The VACS Index
Frequently Asked Questions and
Summary of Evidence as of January, 2015
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 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,
Table 1. The VACS Index
cause specific mortality, and other outcomes
in those living with HIV infection. If one
Component
Level
Points
assumes that uninfected patients have no
Age (years)
<50
0
HIV-1 RNA titer and a CD4 cell count at or
50 to 64
12
above 500 cells/mm3, it predicts all cause
> 65
27
mortality and hospitalization among those
3
without HIV infection. It responds to important
CD4 (cells/mm )
> 500
0
changes in risk related to treatment and health
350 to 499
6
behaviors. It improves upon the accuracy of
provider assessment (clinical judgment) of
200 to 349
6
mortality risk. Specific evidence is bulleted
100 to 199
10
below.
50 to 99
< 50
HIV-1 RNA (copies/ml)
< 500
0
500 to 99,999
7
> 1x105
Hemoglobin (g/dL)
FIB-4
> 14
0
10
10 to 11.9
22
< 10
38
< 1.45
0
1.45 to 3.25
6
25
> 60
0
45 to 59.9
6
30 to 44.9
8
< 30
Hepatitis C Co-Infection
14
12 to 13.9
> 3.25
eGFR (mL/min)
28
29
26
5

It predicts mortality among those in
treatment with HIV infection: The
Index was developed in veteran
patients(1) and its reproducible
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 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) It is also highly
predictive of mortality among young
active duty military relatively free of comorbid disease(6) and among those initiating salvage
antiretroviral therapy after becoming resistant to at least two classes of antiretroviral therapy(7).

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 demonstrated for 30-day mortality from MICU admission(8)
and for long term (median of 5 years) mortality(9)

It predicts 30 day mortality, length of stay, and readmissions after bacterial
pneumonia among HIV infected and uninfected older (50+ years) veterans (Barakat,
IDSA 2013). This paper is currently in press.

It is associated with frailty: frailty is defined as decreased ability to recover from
additional injury.(10) It is associated with increased risk for a number of adverse
outcomes including mortality, hospitalization, geriatric syndromes (falls, fragility fractures,
and cognitive decline) and is strongly associated with chronic inflammation. The VACS
Index is correlated with markers of chronic inflammation, microbial translocation, and
hypercoagulability (IL-6, soluble CD14, D-dimer)(11), with measures of functional
performance(12) and sarcopenia(13), and with multiple measures of neuro cognitive
performance(14). The VACS Index predicts morbidity including hospitalization, medical
intensive care unit admission(15), and fragility fractures(16). It is also associated with
autonomic neuropathy(17). It is likely an excellent measure of physiologic frailty. 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. Few individuals demonstrated frailty based upon the adapted
frailty related phenotype(18). Of note, the approach to frailty employed by the VACS
Index is more attuned to the Rockwood conceptualization(19) of frailty as accumulation of
deficits than that of Fried(20) which describes a clinical syndrome.

It responds to important changes in health and health behaviors: VACS Index
scores change in response to antiretroviral initiation(21) and interruption(6), and
discriminate among levels of ART adherence(21). VACS Index scores differ by level of
smoking, alcohol consumption and hypertension(22, 23). 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 is strongly
predictive of all-cause mortality in a wide range of HIV infected populations including
those first initiating ART(24), after the first year of ART(1, 2), among highly treatment
experienced patients(7) and among young military recruits(6). 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, 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 age(1).
It predicts cardiovascular mortality as accurately as it predicts all cause mortality(25).

It improves accuracy of provider assessment of risk among HIV+/- individuals:
Despite the fact that providers have results of the routine clinical biomarkers included in
the VACS Index available at the time of assessment, provider assessments do not
accurately incorporate the implications of these tests for risk of mortality among those
with or without HIV infection. 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 upon the VACS Index and were
considerably improved when combined with the VACS Index(26). 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 under review.)
Why is this useful?
Potential applications of the VACS Index include mechanistic and clinical research as well as clinical
care:
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 (IL-6, d-dimer, and soluble CD14) compared with an Index
restricted to age, CD4 count and HIV-1 RNA. Of note, hemoglobin was the single index component most
associated with D-dimer(11). The strong and indendent 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 thatearly 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(27).
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 taking into account 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, mapping 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, the 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 the 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 (28)
Independent groups have begun to use the VACS Index as a measure of frailty or severity of illness(17,
29-31).
Clinical Care: As of January 2015, the VACS Index Risk Calculator (link above) has been accessed
>73,000 times since March of 2013 and most of these represent repeated use. Fenway Healthcare
System in Boston is exploring using the VACS Index to identify patients for intensive case management.
The San Francisco General Hospital HIV clinic has incorporated the VACS Index scoring into its
electronic medical record and is using it in patient management. 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 (FBCommunication) is developing an Italian language ap for
the VACS Index for use in Italy.
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