Summary of Evidence Support
The VACS Index
Frequently Asked Questions and
Summary of Evidence as of July, 2016
What is the VACS Index?
The Veterans Aging Cohort Study Index (VACS Index) creates a score by summing pre-assigned points for age, routinely monitored indicators of HIV disease (CD4 count and HIV-1 RNA), and general indicators of organ system injury including hemoglobin, platelets, aspartate and alanine transaminase (AST and ALT), creatinine, and viral hepatitis C infection (HCV) (Table 1)1. This score is weighted to indicate increasing risk of all-cause mortality with increasing score. The score can be used to estimate risk of all-cause mortality using a conversion factor2. A calculator, summary of validation work to date, and a clinical interpretation of VACS Index scores can be found at http://vacs.med.yale.edu.
What does the VACS Index Do?
The VACS Index predicts all cause mortality, cause specific mortality, and other outcomes in those living with HIV infection. If one assumes that uninfected patients have no HIV-1 RNA titer and a CD4 cell count at or above 500 cells/mm3, it predicts all cause mortality and hospitalization among those without HIV infection. It responds to important changes in risk related to treatment and health behaviors. It improves upon the accuracy of provider assessment (clinical judgment) of mortality risk. Specific evidence is bulleted below.
- It predicts mortality among those in treatment with HIV infection: The Index was developed in veteran patients1 and its reproducible accuracy has been validated in other patient populations in North America and Europe1,2. It discriminates risk of mortality more effectively than an index restricted to CD4 count, HIV-1 RNA and age (Restricted Index) especially among those with undetectable HIV-1 RNA and those 50 or more years of age1,2.The accuracy of the Index for predicting mortality among HIV infected individuals in treatment meets or exceeds the accuracy reported for indices currently used in clinical practice3-5. Further, its accuracy is independent of length of antiretroviral treatment and is robust among important patient subgroups including women, people of color, those with HCV coinfection, and those over 50 years of age1,2. It is also highly predictive of mortality among young active duty military relatively free of comorbid disease6 and among those initiating salvage antiretroviral therapy after becoming resistant to at least two classes of antiretroviral therapy7.
- It predicts mortality among uninfected individuals: If you assume that those without HIV infection have no HIV-1 RNA (i.e. 0 points) and a CD4 cell count above 500 cells/mm3 (i.e. 0 points), the VACS Index also predicts mortality among those without HIV infection. This has been shown for 30-day mortality from MICU admission8 and for long term (median of 5 years) mortality9.
- It predicts outcomes after admission for bacterial pneumonia: Among HIV infected and uninfected (age 50+ years) veterans the index predicts 30-day mortality, length of stay, and readmission10
- It is associated with biomarkers of inflammation: The VACS Index is correlated with markers of chronic inflammation, microbial translocation, and hypercoagulability (cystatin C, TNF alpha, IL-6, soluble CD14, soluble CD163, and D-dimer)11-14. The Index is also associated with an immune score composed of CD4 and CD8 activation (DR), naïve and terminally differentiated memory T cells, and CD57CD28 cells which were weighted by principal component analyses (Chronic Immune Activation and Senescence, CIADIS score)15.
- It is associated with frailty states: Frailty is defined as decreased ability to recover from additional injury16. The index is associated with increased risk for a number of frailty related outcomes including mortality, hospitalization, and geriatric syndromes (falls, fragility fractures, and cognitive decline) with measures of functional performance17 and sarcopenia18, and with multiple measures of neuro-cognitive performance19. The VACS Index predicts morbidity including hospitalization, medical intensive care unit admission20, and fragility fractures21, 22. It is also associated with autonomic neuropathy23. It is an effective measure of physiologic frailty 24, 25. Few individuals demonstrated frailty based on the adapted frailty related phenotype26. When compared with an adapted version of the frailty related phenotype, the VACS Index more accurately predicted both all-cause mortality and hospitalization among HIV infected and uninfected individuals26. Of note, the approach to frailty employed by the VACS Index is more attuned to the Rockwood conceptualization27 of frailty as accumulation of deficits than that of Fried28 which describes a clinical syndrome.
- Scores differ among important health states:VACS Index scores differ by level of smoking, alcohol consumption and hypertension29-31. VACS Index scores predict weight gain in the first 12 months after ART initiation32. VACS Index is associated with dependence in one or more activities of daily living33.
- It responds to important changes in health and health behaviors: VACS Index scores change in response to antiretroviral initiation34 and interruption6, and discriminate among levels of ART adherence34. Changes in VACS Index scores correspond to changes in neurocognitive function35. When levels of alcohol consumption change among HIV infected subjects, the index score also changes. Similarly, when HIV infected subjects in treatment for substance abuse have positive urine toxicology screens, their scores are higher than when the same subjects have negative toxicology screens. (Papers reporting responsiveness of the VACS Index to changes in alcohol and substance use are in preparation).
- It is accurate in a wide range of patient population: VACS Index is strongly predictive of all-cause mortality in a wide range of HIV infected populations including those first initiating ART36, after the first year of ART1,2, among highly treatment experienced patients and among young military recruits7. It predicts well among men and women, older and younger subjects, those with and without HCV co infection, and those with and without HIV-1 viral suppression1,2,7
- It predicts cause specific mortality: VACS Index predicts both HIV and non-HIV associated mortality better than an index restricted to CD4 count, HIV-1 RNA, and age1. It predicts cardiovascular mortality as accurately as it predicts all cause mortality37.
- It improves accuracy of provider assessment of risk among HIV+/- individuals: Although providers have results of routine clinical biomarkers included in the VACS Index available at the time of assessment, provider assessments may not accurately incorporate the implications of these tests for risk of mortality. For both veterans with and without HIV infection, provider assessments of severity of illness (“How sick is this patient?”) and risk of 10 year mortality were substantially less accurate than estimates based on the VACS Index and were considerably improved when combined with the VACS Index38. Thus, the VACS Index adds important insight to provider assessment of severity of illness and risk of mortality.
How modifiable is the VACS Index?
Over the course of the first 12 months of ART, CD4 and HIV-1 RNA change dramatically, but so does level of hemoglobin, FIB 4, and, to a lesser extent, eGFR. Similarly, values differ by level of adherence to ART, by smoking, by alcohol, by HCV status, by number of non ARV medications, and by physical function. As mentioned above under responsiveness to changes in health and health behaviors, VACS Index scores rise during negative health behaviors (alcohol and substance use) and fall when these behaviors are diminished or extinguished. It is likely that successful interventions in any or all of these domains would alter the VACS Index Score. (A paper summarizing how VACS Index scores change over the first 12 months of ART using data from NA-ACCORD and ART-CC combined is currently under review.)
Why is this useful?
Potential applications of the VACS Index include mechanistic and clinical research as well as clinical care:
- Translational Research:The VACS Index can inform mechanistic studies focused on long term pathophysiologic effects of aging with HIV. We have demonstrated the superior association of the VACS Index to markers of chronic inflammation and hypercoagulability compared with an Index restricted to age, CD4 count and HIV-1 RNA11 and when compared with the Framingham Index13. Of note, hemoglobin was the single index component most associated with D-dimer11. The strong and independent association of liver injury (measured by FIB 4) and of anemia (measured by hemoglobin) with health outcomes among HIV infected individuals on ART is consistent with the theory that early changes after HIV infection undermine the gut mucosa and expose the liver to a greater burden of microbial products contributing to progressive liver dysfunction and chronic inflammation39.
- Clinical Research: Observational studies frequently struggle with issues around confounding by indication when studying post marketing treatment effects. The VACS Index could be used as a powerful adjustment either directly or as part of a propensity score. Randomized trials often need to insure that the arms of the trial are equally at risk for the observed outcome (i.e., that the randomization worked). The VACS Index offers a means of making this determination, accounting for a number of important predictors of major clinical outcomes. Conversely, randomization could be stratified by VACS Index score. Finally, change in VACS Index score could be used as a response measure for a number of diverse interventions, thereby allowing assessment of their comparative effectiveness.
- Clinical Care: Potential applications include estimating short and long term risk of morbidity and mortality, estimating life expectancy, quantifying response to interventions, and detecting HIV and non-HIV treatment toxicity. The index may also be useful in motivating behavior change and prioritizing treatment. For example, the VACS Index might help inform medical decision making regarding hospitalization, admission to the Medical Intensive Care Unit, timing of discharge, and discharge planning. The index might also inform decisions regarding frequency of clinical follow-up, elective surgical procedures, nursing home placement, and other case management issues. While the index does not include all potentially important targets for intervention (smoking, CVD risk factors, alcohol intake, ART adherence, etc.), it responds to differences in these factors and therefore reflects their effects. We are currently developing an extension of the VACS Index Calculator app (http://vacs.med.yale.edu) that would support use of the index to motivate health behavior change.
How are others using the VACS Index?
- Research: Two NIH funded alcohol intervention trials are underway which include the VACS Index as an outcome. The AIDS Clinical Trials Group has begun to use the VACS Index in randomized trials40. Independent groups have begun to use the VACS Index as a measure of frailty or severity of illness12, 13, 19, 23, 24, 41-47.
- Population Surveillance: The Public Health-Seattle & King County, HIV/STD Program and the Washington State Department of Health are using the VACS Index to monitor risk of mortality and burden of disease among people living with HIV infection over time. They found from 2008-2012 that CD4 counts were improving but overall risk of mortality based on VACS Index score remained stable.
- Clinical Management: As of July 2016, the VACS Index Risk Calculator (link above) has been accessed 76,000 times since March of 2013 and most of these represent repeated use (first time visitors 5,400). Several electronic health record (EHR) based health systems have incorporated the VACS Index as a tool in patient management directly through their EHR. These include: Fenway Healthcare System in Boston; the San Francisco General Hospital HIV clinic and University of California, San Diego Owen Clinic which has incorporated the index into their live HIV registry and reviews VACS Index scores on their patients during morning huddles and care team meetings. Further, providers caring for over 60,000 HIV infected patients (and nearly 600,000 uninfected patients) in 79 healthcare sites in the Observational Pharmaco-epidemiology Research & Analysis (OPERA) database directly access VACS Index scores through a physician portal. Information provided includes VACS Index score, trends over time overall and for the components of the index. Some sites use this data to target care to their sickest patients, while others use it in provider meetings to discuss overall patient management issues. In Italy, the VACS Index is calculated on every patient seen at the University of Modena Metabolic Clinic (a clinic of over 4000 patients) using an automated application. A group in Italy (FB Communication) is developing an Italian language app for the VACS Index for use in Italy.
- Tate JP, Justice AC, Hughes MD, Bonnet F, Reiss P, Mocroft A, et al. An internationally generalizable risk index for mortality after one year of antiretroviral therapy. AIDS 2013;27(4):563-72.
- Justice AC, Modur SP, Tate JP, Althoff KN, Jacobson LP, Gebo KA, et al. Predictive accuracy of the Veterans Aging Cohort Study index for mortality with HIV infection: a North American cross cohort analysis. J Acquir Immune Defic Syndr 2013;62(2):149-63.
- Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 2006;113(19):2335-62.
- D'Agostino RB, Sr., Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286(2):180-7.
- Yourman LC, Lee SJ, Schonberg MA, Widera EW, Smith AK. Prognostic indices for older adults: a systematic review. JAMA 2012;307(2):182-92.
- Bebu I, Tate J, Rimland D, Mesner O, Macalino GE, Ganesan A, et al. The VACS Index Predicts Mortality in a Young, Healthy HIV Population Starting Highly Active Antiretroviral Therapy. J Acquir Immune Defic Syndr 2014;65(2):226-30.
- Brown ST, Tate JP, Kyriakides TC, Kirkwood KA, Holodniy M, Goulet JL, et al. The VACS index accurately predicts mortality and treatment response among multi-drug resistant HIV infected patients participating in the options in management with antiretrovirals (OPTIMA) study. PLoS One 2014;9(3):e92606.
- Akgun KM, Tate JP, Pisani M, Fried T, Butt AA, Gibert CL, et al. Medical ICU admission diagnoses and outcomes in human immunodeficiency virus-infected and virus-uninfected veterans in the combination antiretroviral era. Crit Care Med 2013;41(6):1458-67.
- Tate JP, Brown ST, Rimland D, Rodriguez-Barradas M, Justice AC, Team VP. Comparison of VACS Index Performance in HIV-Infected and Uninfected Veterans from 2000 to 2010. 18th International Workshop on HIV Observational Databases Sitges, Spain March 27-29, 2014. 2014.
- Barakat LA, Juthani-Mehta M, Allore H, Trentalange M, Tate J, Rimland D, et al. Comparing clinical outcomes in HIV-infected and uninfected older men hospitalized with community-acquired pneumonia. HIV Med. 2015;16(7):421-30.
- Justice AC, Freiberg MS, Tracy R, Kuller L, Tate JP, Goetz MB, et al. Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? Clin Infect Dis 2012;54(7):984-94.
- Williams B, Livak B, Bahk M, Keating SM, Adeyemi OM. SCD14 and SCD163 Levels Are Correlated with VACS Index Scores: Initial Data from the Blunted Immune Recovery in CORE Patients with HIV (BIRCH) Cohort. AIDS Res Hum Retroviruses. 2015;Epub.
- Mooney S, Tracy R, Osler T, Grace C. Elevated Biomarkers of Inflammation and Coagulation in Patients with HIV Are Associated with Higher Framingham and VACS Risk Index Scores. PLoS One. 2015;10(12):e0144312.
- Williams B, Livak B, Bahk M, Keating SM, Adeyemi OM. Short Communication: SCD14 and SCD163 Levels Are Correlated with VACS Index Scores: Initial Data from the Blunted Immune Recovery in CORE Patients with HIV (BIRCH) Cohort. AIDS Res Hum Retroviruses. 2016;32(2):144-7.
- Duffau P, Wittkop L, Lazaro E, le Marec F, Cognet C, Blanco P, et al. Association of immune-activation and senescence markers with non-AIDS-defining comorbidities in HIV-suppressed patients. Aids. 2015;29(16):2099-108.
- Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, Studenski SA, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006;54(6):991-1001.
- Erlandson KM, Allshouse AA, Jankowski C, Duong S, Mawhinney S, Kohrt WM, et al. Comparison of functional status instruments in HIV-infected adults on effective antiretroviral therapy. HIV Clin Trials 2012;13(6):324-34.
- Oursler KK, Tate JP, Gill TM, Crothers K, Brown TT, Crystal S, et al. Association of the veterans aging cohort study index with exercise capacity in HIV-infected adults. AIDS Res Hum Retroviruses 2013;29(9):1218-23.
- Marquine MJ, Umlauf A, Rooney AS, Fazeli PL, Gouaux BD, Paul WS, et al. The Veterans Aging Cohort Study Index is Associated With Concurrent Risk for Neurocognitive Impairment. J Acquir Immune Defic Syndr 2014;65(2):190-7.
- Akgun KM, Gordon K, Pisani M, Fried T, McGinnis KA, Tate JP, et al. Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV infected Veterans. J Acquir Immune Defic Syndr 2013;62(1):52-9.
- Womack JA, Goulet JL, Gibert C, Brandt CA, Skanderson M, Gulanski B, et al. Physiologic frailty and fragility fracture in HIV-infected male veterans. Clin Infect Dis 2013;56(10):1498-504.
- Yin MT, Shiau S, Rimland D, Gibert CL, Bedimo RJ, Rodriguez-Barradas MC, et al. Fracture prediction with modified-FRAX in older HIV-infected and uninfected men. J Acquir Immune Defic Syndr. 2016.
- Robinson-Papp J, Sharma SK. Autonomic neuropathy in HIV is unrecognized and associated with medical morbidity. AIDS Patient Care STDS 2013;27(10):539-43.
- Escota G, Patel P, Brooks JT, Bush T, Conley L, Baker J, et al. The VACS Index is an effective tool to assess baseline frailty status in a contemporary cohort of HIV-infected persons. AIDS Res Hum Retroviruses;31(3):313-7.
- Justice AC, McGinnis KA, Tate JP, Braithwaite RS, Bryant KJ, Cook RL, et al. Risk of Mortality and Physiologic Injury Evident with Lower Alcohol Exposure Among HIV Infected Compared with Uninfected Men. Drug Alcohol Depend. In press.
- Akgun KM, Tate Jp Fau - Crothers K, Crothers K Fau - Crystal S, Crystal S Fau - Leaf DA, Leaf Da Fau - Womack J, Womack J Fau - Brown TT, et al. An adapted frailty-related phenotype and the VACS index as predictors of hospitalization and mortality in HIV-infected and uninfected individuals. J. Acquir. Immune. Defic. Syndr. 2014;67(4):397-404.
- Rockwood K, Bergman H. FRAILTY: A Report from the 3(rd) Joint Workshop of IAGG/WHO/SFGG, Athens, January 2012. Can Geriatr J 2012;15(2):31-6.
- Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J.Gerontol A Biol Sci Med Sci 2004;59(3):255-63.
- Tate J, Freiberg M, AC J. Do Risk Factors for Cardiovascular Disease Improve VACS Index Prediction of All Cause Mortality? 16th International Workshop on HIV Observational Databases (IWHOD), 3/29/2012 2012. Athens, Greece. 2012.
- Bryant K, McGinnis KA, Tate JP, Fiellin D, Justice AC. The VACS Index Score Varies By Alcohol Level In Those With HIV. 2013 Research Society on Alcoholism (RSA) Annual Conference. 2013. Orlando, Florida.
- Justice AC, McGinnis KA, Tate JP, Braithwaite RS, Bryant KJ, Cook RL, et al. Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men. Drug Alcohol Depend. 2016;161:95-103.
- Yuh B, Tate J, Butt AA, Crothers K, Freiberg M, Leaf D, et al. Weight change after antiretroviral therapy and mortality. Clin Infect Dis. 2015;60(12):1852-9.
- John M. Greene M, Hessol NA, Zepf R, Parrott AH, Foreman C, et al. Geriatric Assessments And Association With Vacs Index Among Hiv-Infected Older Adults In San Francisco. J Acquir Immune Defic Syndr. 2016.
- Tate JP, Justice AC, Team ftVP. Change in a prognostic index for survival in HIV infection after one year on cART by level of adherence. 48th Annual Meeting of the Infectious Disease Society of America. 2010;Vancouver, British Columbia.
- Marquine MJ, Montoya JL, Umlauf A, Fazeli PL, Gouaux B, Heaton RK, et al. The Veterans Aging Cohort Study (VACS) Index and Neurocognitive Change: A Longitudinal Study. Clin Infect Dis. 2016.
- Justice AC, McGinnis KA, Skanderson M, Chang CC, Gibert CL, Goetz MB, et al. Towards a combined prognostic index for survival in HIV infection: the role of 'non-HIV' biomarkers. HIV Med 2009;11(2):143-51.
- Justice AC, Tate JP, Freiberg MS, Rodriguez-Barradas MC, Tracy R. Reply to Chow et al. Clin Infect Dis. 2012.
- Justice AC, Tate JP, Brown ST, Gibert C, Rodriguez-Barradas M, Rimland D, et al. Can the Veterans Aging Cohort Study Index Improve Clinical Judgement for Both HIV Infected and Uninfected Veterans? Society of General Medicine (SGIM) 36th Annual Meeting. 2013.
- Deeks SG, Tracy R, Douek DC. Systemic Effects of Inflammation on Health during Chronic HIV Infection. Immunity. 2013;39(4):633-45.
- Tashima KT, Smeaton L, Klingman KL, Andrade A, Eron JJ, Fichtenbaum CJ, et al. Mortality among HIV+ Participants Randomized to Omit NRTIs vs. Add NRTIs in OPTIONS (ACTG A5241). 21st Conference on Retroviruses and Opportunistic Infections (CROI). 2014.
- Adeyemi O, Livak B. Higher Veterans Aging Cohort Study (VACS) index scores in HIV-positive adults with CD4 counts <200 cells/mm3 despite viral suppression. J.Acquir.Immune.Defic.Syndr. 2013;63(2):e78-e81.
- Furuya-Kanamori L, Kelly MD, McKenzie SJ. Co-morbidity, ageing and predicted mortality in antiretroviral treated Australian men: a quantitative analysis. PLoS One 2013;8(10):e78403.
- Huggan PJ, Foo RM, Olszyna D, Chew NS, Smitasen N, Mukhopadhyay A, et al. Presentation and outcome amongst older Singaporeans living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS): does age alone drive excess mortality? Ann Acad Med Singapore. 2012;41(12):581-6.
- Marquine MJ, Sakamoto M, Dufour C, Rooney A, Fazeli P, Umlauf A, et al. The impact of ethnicity/race on the association between the Veterans Aging Cohort Study (VACS) Index and neurocognitive function among HIV-infected persons. J Neurovirol. 2015;Epub.
- Cohen MH, Hotton AL, Hershow RC, Levine A, Bacchetti P, Golub ET, et al. Gender-Related Risk Factors Improve Mortality Predictive Ability of VACS Index Among HIV-Infected Women. J Acquir Immune Defic Syndr. 2015;70(5):538-44.
- Erlandson KM, Allshouse AA, Jankowski CM, MaWhinney S, Kohrt WM, Campbell TB. Functional impairment is associated with low bone and muscle mass among persons aging with HIV infection. J.Acquir.Immune.Defic.Syndr. 2013;63(2):209-15.
- Erlandson KM, Allshouse AA, Jankowski CM, Mawhinney S, Kohrt WM, Campbell TB. Relationship of physical function and quality of life among persons aging with HIV infection. AIDS. 2014;28(13):1939-43.