Blood Markers of Inflammation, Blood Clotting and Blood Vessel Function in HIV-infected Adults

D-dimer, a fibrin degradation product generated as a result of plasmin mediated clot
dissolution processes, is an indicator of recent clot formation and subsequent fibrinolysis.
Analysis of D-dimer concentration is employed in the diagnosis of deep vein thrombosis,
pulmonary embolism, and disseminated intravascular coagulation. More recently, D-dimer levels
have been correlated with atherosclerotic cardiovascular disease. In a recent case-control
study of biomarkers for cardiovascular disease in human immunodeficiency virus (HIV)-infected
adults, baseline D-dimer levels strongly correlated with all-cause mortality. Notably, the
association between baseline D-dimer levels and death due to cardiovascular disease was less
significant.

At present, the pathophysiology underlying the association of elevated D-dimer concentrations
with mortality in HIV is not understood. This study seeks to identify possible mechanisms
underlying D-dimer elevations in HIV-infected adults by investigating a number of pathways
that may be associated with the elevations using biomarkers of inflammation, hemostasis,
thrombosis, platelet function, lipid metabolism, and additional indicators of endothelial
function. Further elucidation of plausible pathways contributing to D-dimer elevation could,
ultimately, lead to trials of risk-reducing interventions for patients with an elevated
D-dimer level.

This study, an exploratory, cross-sectional study of up to 350 subjects, seeks to
prospectively collect data on D-dimer and related biomarkers in HIV-infected adults.
Initially, the study will recruit HIV-infected adults with HIV viremia who are not taking
antiretroviral therapy (ART) and compare their clinical histories and biomarker findings with
those from (1) a group of HIV-infected adults with controlled HIV viremia who are receiving
ART, and with those from (2) a control group of HIV-negative healthy subjects. Additionally,
to study the impact of persistent immune activation and inflammation on immune responses to
ART, a cohort of HIV-infected adults with poor CD4+ cell recovery despite effective ART, and
to better understand the mechanisms that contribute to impaired immunologic recovery, a
cohort of HIV-infected adults with poor CD4+ cell recovery despite effective ART will be
enrolled (immunologic non-responder cohort) and for comparison, a control group with similar
nadir CD4 counts but with good CD4+ cell recovery on ART.

The study requires 2 visits for screening, history and physical examination, and phlebotomy.
A wide array of research assays investigating different aspects of inflammation, coagulation,
and endothelial function will be completed. Samples will be stored for future investigation.

- INCLUSION CRITERIA:

- Age greater than or equal to 18 years

- Ability to understand and provide informed consent

- Adequate venous access

- Adequate blood counts (hemoglobin greater than or equal to 9.0 g/dL, platelets greater
than or equal to 50,000 cells/mm(3))

- Willing and able to comply with study requirements and procedures including storage of
blood samples for use in future studies of HIV, AIDS, immune function, inflammation,
coagulation, and atherosclerosis

- Negative serum pregnancy test for females of child-bearing potential (female subjects
who have medical documentation of hysterectomy and/or bilateral oophorectomy do not
need to undergo pregnancy testing)

For HIV-negative subjects:

- No known history of HIV infection. At enrollment, HIV antibody testing will be performed
to confirm negative HIV-1 antibody status.

For HIV-positive subjects:

- Established HIV diagnosis (previous documentation of HIV-1 infection in the subject s
medical record; for subjects without such confirmation, positive ELISA testing
confirmed by Western Blot or plasma HIV viral load greater than 10,000 copies/mL)

- Must be under the care of a physician for HIV and general medical issues.

For HIV-positive subjects enrolling in the immunologic non-responder cohort:

- CD4 count less than 300 cells/mm(3) after two years of effective combination ART with
documentation of viral suppression

- HIV viral load less than 50 copies/mL at screening, with no viral load greater than
1,000 copies/ml during the period of viral suppression.

- Not currently receiving any medication known to be associated with a low CD4 count

- No concurrent illness known to cause a low CD4 count

- Controls for this cohort will have a historical nadir CD4 count less than 300
cells/mm3, with current CD4 count greater than 300 cells/mm3 after three years of
effective combination ART with documentation of viral suppression.

EXCLUSION CRITERIA:

- Pregnant or breast-feeding

- Known bleeding or clotting disorder

- Current use of prescription anticoagulant including warfarin, low molecular weight
heparin, clopidogrel or platelet aggregation inhibitor

- Concurrent malignancy requiring cytotoxic chemotherapy or radiation therapy

- Substance abuse or severe psychiatric disorder that would interfere with adherence to
protocol requirements

- Any serious medical condition for which the principal investigator feels participation
may be contraindicated