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Inflammation and Mortality in HIV-infected Adults:
Analysis of the FRAM Study Cohort
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Reported by Jules Levin
17th CROI Feb 1619 2010 SF
from Jules: several researchers said at the microphones during discussions at sessions that studies reporting inflammation are generally associations and prospective studies are needed to confirm our numerous findings, at CROi this year there were many studies finding inflammation associated with bad outcomes in HIV+ individuals including heart disease. The general literature is filled with studies finding inflammation associated with chronic diseases. Apparently activation & senescence is a root cause, and we do in fact need focused research studies to characterize these issues but more importantly to find interventions. But time is our enemy as patients age s the NIH needs to prioritize this effort and dedicate funding and organize an effort designed to move ahead quickly.
Phyllis C. Tien, MD1,2, Andy I. Choi, MD1,2, Andrew R. Zolopa, MD3, Constance Benson, MD4, Rebecca Scherzer, PhD1,2, Peter Bacchetti, PhD1,
Michael Shlipak, MD1,2, Carl Grunfeld, MD, PhD1,2
1 University of California, San Francisco, San Francisco, CA; 2 San Francisco Veterans Affairs Medical Center, San Francisco, CA;
Stanford University, Stanford, CA; University of California, San Diego, San Diego, CA
INTRODUCTION
· We previously reported that HIV infection was associated with 3-fold higher odds of death even after controlling for demographic and traditional cardiovascular disease (CVD) risk factors [1].
· Whether inflammation (which is thought to be a consequence of chronic infection and immune activation) contributes to death in HIV-infected persons, beyond demographic and CVD risk factors, is the topic of current investigation.
· We evaluated the association of fibrinogen (an inflammatory protein involved in the clotting cascade) and C-reactive protein (CRP) (a proinflammatory biomarker) in a geographically and ethnically diverse U.S. cohort of HIV-infected
individuals in clinical care in the United States. In order to assess the role of immunosuppression severity on the association of inflammation with mortality, we stratified HIV-infected individuals into four CD4 count risk categories
METHODS
Study Population
· From June 2000 – September 2002, 1183 HIV+ men and women from 16 HIV or infectious disease clinics or cohorts were enrolled in the study of Fat Redistribution and Metabolic Change in HIV infection (FRAM)
· A follow-up exam (FRAM2) was conducted approximately five years later from 2004 to 2007. The study design, recruitment methods and data collection procedures have been described [2], and the retention outcomes for participants enrolled in the first exam have been reported previously [1].
· 922 HIV+ participants with known vital status (dead or alive) were included for analysis. Vital status could not be determined for 261. Sensitivity analyses were also conducted to include those with unknown vital status.
Measurements
· Primary predictors:
- Fibrinogen as a continuous (per 100mg/dL increase) and categorical variable (tertiles of fibrinogen levels)
- CRP as a continuous [log transformation (log2)] and categorical variable based on the Center for Disease Control/American Heart Association guidelines: low risk <1mg/dL, average risk 1-3mg/dL, and high risk >3mg/dL
· Secondary predictors: demographic (sex, age, ethnicity); traditional cardiovascular disease (CVD) risk factors (smoking, diabetes, systolic and diastolic blood pressure, HDL cholesterol, and non-HDL cholesterol) ; HIV-related (HIV RNA level, CD4 count, self-reported duration of HIV, AIDS by CD4 or opportunistic infections or malignancies OI/OM), hepatitis C virus infection status, ever use and duration of use of each antiretroviral drug and class)
· Outcome: Death ascertained by clinic notes and provider disclosure
Statistical Analysis
· Characteristics of the HIV+ participants by tertile of fibrinogen were compared (Table 1).
· Association of fibrinogen and CRP with five-year mortality risk was determined by multivariable logistic regression analysis.
· Analyses were stratified by baseline CD4 count (<200, 200 to 350, >350 to 500, and >500).
Figure 1. Elevated Fibrinogen and CRP were associated with higher mortality rates.
*Estimates standardized to 40 years (the approximate mean age of the overall cohort at enrollment)
Table 1: HIV+ with fibrinogen in the highest tertile at the baseline exam were older, more often African-American, had lower HDL and CD4, and higher HIV RNA and CRP levels.
*Statistics estimated using IPCW weights. Continuous data are represented as median (IQR).
** AIDS defined by CD4<200 or history of opportunistic infection or malignancy
Table 2: Fibrinogen and CRP are independently associated with mortality after controlling for demographic, CVD and HIV-related factors
Table 3: Fibrinogen and CRP were independently associated with higher odds of death in every CD4 category, after adjustment for demographic, CVD, and HIV-related factors.
* OR, odds ratio; CI, confidence interval. Multivariate-adjusted model controls for demographics, smoking, non-HDL chol, hepatitis C virus infection, waist circumference, lean mass, CD4 count, and total duration of efavirenz, indinavir, and amprenavir.
** Fibrinogen & CRP are shown entering the model individually.
*** Fibrinogen & CRP are shown entering the model jointly.
CRP is log2-transformed. Estimates are odds of death per doubling of CRP
REFERENCES
1. Cockerham L, Scherzer R, Zolopa A, et al. Association of HIV infection, demographic and cardiovascular risk factors
with all-cause mortality in the recent HAART era. J Acquir Immune Defic Syndr 2010 Jan 1;53(1):102-6
2. Tien PC, Benson C, Zolopa AR, Sidney S, Osmond D and Grunfeld C. The study of fat redistribution and metabolic
change in HIV infection (FRAM): methods, design, and sample characteristics. Am J Epidemiol 2006;163:860-9
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