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O-258
Factors associated with Mortality in the Study of Fat Redistribution and Metabolic Change in HIV infection
Leslie Modrich1, Rebecca Scherzer1,2, Andrew Zolopa3, David Rimland4, Cora E. Lewis5, Peter Bacchetti1, Carl Grunfeld1,2, Michael Shlipak1,2, Phyllis C. Tien1,2
Corresponding Author:
for the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM)
Dr. Phyllis Tien
1University
of California, San Francisco, CA; 2Veterans Affairs Medical Center, San Francisco, CA; 3Stanford University School of Medicine, Stanford, CA;
4Veterans Affairs Medical Center, Atlanta, GA; 5University of Alabama, Birmingham, AL
Results
Introduction


The decrease in HIV-related mortality since the introduction of highly active antiretroviral therapy
(HAART) has been accompanied by increases in non-HIV-related mortality including cardiovascular,
hepatic and pulmonary diseases, and non-AIDS malignancies.
Table 1: Baseline characteristics of the HIV+ and control participants:
Current smoking and diabetes were more common in HIV+; systolic
blood pressure, total cholesterol, and HDL were lower in HIV+
Few have evaluated mortality risk in the recent HAART era relative to controls.
HIV+
We evaluated the association of HIV infection (versus controls of similar age) and other factors with
mortality risk over a five-year follow up period during the recent HAART era in the Study of Fat
Redistribution and Metabolic Changes in HIV infection (FRAM), a geographically and ethnically diverse
U.S. cohort of HIV-infected individuals and controls.
n
Age (y)**
Gender
Female
Methods
Study Population

From June 2000 – September 2002 (FRAM1), 1183 HIV+ men and women were recruited from 16 HIV or
infectious disease clinics or cohorts and 297 controls were recruited from two centers of the Coronary
Artery Risk Development in Young Adults (CARDIA) study.

A follow-up exam (FRAM2) was conducted approximately five years later from 2004 to 2007 to examine
the progression of fat distribution and metabolic parameters, and to obtain carotid intima media thickness
measurements, a marker of subclinical atherosclerosis. Figure 1 shows FRAM2 retention outcomes for
participants enrolled in the first FRAM exam.

922 HIV+ and 280 controls with known vital status (dead or alive) were included for analysis. Sensitivity
analyses were also conducted to include those with unknown vital status.
Figure 1. Schema of FRAM 2 Retention results
FRAM 1
(n=1480)
FRAM 1 HIV+ Enrollment
(n=1183)
(n=297)
(n=24*)
Unable to Re-establish Contact
(n=237)
(age-restricted*) (age-restricted*)
613
294
40.0 (36.0-42.5)
41.0 (37.0-43.0)
(n=6)
(n=9)
(n=213)
Enrolled
(n=581)
Outcome: Death ascertained by clinic notes and provider disclosure in HIV+; Death certificate data
confirmed death only in controls as per the CARDIA protocol
exclusion of HIV+ with opportunistic infections or malignancies (OI/OM) in the same or previous calendar
month as the baseline examination (Table 1).

Association of HIV infection (versus controls) with five-year mortality risk was determined using
multivariable exponential regression analysis

Association of HIV infection further categorized by CD4 count (>350, 200 to ≤350, and <200) versus
controls with mortality risk was determined using the same models

Within HIV+ participants alone, similar analyses were performed to identify HIV-related factors (HIV RNA
level, CD4 count, AIDS by CD4 or OI/OM, and HCV infection status) independently predictive of mortality .
1.47
1.25
(0.81, 2.68)
(1.03, 1.52)
0.21
0.024
1.80
1.61
(0.95, 3.43)
(1.27, 2.05)
0.074
<.0001
0.63
1.92
3.00
2.04
(0.58, 0.69)
(1.32, 2.78)
(1.75, 5.16)
(1.40, 2.97)
<.0001
0.001
<.0001
0.0002
0.65
0.88
1.66
1.16
(0.58, 0.73)
(0.56, 1.37)
(0.90, 3.08)
(0.74, 1.83)
<.0001
0.56
0.11
0.52
2.81
1.40
0.93
0.93
0.98
0.92
0.91
(1.77, 4.46)
(0.79, 2.49)
(0.49, 1.78)
(0.82, 1.05)
(0.83, 1.16)
(0.88, 0.95)
(0.81, 1.03)
<.0001
0.24
0.83
0.25
0.82
<.0001
0.13
2.73
1.46
1.01
0.93
1.15
0.96
0.88
(1.64, 4.53)
(0.81, 2.64)
(0.50, 2.03)
(0.76, 1.13)
(0.88, 1.52)
(0.92, 1.00)
(0.78, 1.01)
0.0001
0.21
0.99
0.45
0.31
0.050
0.063
300 (49%)
78 (13%)
152 (52%)
480 (42%)
257 (23%)
398 (35%)
97 (8%)
115 (107-124)
78 (71-84)
191 (159-229)
41 (33-53)
0.4 (0.4-12.5)
570 (49%)
351 (215-543)
253 (22%)
272 (46%)
113 (19%)
201 (34%)
38 (6%)
113 (105-122)
78 (70-84)
191 (158-228)
41 (33-52)
0.4 (0.4-14.4)
305 (51%)
363 (219-543)
116 (19%)
48 (17%)
37 (13%)
199 (70%)
9 (3%)
116 (108-125)
79 (71-84)
196 (177-224)
51 (42-60)
AIDS (by CD4 or OI/OM)
Elapsed Time (y)
844 (72%)
4.6 (4.1-5.1)
444 (73%)
4.6 (4.2-5.1)
HIV+
Controls
(N = 469*)
(N = 280*)
54 (11.5%)
6 (2.1%)
Unadjusted Hazard Ratio (95% CI)
7.0 (3.0, 16.2), p<.0001
Demographic Adjusted HR (95% CI)†
7.1 (3.0, 16.7), p<.0001
3.4 (1.3, 8.5), p=0.009
Figure 2. Compared with controls, mortality risk was highest for HIV+ with
CD4<200, followed by CD4 200-350, and CD4>350 after adjustment
6.3 (2.2, 18.2)
Traditional Risk Factors
Smoking: current vs. never
Smoking: past vs. never
Diabetic
Systolic BP (per 10 mmHg)
Diastolic BP (per 10 mmHg)
Non HDL Cholesterol (per 10 mg/dL)
HDL Cholesterol (per 10 mg/dL)
HR, hazard ratio; CI, confidence interval; BP, blood pressure; OI, opportunistic infection; OM, opportunistic malignancy
† Observed case exponential regression mortality analysis
*adjusted for demographic, traditional CVD risk factors, and HIV-related factors
Total N (n=922) includes all HIV-infected participants known to be dead (n=128) or alive (n=794) and excludes those who were lost to follow-up
60
Current Smoking
50
Past/Never
40
30
20
10
0
<200
200-350
350+
Baseline CD4 Count
Note: unadjusted results from observed case analysis
Conclusions
 We found that mortality risk remains three times as high among HIV+ in the recent
HAART era compared to controls of similar age.
 Cigarette smoking, older age and lower CD4 count were independent predictors of
mortality in those with HIV infection.
35
30
25
20
 We observed that HIV+ patients were at greater mortality risk compared to
controls, even among those with CD4>350. This finding suggests a possible role of
chronic inflammatory changes (from HIV infection) leading to increased mortality
risk, an association that needs further investigation .
4.3 (1.14, 16.0)
15
2.3 (0.78, 6.9)*
10
5
0
Current CD4 (log2)
Detectable HIV RNA
AIDS (by CD4 or OI/OM)
HCV infection
Figure 3. In HIV+ participants, smoking was associated with higher mortality regardless of CD4
strata; mortality was highest among those with both low CD4 counts and current smoking status
(40%) compared with the lowest risk group of high CD4 count non-smokers (5.3%).
HR, hazard ratio; CI, confidence interval; CVD, cardiovascular disease.
Observed case exponential regression mortality analysis
* N denotes number of participants between the ages of 33 and 45 at the baseline examination with
vital status determined (dead or alive) at FRAM2 and excludes those with recent opportunistic
infection/malignancy at baseline, and those who were lost to follow-up.
† Demographics (gender, age and ethnicity).
†† Traditional CVD risk factors (smoking, diabetes, systolic and diastolic blood pressure, HDL, and
non-HDL cholesterol) at baseline.
% Deceased (± 95%CI)
Characteristics of the HIV+ and control participants between the ages of 33 and 45 were compared after
0.36
0.30
569 (48%)
148 (13%)
40

(0.79, 1.91)
(0.81, 1.97)
Caucasian
Other
Smoking Status
Current
Past
Never
Diabetic
Systolic BP (mmHg)
Diastolic BP (mmHg)
Total Cholesterol (mg/dL)
HDL Cholesterol (mg/dL)
HIV RNA (/1000)
Detectable HIV RNA
Current CD4
HCV infection
Demographic & Traditional CVD-Adjusted HR (95% CI) ††
Statistical Analysis
1.23
1.27
HIV-related Factors
cholesterol)

0.53
0.006
142 (48%)
(n=3)
risk factors (smoking, diabetes, systolic and diastolic blood pressure, HDL cholesterol, and non-HDL
(0.77, 1.66)
(1.17, 2.52)
235 (38%)
(n=241)
Secondary predictors: demographic (gender, age, ethnicity) and traditional cardiovascular disease (CVD)
1.13
1.72
466 (39%)
Enrolled
Primary predictor: HIV versus Control
Female vs. Male
African-American vs. Caucasian
Demographic Factors
Other vs. Caucasian
Age (per decade)
Ineligible**


P-value
152 (52%)
Death
Measurements
95% CI
426 (69%)
3 (1%)
Refused
* Two FRAM 1 sites were not included in FRAM 2 (n=23)
** Control participants found to be taking antiretroviral drugs for HIV infection on chart review; these 3 participants are excluded from analysis
HR
825 (70%)
8 (1%)
(n=5)
(n=36)
P-value
Male
Transgender
Race
African-American
Unable to Re-establish Contact
Refused
95% CI
142 (48%)
5.7 (5.6-5.9)
Adjusted*
HR
184 (30%)
Table 2: HIV infection remained associated with a three-fold higher
mortality risk compared to controls, after controlling for demographic
and traditional CVD risk factors.
Never Contacted
Unadjusted
350 (30%)
Deceased
(n=128)
Never Contacted
Controls
BP, blood pressure; OI, opportunistic infection; OM, opportunistic malignancy
*Participants were restricted to those between the ages of 33 and 45 y at baseline
** Data are presented as Median (Interquartile range) for all continuous measures.
FRAM 1 Controls Enrollment
Deceased
(all)
1183
42.0 (37.0-48.0)
HIV+
Table 3: Current smoking and older age were associated with higher mortality risk in HIV+
participants†.
% Deceased (± 95%CI)

University of California, San Francisco
VAMC, Infectious Disease Section, 111W
4150 Clement Street, San Francisco, CA 94121
Phone: (415) 221-4810, ext 2577
E-mail: [email protected]
Controls
HIV+
CD4 350+
HIV+
CD4 200-350
HIV+
CD4<200
n=280
n=245
n=114
n=105
*Hazard Ratio (95% Confidence Interval)
Note: results from observed case analysis. Age restricted to 33-45 years at baseline; those
with OI at baseline were excluded.
Acknowledgements
FRAM is funded by and performed in cooperation with NIDDK, NHLBI, NIAID, NIDA & OAR, of the NIH, U.S.A. (DK 57508, HL53359 & HL74814)