VACS Index Information and VACS Calculator

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, 6. It is also highly predictive of mortality among young active duty military relatively free of comorbid disease7 and among those initiating salvage antiretroviral therapy after becoming resistant to at least two classes of antiretroviral therapy8.
• 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 admission9 and for long term (median of 5 years) mortality10.
• When used in a time updated fashion, the VACS Index predicts acute myocardial infarction events better than time updated CD4 or HIV-1 RNA11.
• 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 readmission12
• 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 injury18. 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 performance19 and sarcopenia18, and with multiple measures of neuro-cognitive performance21, 22. The VACS Index predicts morbidity including hospitalization, medical intensive care unit admission23, and fragility fractures24, 25. It is also associated with autonomic neuropathy26. The VACS Index is an effective measure of physiologic frailty 27-29. Few individuals demonstrated frailty based on the adapted frailty related phenotype30. 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 individuals30. Of note, the approach to frailty employed by the VACS Index is more attuned to the Rockwood conceptualization31 of frailty as accumulation of deficits than that of Fried32 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 initiation38 and interruption7, and discriminate among levels of ART adherence38. Changes in VACS Index scores correspond to changes in neurocognitive function39. 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 ART40, 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, 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 age1. It predicts cardiovascular mortality as accurately as it predicts all cause mortality41.
• 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 Index42. Thus, the VACS Index adds important insight to provider assessment of severity of illness and risk of mortality.

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.

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 RNA13 and when compared with the Framingham Index15. Of note, hemoglobin was the single index component most associated with D-dimer13. 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 inflammation43. C
• 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.

• 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 trials44. Independent groups have begun to use the VACS Index as a measure of frailty or severity of illness14, 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.

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