HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.

There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28− and CD57+CD28−), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

Background-HIV-infected patients may be at increased risk for coronary events. The purpose of this study was to identify predictors of carotid intima-media thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1 year. Methods and Results-We measured blood lipids, inflammatory markers, and IMT in 148 HIV-infected adults (mean age, 45Ϯ8 years) and in 63 age-and sex-matched HIV-uninfected control subjects. The mean duration of HIV infection was 11 years, and the median duration of protease inhibitor treatment was 3.3 years. Mean baseline IMT was 0.91Ϯ0.33 mm in HIV patients and 0.74Ϯ0.17 mm in control subjects (Pϭ0.0001). Multivariable predictors of baseline IMT in HIV patients were age (PϽ0.001), LDL cholesterol (PϽ0.001), cigarette pack-years (Pϭ0.005), Latino race (Pϭ0.062), and hypertension (Pϭ0.074). When the control group was added to the analysis, HIV infection was an independent predictor of IMT (Pϭ0.001). The rate of progression among the 121 HIV patients with a repeated IMT measurement at 1 year was 0.074Ϯ0.13 mm, compared with Ϫ0.006Ϯ0.05 mm in 27 control subjects (Pϭ0.002). Age (PϽ0.001), Latino race (Pϭ0.02), and nadir CD4 count Յ200 (Pϭ0.082) were multivariable predictors of IMT progression. Conclusions-Carotid IMT is higher in HIV patients than in age-matched control subjects and progresses much more rapidly than previously reported rates in non-HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary risk factors and with nadir CD4 count Յ200, suggesting that immunodeficiency and traditional coronary risk factors may contribute to atherosclerosis.