1. Factors associated with Mortality in the Study of Fat Redistribution and Metabolic Change in HIV infection Leslie Modrich 1, Rebecca Scherzer 1,2, Andrew Zolopa 3, David Rimland 4, Cora E. Lewis 5, Peter Bacchetti 1, Carl Grunfeld 1,2, Michael Shlipak 1,2, Phyllis C. Tien 1,2 for the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 1 University of California, San Francisco, CA; 2 Veterans Affairs Medical Center, San Francisco, CA; 3 Stanford University School of Medicine, Stanford, CA; 4 Veterans Affairs Medical Center, Atlanta, GA; 5 University of Alabama, Birmingham, AL Methods ResultsIntroduction 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. Measurements  Primary predictor: HIV versus Control  Secondary predictors: demographic (gender, age, ethnicity) and traditional cardiovascular disease (CVD) risk factors (smoking, diabetes, systolic and diastolic blood pressure, HDL cholesterol, and non-HDL cholesterol)  Outcome: Death ascertained by clinic notes and provider disclosure in HIV+; Death certificate data confirmed death only in controls as per the CARDIA protocol Statistical Analysis  Characteristics of the HIV+ and control participants between the ages of 33 and 45 were compared after 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.  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.  Few have evaluated mortality risk in the recent HAART era relative to controls.  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. Corresponding Author: Dr. Phyllis Tien 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: ptien@ucsf.edu Table 1: B aseline 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+ 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) 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.  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. HIV+ Controls (all)(age-restricted*) n1183613294 Age (y)**42.0 (37.0-48.0)40.0 (36.0-42.5)41.0 (37.0-43.0) Gender Female350 (30%)184 (30%)142 (48%) Male825 (70%)426 (69%)152 (52%) Transgender8 (1%)3 (1%) Race African-American466 (39%)235 (38%)142 (48%) Caucasian569 (48%)300 (49%)152 (52%) Other148 (13%)78 (13%) Smoking Status Current480 (42%)272 (46%)48 (17%) Past257 (23%)113 (19%)37 (13%) Never398 (35%)201 (34%)199 (70%) Diabetic97 (8%)38 (6%)9 (3%) Systolic BP (mmHg)115 (107-124)113 (105-122)116 (108-125) Diastolic BP (mmHg)78 (71-84)78 (70-84)79 (71-84) Total Cholesterol (mg/dL)191 (159-229)191 (158-228)196 (177-224) HDL Cholesterol (mg/dL)41 (33-53)41 (33-52)51 (42-60) HIV RNA (/1000)0.4 (0.4-12.5)0.4 (0.4-14.4) Detectable HIV RNA570 (49%)305 (51%) Current CD4351 (215-543)363 (219-543) HCV infection253 (22%)116 (19%) AIDS (by CD4 or OI/OM)844 (72%)444 (73%) Elapsed Time (y)4.6 (4.1-5.1)4.6 (4.2-5.1)5.7 (5.6-5.9) 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. HIV+ (N = 469*) Controls (N = 280*) Death54 (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 Demographic & Traditional CVD-Adjusted HR (95% CI) †† 3.4 (1.3, 8.5), p=0.009 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. 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. UnadjustedAdjusted* HR95% CIP-valueHR95% CIP-value Demographic Factors Female vs. Male1.13(0.77, 1.66)0.531.23(0.79, 1.91)0.36 African-American vs. Caucasian1.72(1.17, 2.52)0.0061.27(0.81, 1.97)0.30 Other vs. Caucasian1.47(0.81, 2.68)0.211.80(0.95, 3.43)0.074 Age (per decade)1.25(1.03, 1.52)0.0241.61(1.27, 2.05)<.0001 HIV-related Factors Current CD4 (log2)0.63(0.58, 0.69)<.00010.65(0.58, 0.73)<.0001 Detectable HIV RNA1.92(1.32, 2.78)0.0010.88(0.56, 1.37)0.56 AIDS (by CD4 or OI/OM)3.00(1.75, 5.16)<.00011.66(0.90, 3.08)0.11 HCV infection2.04(1.40, 2.97)0.00021.16(0.74, 1.83)0.52 Traditional Risk Factors Smoking: current vs. never2.81(1.77, 4.46)<.00012.73(1.64, 4.53)0.0001 Smoking: past vs. never1.40(0.79, 2.49)0.241.46(0.81, 2.64)0.21 Diabetic0.93(0.49, 1.78)0.831.01(0.50, 2.03)0.99 Systolic BP (per 10 mmHg)0.93(0.82, 1.05)0.250.93(0.76, 1.13)0.45 Diastolic BP (per 10 mmHg)0.98(0.83, 1.16)0.821.15(0.88, 1.52)0.31 Non HDL Cholesterol (per 10 mg/dL)0.92(0.88, 0.95)<.00010.96(0.92, 1.00)0.050 HDL Cholesterol (per 10 mg/dL)0.91(0.81, 1.03)0.130.88(0.78, 1.01)0.063 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 Table 3: Current smoking and older age were associated with higher mortality risk in HIV+ participants †. Figure 2. Compared with controls, mortality risk was highest for HIV+ with CD4 350 after adjustment 0 10 20 30 40 50 60 <200200-350350+ Baseline CD4 Count % Deceased (± 95%CI) Current Smoking Past/Never 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%). Note: unadjusted results from observed case analysis * 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 FRAM 1 HIV+ Enrollment (n=1183) FRAM 1 Controls Enrollment (n=297) FRAM 1 (n=1480) Enrolled (n=581) Enrolled (n=241) Unable to Re-establish Contact (n=237) Unable to Re-establish Contact (n=5) Refused (n=213) Refused (n=36) Deceased (n=128) Deceased (n=6) Never Contacted (n=24*) Never Contacted (n=9) Ineligible ** (n=3) Figure 1. Schema of FRAM 2 Retention resultsO-258 *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. 0 5 10 15 20 25 30 35 40Controls HIV+ CD4 350+ HIV+ CD4 200-350 HIV+ CD4<200 % Deceased (± 95%CI) n=280n=245n=114n=105 6.3 (2.2, 18.2) 4.3 (1.14, 16.0) 2.3 (0.78, 6.9)*