.63 (0.51–0.74)0.60 (0.40–0.75)High0.60 (0.43–0.74)0.55 (0.37–0.70)0.50 (0.23–0.72) Disclosures:No relevant conflicts of interest to declare.