Association of Age and Comorbidity with Physical
Function in HIV-Infected and Uninfected Patients:
Results from the Veterans Aging Cohort Study
Krisann K. Oursler, M.D., Sc.M.,1Joseph L. Goulet, Ph.D., Sc.M.,2Stephen Crystal, Ph.D.,3
Amy C. Justice, M.D., Ph.D.,2Kristina Crothers, M.D.,4Adeel A. Butt, M.D., M.S.,5
Maria C. Rodriguez-Barradas, M.D.,6Knachelle Favors, M.H.,1David Leaf, M.D.,7
Leslie I. Katzel, M.D., Ph.D.,1,8and John D. Sorkin, M.D., Ph.D.1,8
HIV clinical care now involves prevention and treatment of age-associated comorbidity. Although physical
function is an established correlate to comorbidity in older adults without HIV infection, its role in aging of HIV-
infected adults is not well understood. To investigate this question we conducted cross-sectional analyses
including linear regression models of physical function in 3227 HIV-infected and 3240 uninfected patients
enrolled 2002–2006 in the Veterans Aging Cohort Study-8-site (VACS-8). Baseline self-reported physical function
correlated with the Short Form-12 physical subscale (r¼0.74, p<0.001), and predicted survival. Across the age
groups decline in physical function per year was greater in HIV-infected patients (bcoef?0.25, p<0.001) com-
pared to uninfected patients (bcoef?0.08, p¼0.03). This difference, although statistically significant (p<0.01),
was small. Function in the average 50-year old HIV-infected subject was equivalent to the average 51.5-year-old
uninfected subject. History of cardiovascular disease was a significant predictor of poor function, but the effect
was similar across groups. Chronic pulmonary disease had a differential effect on function by HIV status (Dbcoef
?3.5, p¼0.03). A 50-year-old HIV-infected subject with chronic pulmonary disease had the equivalent level of
function as a 68.1-year-old uninfected subject with chronic pulmonary disease. We conclude that age-associated
comorbidity affects physical function in HIV-infected patients, and may modify the effect of aging. Longitudinal
research with markers of disease severity is needed to investigate loss of physical function with aging, and to
develop age-specific HIV care guidelines.
ease and cardiovascular risk factors,1–4chronic pulmonary
disease,5–7low bone mineral density,8and frailty9supports
the concern that chronic HIV infection and prolonged anti-
retroviral therapy might be associated with an accelerated
aging process.2,5,7,10,11In adults without HIV, history of these
in HIV-infected patients, including coronary artery dis-
age-associated conditions is an independent risk factor for
decline in physical function with aging.12–16The purpose of
this study was to investigate the effect of age-associated
conditions on physical function in HIV-infected patients
compared to uninfected patients with similar demographic
characteristics and medical care setting. Prior to combination
antiretroviral therapy (cART) physical function in HIV-
infected patients was studied in younger adults with AIDS.17
Limitation with activities of daily living (ADL) was common,
1University of Maryland School of Medicine, Veterans Affairs Maryland Healthcare System, Baltimore, Maryland.
2Yale University School of Medicine and Public Health, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
3Center for Health Services Research on Pharmacotherapy, Chronic Disease Management, and Outcomes, Institute for Health, Rutgers
University, New Brunswick, New Jersey.
4University of Washington, Seattle, Washington.
5University of Pittsburgh School of Medicine, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
6Michael E. DeBakey VA Medical Center, Department of Medicine, Baylor College of Medicine, Houston, Texas.
7UCLA School of Medicine, Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California.
8Baltimore Veterans Affairs Medical Center Geriatric Research, Education, and Clinical Center, Baltimore, Maryland.
AIDS PATIENT CARE and STDs
Volume 25, Number 1, 2011
ª Mary Ann Liebert, Inc.
and was associated with leg muscle atrophy and weakness in
the setting of AIDS wasting syndrome.18Research in the
cART era shows that ADL capacity is preserved in more than
90% of the HIV-infected patients, but these patients remain
limited in vigorous activities (exercise, walking hills, heavy
work).19,20The prevalence of age-associated conditions, such
as chronic lung disease and coronary artery disease, was as-
sociated with decreased self-reported physical function in a
2001–2002 cross-sectional study of 889 HIV-infected and 647-
uninfected veterans.20Association of the conditions with
function was independent of age, race, and smoking history
and was not affected by HIV status. However, only 88 (10%)
of the HIV-infected patients were 60 years of age and older.
We hypothesized that older HIV-infected patients would
have greater limitations in function compared to older un-
infected patients, and that this effect would be amplified
by cardiac and pulmonary disease. We conducted a cross-
sectional study to investigate the relationship of self-reported
physical function with prevalent age-associated conditions
defined by ICD-9 codes at the baseline visit for HIV-infected
and -uninfected patients enrolled in the Veterans Aging Co-
hort Study- 8 site (VACS-8), an ongoing longitudinal study.21
Mortality data currently available during follow-up were
used to test construct validity of function survey items.
VACS-8 participants are enrolled prospectively from eight
VA Medical Centers and include patients with HIV infection
followed in infectious disease clinics, and age and race group-
matched uninfected patients followed in general medicine
clinics.21All participants provided written informed consent
for the protocol, which is approved by the respective In-
stitutional Review Board (IRB) and VA research and devel-
is ongoing. Patients provide information on physical activity,
smoking, alcohol use, illicit drug use, health-related quality of
life (SF-12), and demographic characteristics at study entry
and then yearly. Clinical and administrative data are ab-
stracted from the VA electronic medical record using meth-
odology validated by chart review21(details available,
www.vacohort.org). Comorbid conditions are defined by
ICD-9 diagnostic codes and require at least one inpatient or
two outpatient encounters within 12 months prior to or 6
months after study enrollment to be considered present at
baseline.22For this analysis comorbid conditions were chosen
based on available ICD-9 data, and plausible relationship
with physical function in HIV-infected patients20and unin-
fected patients.12For instance, despite the increased risk of
low bone mineral density8,23and certain cancers in HIV-
infected patients, and the probable impact on function, these
conditions were not included since VACS-8 data are not yet
available. Patients were classified with chronic obstructive
lung disease if they had a diagnosis of chronic obstructive
pulmonary disease (COPD; including ICD-9 codes for bron-
chitis and emphysema) or asthma, based on VACS research
focused on obstructive lung disease and relationship to
smoking and mortality.24,25The analytic set includes baseline
data collected from 2002–2006 in 3227 HIV-infected patients
and 3240 uninfected patients. Only 213 individuals were ex-
luded because of incomplete survey items for physical func-
tion. In the HIV group CD4 cell count, HIV-1 viral load, and
hemoglobin concentration at baseline were available for 90%
of the patients.
Physical function was quantified using the VACS function
questions included in the VACS-5 survey20and originally
adapted from the HIV Cost and Services Utilization Study
(HCSUS; available online, www.vacohort.org). The questions
span the continuum from basic activities of daily living
(feeding, bathing, and dressing one’s self) to instrumental
activities of daily living (light, moderate, and heavy types of
work), mobility (walking a few steps, walking inside, and
walking one block) and vigorous activity (walking uphill,
running, sports). Patients report their current ability to per-
form each physical activity. For analysis of VACS-8 data, we
refined the previously used scale20to facilitate comparison
with physical function scales in the HIV literature.26,27First,
we scored the items so that higher numbers represented
but slowly¼1, yes¼2). Then, we transformed the raw scale
to a scale of zero to 100 by dividing the sum by the maximum
possible score (24) and multiplying by 100. The interitem
consistency of the scale and domains were tested using
Cronbach a and factor analysis. To assess the content validity
we tested the VACS function scale and the physical com-
ponent scale of the SF-12 by Spearman’s r. To assess con-
struct validity, we performed survival analyses to determine
whether baseline physical function measured by the VACS
function scale predicted death through the most recent
Differences in clinical characteristics between HIV-
infected and uninfected patients were assessed using log-
linear models adjusted for demographic factors after initial
univariate comparisons by t-test or chi-squared test. The
function scale was used as the main outcome measure in
linear regression models. Parallel models stratified by HIV
status tested the association of function with independent
variables (demographics, lifestyle factors, comorbidity) for
each patient group. Differences in the b coefficient of the
independent variables between HIV-positive and HIV-
negative models were tested using a z statistic. To test for
effect modifiers, independent variables that were signifi-
cantly different (p<0.05) in the stratified analysis were in-
cluded in a single combined multivariable model with all
subjects and an HIV-interaction term. In order to provide a
clinical context for the impact of effect modifiers (x), age
equivalent function in an uninfected subject was calculated
for a 50-year-old HIV-infected subject. First we computed
the predicted function in HIV-infected subjects alone
(gHIV¼b0þb1ageþb2x) using age¼50 years. Then using
this function outcome (yHIV) we solved for age of uninfected
subjects using coefficients derived from the model in unin-
fected subjects alone.
Cox regression was used to test the association of mortality
with baseline physical function, categorized as impaired
(lowest tertiary, score<67), moderate limitations (score 67–
99), and no limitations (score¼100). Eight subjects did not
have any follow-up data. The remaining subjects were in-
cluded in the survival analysis that included event data
through follow-up visit 4. Subjects were censored at the date
of their last survey. Cox proportional hazards models were
tested for proportionality assumption and were valid. Sig-
nificance was defined as a two-tailed a of 0.05.
14OURSLER ET AL.
The age distribution was similar in HIV-infected and un-
infected patients (mean years?standard deviation [SD],
49.5?8.7 versus 50.7?10.0). Differences in lifestyle factors
and comorbid conditions between groups adjusted for
demographic factors (age, race, gender) are summarized in
Table 1. HIV-infected patients reported exercising less fre-
quently than uninfected patients (p¼0.03). When this anal-
ysis was stratified by age, exercise frequency remained lower
among older HIV-infected patients (age?55 years, p¼0.05),
but was similar between younger HIV-infected and unin-
fected patients (age?44 years, p¼0.1).
Factor analysis showed that the VACS physical function
scale had a single domain with high degree of interitem
consistency (Cronbach a¼0.9). A ceiling effect was present;
35% of the subjects reported no limitations in physical activ-
ities (score of 100). The VACS physical function score corre-
lated with the SF-12 physical subscale (r¼0.74 p<0.001),
function score (adjusted mean?standard error [SE]), was
significantly higher in patients who exercised weekly 5 or
more times (86.0?0.8), 3–4 times (85.0?0.7), 1–2 times
(81.8?0.8), and less than once (77.0?0.8) compared to pa-
tients who never exercised (68.0?0.9; all p<0.001). The me-
dian follow-up time was 5.2 years (interquartile range [IQR]
4.2–5.7 years). During this time, 560 (18.0%) of the HIV-
infected patients and 232 (7.4%) of the uninfected patients
died. Patients with functional impairment (those scoring
below 67,lowesttertile)had atwo-fold increased riskofdeath
compared to patients without any functional impairment
clinical characteristics (Table 2).
HIV infection, age, and physical function
There was no significant difference in the mean physical
function score between HIV-infected patients (mean?SD;
multivariable model including demographic and clinical
factors for all subjects, physical function was significantly
lower in HIV-infected patients compared to uninfected
patients, but the effect was very modest (bHIV?1.3, 95% con-
fidence interval [CI] [?2.3, ?0.2] p¼0.02). In the stratified HIV
model higher HIV-1 viral load (log10copies per milliliter) was
not remain significant in the multivariable model (Table 3).
Patients with a hemoglobin ?12g/dL had on average a
7-point lower score than those with higher hemoglobin.
Patients who were within 180 days of starting combination
antiretroviral therapy (cART, 3 or more antiretroviral medica-
tions) at baseline had worse function compared to patients not
receiving cART. However, there was no significant difference
for patients who had been on cART for greater than 180 days.
The decline in physical function score associated with
each additional year of age was three times greater for
HIV-infected patients (bHIVþ?0.25, 95% CI [?0.33, ?0.17])
CI [?0.16, ?0.01]; Table 4). Stratified analysis by age group
Table 1. Description of Study Population
by Demographic and Clinical Characteristics
n % Total
n % Total p Valuea
Body mass index
History of alcohol
History of injection
ap Value for difference between HIV-uninfected and HIV-infected
patients, w2tests used for demographic characteristics, log linear
regression models adjusted for demographics used for lifestyle and
bHow often engage in regular activities (e.g., brisk walking,
jogging, etc.) long enough to work up a sweat?
cHistory of alcohol disorders by ICD-9 codes; Injection drug use,
prior self-reported use.
dPulmonary disease included chronic obstructive pulmonary
disease (bronchitis and emphysema) or asthma.
HIV AND PHYSICAL FUNCTION 15
and HIV status showed better function in the younger (?44
years) HIV-infected patients compared to the uninfected
(p<0.01), and worse function in the older (>55 years) HIV-
infected patients compared to the uninfected (p<0.01; Fig. 1).
Although the HIV-age interaction was statistically significant
(HIV*age ßcoeff¼?0.17, p<0.01), function differences were
small. In terms of equivalent years without adjustment for
comorbidity, the average 50-year-old HIV-infected subject
had the same level of function as the average 51.5-year-old
Comorbid conditions and physical function
HIV-infected and uninfected patients with a history of
cardiovascular disease, including congestive heart failure,
coronary artery disease, peripheral vascular disease, and
stroke had on average function scores 9–12 points lower than
patients without the condition (Table 4). Diagnosis of hyper-
tension was significantly associated with worse physical
function controlled for demographic factors (bHTN?2.8, 95%
CI [?3.9, ?1.8]) but was no longer significant in the multi-
variable model. These relationships were similar in HIV-
infected and uninfected patients.
The independent effect of the history of chronic obstructive
lung disease on function was greater in HIV-infected patients
(Fig. 2). Physical function adjusted for demographic, lifestyle,
and comorbidity factors was comparable in HIV-infected and
uninfected patients without pulmonary disease across all age
groups. However, among patients with pulmonary disease,
HIV-infected patients had significantly worse function com-
had the equivalent level of function as a 68.1-year old unin-
fected subject. These results were confirmed in the full multi-
variable model; the interaction term for HIV and pulmonary
disease was significant (HIV*pulmonary ßcoeff¼?3.6, 95% CI
[?6.6, ?0.4], p¼0.03).
Obesity, based on body mass index (BMI)?30, was
associated with poor function in uninfected patients but
not in HIV-infected patients (Table 4). Being underweight
(BMI<18.5) was associated with poor function in HIV-
infected patients, but not in uninfected patients. However,
these differences in the relationship of BMI group and func-
tion by HIV status were small and were not statistically sig-
nificant (Table 4).
Among HIV-infected patients, history of diabetes was not
associated with function when adjusted for effect of BMI and
comorbidity (Table 4). However, in uninfected patients dia-
betes was significantly related to function. This differential
effect of diabetes on function by HIV status was statistically
significant, and reflected the finding that a 50-year-old
diabetic HIV-infected subject had the equivalent level of
function as a 36-year-old diabetic uninfected subject.
In this cross-sectional study we compare physical function
of HIV-infected patients to uninfected patients who are de-
mographically similar and under care in the same medical
the established SF-12physical subscale, and is associated with
differential survival. The majority of patients in this clinic-
based cohort are 50 years of age and older in both patients
groups, a frequently used benchmark to designate older HIV-
relationship of age and function with comorbidity between
HIV-infected and uninfected patients.
function between younger and older patients was greater in
HIV-infected patients compared to the uninfected patients,
adjusted forcomorbidity.The magnitudeoftherateofdecline
Table 2. Baseline Physical Function Independently Predicts Mortality
Physical function at baselineN (%)HR 95% CI HR95% CI
No limitations (score¼100)
Severe limitations (score <67, lowest 20%)
aAdjusted for demographic characteristics, baseline lifestyle factors, and comorbid conditions.
HR, hazard ratio; CI, confidence interval.
Table 3. Association of Physical Function
with HIV-Related Factors Based on a Multivariable
Linear Regression Model Including Demographic
and Clinical Variables Listed in Table 1
CharacteristicNb 95% CIp Value
HIV-1 RNA, per
cART history in
Cumulative use, days
cART, combination antiretroviral therapy; CI, confidence interval.
16 OURSLER ET AL.
in function across the age groups was greater in the HIV-
infected patients. In both the 50–54 and 55þage groups
physical function was worse in the HIV-infected patients.
These results are supported by exercise performance testing
that shows significantly lower aerobic capacity among older
HIV-infected patients compared to age-matched uninfected
adults.28It should be noted in the younger (age?44 years)
than uninfected patients. Only this age group of HIV-infected
patients had similar frequency of exercise compared to the
of physical inactivity in worse physical function among older
In the general medical literature, poor physical function is
strongly associated with cardiovascular disease (CVD), in-
cluding coronary artery disease, congestive heart failure,
peripheral vascular disease, and stoke.12,13,15,16Forall of these
conditions we found a significant independent association
Table 4. Multivariable Linear Regression Models of Physical Function
in HIV-Infected and Uninfected Subjects
bp Valuebp Value DeltaSEp Valuea
Age, per year
Body mass index (BMI, kg/m2)
Overweight (BMI 25.0–29.9)
History of alcohol disorders
Congestive heart failure
Coronary artery disease
Peripheral vascular disease
?0.08 (?0.16, ?0.01)
<.0001 ?0.17 0.06
(?10.14, ?6.32) <0.0001 ?4.9
(?10.28, ?3.18) <0.01
?9.5(?14.49, ?4.51) <0.001
<.0001 ?2.11 2.04
<0.0001 ?1.64 1.26
<0.0001 ?3.48 1.60
ap value between groups.
bPulmonary disease includes chronic obstructive pulmonary disease (bronchitis and emphysema) or asthma.
Reference groups: white race, normal BMI (18.6-24.9), former/never smoker, and for each comorbidity, patients without the condition
based on ICD-9 codes.
CI, confidence interval.
<44 yrs45-49 yrs 50-54 yrs >55 yrs
Mean function score, predicted
HIV negativeHIV positive
function score by HIV status and age group based on mul-
tivariable models. *p<0.05.
Mean (standard error [SE]) of predicted physical
<44 yrs45-49 yrs50-54 yrs>55 yrs
Mean function score, predicted
HIV neg, No Lung Ds.
HIV +, Yes Lung Ds.
HIV +, No Lung Ds.
HIV neg,Yes Lung Ds.
status for patients with and without lung disease (lung ds.)
by subject age group based on multivariate models.
Mean predicted physical function score by HIV
HIV AND PHYSICAL FUNCTION17
with function in HIV-infected patients that was similar to
uninfected patients. Given that HIV-infected patients may
have increased risk of coronary heart disease and cardiac
of physical disability in HIV-infected patients who are oth-
erwise stable on cART, and thus provides additional incen-
tive to reduce cardiac risk factors.4Although none of the
CVD conditions in our study were associated with worse
function in HIV-infected patients compared to uninfected
patients, our function scale may be unable to distinguish
these differences given the scale’s ceiling effect. In addition,
self-report in general may be limited in its capacity to mea-
sure specific functional performance parameters, such as
endurance, which are related to cardiovascular disease. For
instance, exercise treadmill testing has shown that aerobic
capacity is reduced 16% in older HIV-infected men with
hypertension compared to those without hypertension.30
Further research is needed to investigate the specific mech-
anisms underlying poor function for different types of CVD,
and whether differences exist between HIV-infected and
In contrast, the VACS function score clearly showed an
additive effect of chronic obstructive lung disease and HIV on
physical function. The results were consistent across the age
groups with adjustment for other comorbid conditions and
smoking history. Chronic pulmonary disease is indepen-
dently related to functional limitations in uninfected
adults,31,32and may occur more frequently in HIV-infected
adults.5–7Our results suggest that among those with chronic
obstructive lung disease, HIV-infected patients have worse
physical function compared to uninfected patients. However,
conclusions should be tempered given the lack of information
on lung function. Physical function in HIV-infected patients
among those with chronic pulmonary disease could be worse
due to either accelerated progression33or longer duration of
lung disease. A third possibility is a confounding factor re-
lated to both chronic pulmonary disease and function. Recent
research shows that the adjusted risk of lung cancer, pulmo-
nary hypertension and pulmonary fibrosis is greater in HIV-
infected compared to uninfected patients.6Although these
conditions may be less common, they are associated with
chronic lung disease and were not considered in our analyses.
While understanding these mechanisms is beyond the scope
of this study, the results support an HIV aging interaction
driven by comorbidity that warrants further investigation.
With regard toHIV care, this finding supports the importance
of smoking cessation.24,34
Finally, the contrasting results for BMI and diabetes in
HIV-infected versus uninfected patients highlights the
challenge of differentiating effects of medication, HIV
infection, and aging. HIV-infected patients classified as
obese by BMI likely represent a heterogeneous group, which
includes those experiencing a restoration to health phe-
nomenon that comes with successful antiretroviral therapy.
This supposition is supported by the Nutrition for Healthy
Living study, a prospective longitudinal study that showed
thatHIV-infectedmenwitha five kilogramor largerincrease
in total body weight reported improvement in physical
Importantly, HIV-infected individuals have
experienced the effects of obesity for a shorter period of time
than uninfected subjects since they were likely thinner
prior to receiving cART treatment. The attenuated negative
association of diabetes with function in the HIV-infected
group supports this possibility. However, our findings are
limited without data on duration or severity of diabetes, and
need to be investigated further. In addition, anthropomet-
rics may provide information that is missed by measure of
Our findings confirm that advanced HIV disease is asso-
ciated with worse physical function. However, in comparison
to earlier studies which focused on the effect of AIDS on
function,17the majority of HIV-infected VACS participants
receive cART and have high CD4 cell counts. Our findings
demonstrate that age-related comorbidity should be consid-
ered an important risk factor for poor physical function in this
clinical setting. For example, history of congestive heart fail-
ure is independently associated with a 10-point lower func-
tion score, compared to a low CD4 cell count (<200 cells/
cm3), which is associated with a 3-point lower score. Unlike
our preliminary study,20in this larger cohort with over 1450
patients with hepatitis C infection, the relationship between
hepatitis C and function was similar in HIV-infected and
uninfected patients (Table 4). The absence of a significant in-
teraction was confirmed in the full multivariable model
(HIV*HCV ßcoeff¼?1.7, p¼0.1). However, further work is
needed to investigate this relationship as we defined hepatitis
C infection by ICD-9 code and did not differentiate cases by
ongoing viral replication, nor severity of liver disease.
The primary limitation of the study is related to the cross-
sectional design. We report a decline in function with age that
that compares individuals at different ages, not a within-
person difference in rate of decline. Therefore, findings could
reflect selection or cohort effects, and require confirmation in
longitudinal analysis. An additional limitation is the defini-
tion of comorbid conditions by history only, without data on
disease severity and duration. While most cross-sectional
studies are limited to prevalent cases, it is possible that du-
ration and severity of some comorbid conditions may be
greater in HIV-infected patients and then translate to worse
function. Self-reported limitations in physical activities allow
for measure of function within the social context, but can be
proportion of patients that denied any physical limitations.
function in community dwelling HIV-infected patients,26it
limits the ability to investigate higher level of functioning.
of causal inference, they provide important direction for fu-
ture research in aging and physical function.
In summary, age-associated comorbidity affects physical
function in HIV-infected patients. Longitudinal research with
measure of disease incidence and severity is needed to de-
termine if there is an accelerated loss of function with aging.
However, our results highlight the potential role of co-
morbidity as an effect modifier in the relationship of HIV and
aging. The study supports further integration of primary
health care and prevention into HIV care with increased focus
on age-associated comorbidity.36
Supported by the National Institutes of Health (NIH)
K23AG024896 (K.K.O.); U01AA13566 (A.C.J.); R01HL090342
(K.C.); R01MH058984 (S.C.); University of Maryland Claude
18OURSLER ET AL.
D. Pepper Older Americans Independence Center P60AG
028747 (K.K.O., L.I.K., J.D.S., K.F.), and Department of Ve-
terans Affairs Baltimore Geriatric Research, Clinical and
Education Center (L.I.K., J.D.S.).
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Krisann K. Oursler, M.D., Sc.M.
Department of Medicine
University of Maryland School of Medicine
10 North Greene Street
Baltimore, MD 21201-1524
20 OURSLER ET AL.