1. A Prognostic Index for those Aging with HIV: Extension of the VACS Index to those on Combination Anti-Retroviral Therapy (cART) AC Justice* 1,2, S Modur 3, JPTate 1,2, KN Althoff 3, SJ Gange 3, LP Jacobson 3, K Gebo 3, M Kitahata 4, M Horberg 5, S Napravnik 6 for the NA-ACCORD and VACS Project Teams 1 Yale University, New Haven, CT, US~ 2 VA Connecticut Healthcare System, West Haven, CT, US~ 3 Johns Hopkins University, Baltimore, MD~ 4 University of Washington, Seattle, WA~ 5 Kaiser Permanente Northern California, Oakland, CA~ 6 University of North Carolina, Chapel Hill, NC ABSTRACT Background: As HIV-infected persons age with cART, there is increased interest in clinical factors associated with aging that are prognostic for death beyond CD4 count and HIV-1 RNA. The Veterans Aging Cohort Study (VACS) Index, composed of routinely collected measures of organ system injury, predicts all cause mortality more accurately than an index restricted to CD4 count, HIV-1 RNA, and age, but has not been tested among non-veterans on cART. Methods: We used data from the NA-ACCORD US and Canadian cohort collaboration to validate the VACS Index using previously developed weights and cutpoints for CD4 count, HIV-1 RNA, hemoglobin, HCV serostatus, eGFR, FIB-4, and age. A randomly selected CD4 count measured after at least 12 months of cART exposure was used as a baseline; other labs were selected to be closest to the CD4 measurement date. Only subjects with complete labs within a 90-day window were included. Cox proportional hazards models and accompanying c statistics were used to compare the prognostic value for 5-year mortality using the full VACS Index with a restricted model using only age, CD4 count, & HIV RNA. Results: 5,980 subjects had complete data contributing 14,040 person years of observation and 390 deaths; 13% were ≥50 years of age, 42% had a CD4 count ≥500 cells/mm 3, 76% had an HIV RNA ≤500 copies/mL, 12% were anemic (hemoglobin <12 g/dL), 6% had stage III renal impairment (eGFR <60 mL/min/1.73m 3 ), 17% were HCV co-infected, and 19% had some evidence of liver fibrosis (FIB-4 of ≥1.45). Median and interquartile ranges were 13 (6-24) for the VACS Index and 10 (0-21) for the restricted index. Compared to the restricted index, the VACS Index showed improved discrimination of all cause mortality (c statistic 0.81 vs. 0.74, p<0.0001). Results were consistent when narrower windows were used for allowable laboratory values. Conclusions: The VACS Index predicts 5 year, all-cause mortality substantially better than an index restricted to CD4 count, HIV RNA, and age among a cross cohort sample representative of those in treatment in North America with varying periods of cART exposure. The variables included in the VACS Index are recommended for routine monitoring by current guidelines. Because the VACS Index both accurately predicts mortality and indicates specific organ systems at risk it may be a useful tool with which to monitor treatment response and assess prognosis among those on cART. BACKGROUND Everywhere ART available: most patients achieve viral suppression; incident AIDS events are rare and variably associated with mortality; life expectancy is extended; and HIV Associated Non AIDS (HANA) Conditions determine disease burden. We need a clinically accessible and reasonably standardized approach to tracking disease progression that: integrates CD4 count, HIV-1 RNA, and age and includes other important measures of injury such as hematologic disease; liver disease; and renal disease. We have developed the Veterans Aging Cohort Study Risk Index (VACS Index), a prognostic index composed of routinely available clinical laboratory markers and age. It is highly predictive of short and long term all cause mortality among those initiating cART both among the veteran subjects used to develop and initially validate the index and among HIV infected individuals initiating care in Europe and the United States. Here we ask whether the VACS Index improves prognostic accuracy overall and among important subgroups including those aging with HIV, women, those with undetectable HIV-1 RNA, and people of color. RESULTS: Characteristics of Sample # 793 ACKNOWLEDGEMENT: This research was supported by NIH: NIAAA (2U10AA13566), NIAID (5U01A1069918) SUMMARY/DISCUSSION The VACS Index is more discriminating and better calibrated than the Restricted Index when tested in an independent sample from North America. When compared to the Restricted Index classifications, the VACS Index results in substantial risk reclassification for approximately a third of the subjects. Interestingly, women were more likely to be assigned a higher risk of mortality than a lower one, blacks were about equally likely to be assigned a higher or a lower risk, whereas those with undetectable HIV-1 RNA and Hispanics were twice as likely to be assigned a lower than a higher risk. * Correlations are shown as absolute values. Starred biomarkers demonstrated NEGATIVE correlations with the indicated biomarker of inflammation. Specifically, eGFR, hemoglobin, and CD4 count were all negatively correlated with all three biomarkers of inflammation. CONCLUSIONS The VACS Index offers a clinically superior estimation of mortality risk compared to the Restricted Index and should be used in patient care and clinical research. Index Points* Eligible (n=5484)N (%)RestrictedVACS Age in Years at Anchor * <50 50-64 >= 65 Median (IQR) 4311(79) 1082(20) 91 (2) 39(34-46) 0 23 44 0 12 27 CD4 count/mm 3 >=500 350-499 200-349 100-199 50-99 <50 Median (IQR) 1855(34) 1237(23) 1291(24) 738(13) 188(3) 175(3) 388 (231-581) 0 10 19 40 46 0 6 10 28 29 HIV-1 RNA <500 500-1x10 5 >=1x10 5 Median (IQR) 4216(76) 1083(21) 185(3) 75(50-400) 0 11 25 0 7 14 Hemoglobin g/dL >=14 12-13.9 10-11.9 <10 Median (IQR) 3206(59) 1750(32) 446(8) 82(1) 14.3(13.2-15.4) 0 10 22 38 FIB-4 <1.45 1.45-3.25 >3.25 Median (IQR) 4249(78) 959(17) 231(4) 0.93(0.68-1.37) 0 6 25 eGFR mL/min >=60 45 to 59.9 30 to 44.9 <30 Median(IQR) 5177(94) 188(3) 61(1) 58(1) 96(81-112) 0 6 8 26 Hep C Infection Present938(17)5 Deaths* 1 year 5 years 98(2) 376(7) Year of cART Initiation < 2000 2000-2003 2004-2008 Median (IQR) 2169(40) 2001(36) 1314(24) 2001(1998.3- 2003.8) Gender Male Female 4515(82) 969 (18) Race White Black Hispanic Other/Unknown 3017 (55) 1684 (31) 494 (9) 310 (5) FUP Time Median (IQR)3.2(1.8-5.0) *Index Score is calculated by summing points assigned based on age and lab cut points in this table. VACS Index HR (95% CI) C-stat Restricted Index HR (95% CI) C-statp-value** Overall1.25 (1.23-1.27)0.801.24(1.21-1.26)0.75<0.0001 Time on cART Year 1 Year 2 Year 3 Year 4 Year 5 1.25 (1.23-1.27) 1.24(1.21-1.26) 1.27(1.25-1.30) 1.27(1.24-1.30) 1.28 (1.24-1.32) 0.80 0.83 0.81 0.83 1.23(1.19-1.28) 1.24(1.22-1.27) 1.23(1.20-1.26) 1.22(1.19-1.26) 1.23(1.19-1.28) 0.75 0.74 0.75 0.76 <0.0001 Gender Male Female 1.24 (1.22-1.27) 1.28(1.23-1.34) 0.81 1.24(1.21-1.27) 1.22(1.17-1.28) 0.75 0.77 <0.001 Race White Black Hispanic 1.26(1.23-1.29) 1.24(1.20-1.27) 1.35(1.25-1.45) 0.79 0.81 0.90 1.24(1.21-1.28) 1.24(1.19-1.28) 1.26(1.16-1.37) 0.74 0.76 0.78 <0.001 Age <50 >= 50 1.29(1.26-1.32) 1.20(1.16-1.24) 0.81 0.74 1.27(1.23-1.30) 1.23(1.17-1.29) 0.75 0.69 <0.001 <0.0001 HIV-1 RNA <500 >=500 1.29(1.25-1.33) 1.20(1.17-1.23) 0.77 0.78 1.22(1.17-1.27) 1.22(1.18-1.25) 0.68 0.74 <0.0001 ** p value is based on Likelihood ratio test Discrimination of Indices for 5 Year Mortality Calibration of Indices for 5 Year Mortality Reclassification of 5 Year Risk Due to More Complete Information in VACS Index Compared to Restricted Index* ANALYSIS We identified 12 cohorts, excluding VACS and HIV RN, in the NA-ACCORD cross cohort collaboration that collect all clinical laboratories necessary to calculate the VACS Index. We then restricted the analytic sample to those who have received at least 12 months of cART during 2000- 2008. All lab data had to be drawn within 90 days before or 180 after the 12 month point of cART. Of the 12,219 subjects identified as eligible, 5484 had complete laboratory data within this window. (Note, these numbers are somewhat different than in the submitted abstract due to a modification in our definition of baseline. However, our results are very consistent.) GroupnHigher RiskLower RiskTotal Reclassified Women96925% (24%)7% (11%)32% (36%) HIV RNA<500 copies/ml421610% (11%)15% (21%)26% (32%) Black Race168418% (18%)15% (20%)33% (39%) Hispanic Ethnicity4949% (8%)22% (24%)31% (32%) Overall548411% (11%)19% (26%)30% (37%) Reclassification by Subgroup with (without) Censored Observations VACS % Risk Restricted 0-<55-<1010-<1515-<20>=20Total 0-<5 2884 9% 226 16% 42 38% 18 44% 11 65% 3181 5-<10 582 7% 716 4% 141 12% 29 28% 44 13% 1512 10-<15 12 17% 205 7% 96 8% 27 25% 37 31% 377 15-<200 38 13% 41 16% 21 21% 19 27% 119 >=200 13 15% 80 6% 56 21% 146 22% 295 Total347811984001512575484 *Estimated and Observed rates calculated using Proportional Hazards Model output. SUPPORTING REFERENCES Sterling RK, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43(6):1317-1325. Stevens LA, et al. Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med 2006;354(23):2473-2483. Gange SJ, et al. Cohort Profile: The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Int J Epidemiol 2007;.(36):294-301. Justice AC, et al. Assessing the generalizability of prognostic information. Ann Intern Med 1999;130(6):515-524. Cook NR, Ridker PM. Advances in measuring the effect of individual predictors of cardiovascular risk: the role of reclassification measures. Ann Intern Med 2009;150(11):795-802.