The VACS Index
Frequently Asked Questions and
Summary of Evidence as of July, 2017
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).. The 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 factor.(2). 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 also predicts all-cause mortality and hospitalization among those without HIV infection. The index responds to important changes in risk related to treatment and health behaviors. It improves accuracy of provider assessment (clinical judgment) of mortality risk. Specific evidence is bulleted below.
· It predicts mortality among those with HIV infection: The Index was developed in veteran patients(1) and its accuracy has been validated in other patient populations in North America and Europe(1, 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 age(1, 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 practice(3-5). Further, its accuracy is independent of length of time on antiretroviral treatment and is robust among important patient subgroups including women, people of color, those with HCV coinfection, and those over 50 years of age(1, 2, 6). It is also predicts mortality among young active duty military, relatively free of comorbid disease(7) and among those initiating salvage antiretroviral therapy after becoming resistant to at least two classes of antiretroviral therapy(8).
· 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 admission(9) and for long term (median of 5 years) mortality(10).
· When used in a time updated fashion, the VACS Index predicts acute myocardial infarction events better than time updated CD4 or HIV-1 RNA(11).
· 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 readmission(12).
· 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)(13-16). 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)(17).
· It is a superior measure of physiologic frailty: Frailty is defined as decreased ability to recover from additional injury(18). 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 performance(19) and sarcopenia(20), and with multiple measures of neuro-cognitive performance(21, 22). The VACS Index predicts morbidity including hospitalization, medical intensive care unit admission(23), and fragility fractures(24, 25). It is also associated with autonomic neuropathy(26). The VACS Index is an effective measure of physiologic frailty (6, 27-29). Few individuals demonstrated frailty based on the adapted frailty related phenotype(30).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 individuals(6, 30). Of note, the approach to frailty employed by the VACS Index is more attuned to the Rockwood conceptualization(31) of frailty as accumulation of deficits than that of Fried(32) which describes a clinical syndrome. A major advantage of using the VACS Index as an indicator of physiologic frailty is that it does not rely on administrative codes or clinical diagnoses which may be assigned in a biased manner. The laboratory values used in the index are highly standardized based on Clinical Laboratory Improvement Amendments (CLIA) requirements.
· Scores differ among important health states: VACS Index scores differ by level of smoking, alcohol consumption and hypertension(33-35). VACS Index scores predict weight gain in the first 12 months after ART initiation(36). VACS Index is associated with dependence in one or more activities of daily living(37).
· It responds to important changes in health and health behaviors: VACS Index scores change in response to antiretroviral initiation(38) and interruption(7), and discriminate among levels of ART adherence(38). Changes in VACS Index scores correspond to changes in neurocognitive function(39). 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 populations: VACS Index predicts all-cause mortality in a wide range of HIV infected populations including those first initiating ART(40), after the first year of ART(1, 2), among highly treatment experienced patients(8) and among young military recruits(7). 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 suppression(1, 2, 8).
· 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 age(1). It predicts cardiovascular mortality as accurately as it predicts all-cause mortality(41).
· It improves accuracy of provider assessment of risk: 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 Index(42). 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 do level of hemoglobin, FIB 4, and, to a lesser extent, eGFR. Values also 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.
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 stronger association of the VACS Index to markers of chronic inflammation and hypercoagulability compared with an Index restricted to age, CD4 count and HIV-1 RNA(13) and when compared with the Framingham Index(15). Of note, hemoglobin was the single index component most associated with D-dimer(13). 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 inflammation (43).
· 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 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 trials(44). Independent groups have begun to use the VACS Index as a measure of frailty or severity of illness (14, 15, 21, 26, 27, 45-51).
· 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 2017, the VACS Index Risk Calculator (link above) has been accessed 78,481 times since March of 2013 and most of these represent repeated use (first time visitors 6,220). 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.
References
1. 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.
2. 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.
3. Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation. 2006;113(19):2335-62.
4. 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.
5. Yourman LC, Lee SJ, Schonberg MA, Widera EW, Smith AK. Prognostic indices for older adults: a systematic review. JAMA. 2012;307(2):182-92.
6. Gustafson DR, Shi Q, Holman S, Minkoff H, Cohen MH, Plankey MW, et al. Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study. BMJ Open. 2017;7(6):e013993.
7. 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.
8. 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.
9. 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.