Nonantiretroviral polypharmacy and adverse health

outcomes among HIV-infected and

uninfected individuals
Amy C. Justicea, Kirsha S. Gordona, Melissa Skandersona,
Eva Jennifer Edelmana, Kathleen M. Akgüna, Cynthia L. Gibertb,
Vincent Lo Re IIIc, David Rimlandd, Julie A. Womacke,
Christina M. Wyattf, Janet P. Tatea, for the VACS Project Team

Background: HIV-positive individuals (HIVþ) on antiretrovirals commonly take enough

other medications to cross a threshold for polypharmacy but little is known about
associated outcomes. We asked whether non-antiretroviral polypharmacy is associated
with hospitalization and mortality and whether associations differ by HIV status.
Methods: Data on HIVþ and uninfected individuals in the US Veterans Affairs
Healthcare System were analyzed. Eligible HIVþ were on antiretrovirals with sup-
pressed HIV-1 RNA and uninfected individuals received at least one medication. We
calculated average non-antiretroviral medication count for fiscal year 2009. As there is
no established threshold for non-antiretroviral polypharmacy, we considered more than
two and at least five medications. We followed for hospitalization and mortality (fiscal
year 2010–2015), adjusting for age, sex, race/ethnicity and VACS Index.
Results: Among 9473 HIVþ and 39 812 uninfected individuals respectively, non-
antiretroviral polypharmacy was common (>2: 67, 71%; 5: 34, 39%). VACS Index
discriminated risk of hospitalization (c-statistic: 0.62, 0.60) and mortality (c-statistic: 0.72,
0.70) similarly in both groups. After adjustment, more than two (hazard ratio 1.51, 95% CI
1.46–1.55) and at least five non-antiretrovirals (hazard ratio 1.52, 95% CI 1.49–1.56)
were associated with hospitalization with no interaction by HIV status. Risk of mortality
associated with more than two non-antiretrovirals interacted with HIV status (P ¼ 0.002),
but not for at least five (adjusted hazard ratio 1.43, 95% CI 1.36–1.50). For both groups
and both outcomes, average medication count demonstrated an independent, dose
response, association.
Conclusion: Neither severity of illness nor demographics explain a dose response,
association of non-antiretroviral polypharmacy with adverse health outcomes among
HIVþ and uninfected individuals.
Copyright ß 2018 The Author(s). Published by Wolters Kluwer Health, Inc.

AIDS 2018, 32:739–749

Keywords: adverse drug events, HIV, hospitalization, mortality, polypharmacy,

United States veterans, VACS Index

a
Veterans Affairs Connecticut Healthcare System, Yale University School of Medicine and Public Health, West Haven,
Connecticut, bWashington DC Veterans Affairs Medical Center and George Washington University School of Medicine and
Health Sciences, Washington, DC, cDepartment of Medicine (Infectious Diseases), Department of Biostatistics and Epidemiology,
Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, dEmory University School of Medicine, Atlanta, Georgia, eVA
Connecticut Healthcare System and Yale School of Nursing, West Haven, Connecticut, and fIcahn School of Medicine at Mount
Sinai, New York City, New York, USA.
Correspondence to Amy C. Justice, MD, PhD, VA Connecticut Healthcare System, Yale University School of Medicine and Public
Health, 950 Campbell Avenue, Building 35a Room 2-212 (11-ACSLG), West Haven, CT 06516, USA.
Tel: +1 203 932 5711 x3541; fax: +1 203 937 4926; e-mail: [email protected]
Received: 21 September 2017; revised: 14 November 2017; accepted: 25 November 2017.
DOI:10.1097/QAD.0000000000001756
ISSN 0269-9370 Copyright Q 2018 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the
terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and
share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 739
740 AIDS 2018, Vol 32 No 6

Introduction dose–response association exists between the number of

non-antiretroviral medications and risk of hospitalization
In observational studies of the general population, the use or mortality.
of more than five concurrent medications constitutes
polypharmacy [1]. In this group, polypharmacy is
widespread and associated with adverse drug events,
inappropriate prescribing, falls, cognitive compromise, Methods
hospitalization, and mortality [2,3]. Combination antire-
troviral treatment for HIV infection with three or more Study overview
medications dramatically improves morbidity and extends We conducted a prospective analysis of the VACS
survival but requires life-long treatment. Yet, antiretro- described previously [21]. Briefly, VACS is a cohort of
virals are known to have many drug–drug interactions HIVþand uninfected individuals matched 1 : 2 on age, sex,
with commonly co-prescribed medications [4,5]. If two race/ethnicity, and site of care identified from the United
or more non-antiretroviral medications are added, HIV- States Veterans Health Administration (VA) administrative
positive individuals (HIVþ) would conventionally cross data. Baseline was established in fiscal year 2009 (1 October
the threshold for polypharmacy [6]. Yet, no group has 2008 to 30 September 2009). Data were obtained from the
established a threshold for non-antiretroviral polyphar- VA corporate data warehouse and included demographic
macy among HIVþ based on associations with hospitali- characteristics, hospital and outpatient diagnoses [recorded
zation or mortality or compared associations with using International Classification of Diseases, Ninth
demographically similar uninfected individuals. Instead, Revision (ICD-9) codes], laboratory results, and dispensed
studies characterizing non-antiretroviral polypharmacy in medications from the Pharmacy Benefits Management
HIVþ have considered only potentially inappropriate (PBM) Program. United States Medicare claims data were
medications because of drug–drug interactions or side available for veterans also enrolled in this program and were
effects [4,5,7–10]. merged with the VACS data. Patients were followed
through September 2015.
Of special note, non-antiretroviral medications are
prescribed to treat comorbid health conditions, as Study population
prophylaxis, or to treat adverse effects of antiretrovirals. We included HIVþ individuals receiving ART and
Severity of illness because of comorbid conditions, not uninfected individuals who were receiving at least one
polypharmacy, may explain observed associations (con- prescription medication from the VA in fiscal year 2009.
founding by indication) [11]. Although only a random- HIVþ individuals were considered to be on ART if they
ized trial can completely address this issue, adjusting for were prescribed three or more antiretroviral agents,
severity of illness using an accurate and validated excluding low-dose ritonavir. We required uninfected
prognostic index can help. However, few studies in the individuals to be on at least one VA dispensed medication
general population and no study among HIVþ, have to insure that they were obtaining medications from the
adjusted for severity of illness. In the general population, VA. Among patients alive at the end of fiscal year 2009,
the studies that have adjusted for severity of illness have we excluded patients who had any cancer diagnosis
used self-reported functional status, health status, or except nonepithelial skin cancer (n ¼ 1874) as their
comorbid conditions [11,12]. Such measures are often severity of illness may not be adequately reflected in the
based on self-report or administrative diagnostic codes VACS Index; ambiguous HIV status (n ¼ 99) to make a
and provide limited discrimination of mortality [13–15]. clear comparison between HIVþ and uninfected
No prior study associating polypharmacy with health individuals; HIVþ individuals who were not virally
outcomes, among those with or without HIV infection, suppressed (>400 HIV-1 RNA copies/ml) in the last 6
has used a well validated, highly discriminating, index to months of baseline fiscal year 2009 (n ¼ 9018) – we
comprehensively adjust for severity of illness. sought to study polypharmacy among those on successful
ART; 4) no VACS index score (n ¼ 4085); and on more
On the basis of routine clinical laboratory data, the than 15 medications to eliminate highly leveraged
Veterans Aging Cohort Study (VACS) Index has been observations (n ¼ 534, 1% of the analytic sample).
widely validated as a highly discriminating measure of
severity of illness [16,17]. It accurately and reproducibly Nonantiretroviral medication count and
predicts all-cause mortality among those with and polypharmacy
without HIV infection and is associated with hospitaliza- We determined receipt of all outpatient preparations (i.e.
tion [18–20]. In this study, we compare nonantiretroviral oral, inhaled, or injectable) of medications dispensed
polypharmacy, considering both more than two and at through the VA using prescription pharmacy fill/refill
least five thresholds, between HIVþand demographically data [21]. We excluded prescriptions classified as
matched uninfected patients to determine: associated diagnostic supplies (e.g. glucose test strips); emollients;
unadjusted and adjusted risk of hospitalization and eye washes and lubricants; soaps, shampoos and soap-free
mortality, whether risks differ by HIV status, and if a cleaners; mouthwashes; sun protectants and screens;
 Non-antiretroviral polypharmacy and adverse health outcomes Justice et al. 741

irrigation solutions; ceruminolytics; deodorants and higher scores being associated with a greater risk of
antiperspirants; and contact lens solutions from analyses. mortality. A five-point increase in VACS Index score is
Our analysis was restricted to medications, which were associated with a 20% increase in 5-year mortality risk (e.g.
filled on a chronic basis, defined as at least 90 consecutive hazard ratio of 1.2). Scores were determined using
days allowing for a 30-day refill window, consistent with laboratory values closest to the end of fiscal year 2009.
previous definitions [22].
Analyses
Days of medication receipt were calculated based on In bivariate analyses, we evaluated characteristics of HIVþ
prescription information, assuming the prescription was and uninfected individuals associated with non-antiretro-
taken as directed. Patients may have started a medication viral polypharmacy using a chi-square test and calculating
before fiscal year 2009 or continued them after fiscal year odds ratios for more than two and at least five non-
2009; we captured only days supplied within fiscal year antiretroviral polypharmacy. We used Cox proportional
2009. Medications were categorized according to VA hazard models to determine the association between non-
class. We calculated the mean number of unique non- antiretroviral medication count (and >2 and 5 thresholds
antiretroviral long-term medications received by each for non-antiretroviral polypharmacy), hospitalization, and
patient during fiscal year 2009 by summing the number of mortality adjusted for disease severity (as measured by the
days supplied for each medication and dividing the total VACS Index) and demographic factors. All statistical
by 365 days. Each component of co-formulated analyses were performed using SAS version 9.4 (SAS
medications was counted separately. Institute Inc., Cary, North Carolina, USA).

Adverse health outcomes Role of the funding source

Hospitalization was identified from the VA (including The funding source played no role in this analysis.
fee-based) and Center for Medicare and Medicaid
Services (CMS). All-cause mortality was obtained from
the VA Vital Status File, which includes data from
inpatient records, the VA Beneficiary Identification Results
Records Locator Subsystem (BIRLS), Social Security
Administration, and CMS. Excellent reliability and Sample characteristics
validity of the Vital Status File has been established by During fiscal year 2009 (baseline), 9473 HIVþ were on
comparison with the National Death Registry [23]. We antiretrovirals with suppressed HIV-1 RNA and 39 812
conducted surveillance for hospitalization and mortality; uninfected individuals were receiving at least one
time to event was calculated from the start of fiscal year medication from VA pharmacy. Overall, the sample
2010 to the date of first event or censored at the end of was predominantly 50–64 years of age (Table 1, 64, 64%),
fiscal year 2015. racially and ethnically diverse (41% white, 46% black, 9%
Hispanic), predominantly men (98%) and demographi-
Covariates cally similar by HIV status. Both HIVþ and uninfected
Demographic variables included age, race/ethnicity, and were actively engaged in care (mean visits/year: HIVþ
sex. Diabetes mellitus status was determined based on 2.1, uninfected 1.9). Among HIVþ individuals, median
laboratory and pharmacy data [24]. BMI and blood CD4 count was 515 (IQR 347, 720). By design, all
pressure (uncontrolled hypertension) were obtained from HIVþ individuals were on antiretrovirals (60% protease
clinic visit records. Controlled hypertension was based on inhibitor-based, 40% nonnucleoside reverse transcriptase
a normal blood pressure and receipt of an antihyperten- inhibitors, and <0.1% on an Integrase inhibitor) and had
sive. Hepatitis C virus (HCV) status was considered HIV-1 RNA 400 copies/ml or less.
positive if a patient had a positive HCV antibody test or
HCV RNA or ICD-9 codes for HCV infection. We Several common comorbidities were similarly distributed
determined the presence of other comorbid medical and among HIVþ and uninfected individuals included
psychiatric diseases by requiring at least one inpatient or current or past smoking (Table 1, 69%), hypertension
two outpatient ICD-9 codes [25]. (64%), hyperlipidemia (40%), and psychiatric diagnoses
(27%). HIVþ individuals experienced more HCV
We used the VACS Index to adjust for disease severity [16– infection (35% HIVþ, 15% uninfected). Uninfected
20]. The VACS Index is a physiologic score predicting risk individuals were more likely to experience chronic pain
of all-cause mortality initially developed among HIVþ (49% uninfected, 36% HIVþ), diabetes (33% uninfected,
individuals that integrates data on age; HIV biomarkers 22% HIVþ), morbid obesity (BMI > 35, 19% uninfected,
(HIV-1 RNA viral load; CD4 cell count); and non-HIV 5% HIVþ), or a psychiatric diagnosis (29% uninfected,
biomarkers (hemoglobin, hepatitis C; FIB-4 to assess liver 20% HIVþ). HIVþ individuals demonstrated greater
function, and estimated glomerular filtration rate to assess severity of illness than uninfected. HIVþ individuals had
renal function). It has also been validated in uninfected higher VACS Index scores (Table 1, 24 vs. 18). During
individuals [20]. Potential scores range from 0 to 164, with the observation period HIVþ were also more likely than
742 AIDS 2018, Vol 32 No 6

Table 1. Characteristics of sample overall and by HIV status.

Overall HIV Uninfected

N % by column N % by column N % by column

Totals 49285 100.0% 9473 100.0% 39812 100.0%

Age
<50 years 10457 21.2% 2299 24.3% 8158 20.5%
50–64 years 31756 64.4% 5863 61.9% 25893 65.0%
65 years 7072 14.3% 1311 13.8% 5761 14.5%
Sex
Female 1249 2.5% 199 2.1% 1050 2.6%
Male 48036 97.5% 9274 97.9% 38762 97.4%
Race
White, nonhispanic 20302 41.2% 4154 43.9% 16148 40.6%
Black, nonhispanic 22845 46.4% 4154 43.9% 18691 46.9%
Hispanic 4320 8.8% 804 8.5% 3516 8.8%
Other/missing 1818 3.7% 361 3.8% 1457 3.7%
Medical diagnoses
Hypertension, controlled, with Rx 21501 43.6% 3613 38.1% 17888 44.9%
Hypertension, uncontrolled 10612 21.5% 1644 17.4% 8968 22.5%
Diabetes 16000 32.5% 2059 21.7% 13941 35.0%
Hyperlipidemia 20619 41.8% 3702 39.1% 16917 42.5%
Coronary artery disease 4858 9.9% 695 7.3% 4163 10.5%
Chronic obstructive Pulmonary disease 3422 6.9% 522 5.5% 2900 7.3%
Cirrhosis 575 1.2% 169 1.8% 406 1.0%
Chronic pain 23809 48.3% 3437 36.3% 20372 51.2%
Gastroesophageal reflux disease 5348 10.9% 647 6.8% 4701 11.8%
Obesity (BMI 35) 8215 16.7% 449 4.7% 7766 19.5%
Psychiatric diagnoses
Major depression 3744 7.6% 789 8.3% 2955 7.4%
Bipolar disorder 2940 6.0% 498 5.3% 2442 6.1%
Posttraumatic stress disorder 6800 13.8% 753 7.9% 6047 15.2%
Schizophrenia 2761 5.6% 218 2.3% 2543 6.4%
Any psychiatric disorder 13541 27.5% 1907 20.1% 11634 29.2%
Substance use
Alcohol related diagnosis 5297 10.7% 820 8.7% 4477 11.2%
Drug abuse and dependence 4889 9.9% 1101 11.6% 3788 9.5%
Alcohol and/or drugs diagnoses 7437 15.1% 1402 14.8% 6035 15.2%
Current smoker 24666 50.0% 4987 52.6% 19679 49.4%
Former smoker 9112 18.5% 1575 16.6% 7537 18.9%
VACS Index score and components, median (IQR)
Total score NA 18 (12,28) NA 24 (12,38) NA 18 (12,28)
Age NA 56 (51,62) NA 56 (50,61) NA 57 (51,62)
HIV-1 RNA NA NA NA <400 copies NA NA
CD4þ cell count NA NA NA 515 (347,720) NA NA
Hemoglobin NA 14 (13,15) NA 14 (13,15) NA 14 (13,15)
FIB4 NA 1.23 (0.91,1.71) NA 1.44 (1.04,2.08) NA 1.19 (0.89,1.63)
Estimated glomerular filtration rate NA 87 (73,101) NA 86 (72,102) NA 87 (73,101)
Hepatitis C infection (col%) 9393 19.1% 3257 34.4% 6136 15.4%
Medication classes
ACE inhibitors 16330 33.1% 2467 26.0% 13863 34.8%
Beta blockers 13972 28.3% 2064 21.8% 11908 29.9%
Diuretics 10203 20.7% 1442 15.2% 8761 22.0%
Calcium channel blockers 11492 23.3% 1348 14.2% 10144 25.5%
Lipid-lowering agents 24927 50.6% 3979 42.0% 20948 52.6%
Oral glucose-lowering agents 9727 19.7% 1016 10.7% 8711 21.9%
Gastric medications 14814 30.1% 1823 19.2% 12991 32.6%
Antidepressants 15322 31.1% 3021 31.9% 12301 30.9%
Nonopioid analgesics 12744 25.9% 1779 18.8% 10965 27.5%
Genitourinary agents 9806 19.9% 1840 19.4% 7966 20.0%
Outcomes
Hospitalizaton 27400 55.6% 5505 58.1% 21895 55.0%
Death 7169 14.5% 1594 16.8% 5575 14.0%

uninfected individuals to be hospitalized (58 and 55%) or respectively, the 10 most commonly received medication
die (17 and 14%). classes were lipid-lowering medications (Table 1, 42 and
53%), ACE-inhibitors (26 and 35%), antidepressants (32
Common non-antiretroviral medications were similar in and 31%), gastric medications (19 and 33%), beta-
both groups. Among HIVþ and uninfected individuals, blockers (22 and 30%), nonopioid analgesics (19 and
 Non-antiretroviral polypharmacy and adverse health outcomes Justice et al. 743

20

18

16

14

Percent of Paents 12

10
HIV+
8
Uninfected
6

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Non-ARV Medicaon Count

Fig. 1. Nonantiretroviral medication count by HIV status.

28%), calcium channel blockers (14 and 26%), diuretics polypharmacy among HIVþ than uninfected (30–
(15 and 22%), genitourinary agents (19 and 20%), and 60% increased risk for HIVþ versus 10% for uninfected).
hypoglycemic medications (11 and 22%). Of note, long-
term prescription opioids (17 and 21%) were commonly VACS Index scores were similarly and moderately
prescribed to both HIVþ and uninfected individuals and correlated with non-antiretroviral medication count
proton pump inhibitors, by far the most common gastric among HIVþ and uninfected (Spearman correlation
medications, were also commonly used for more than 90 HIVþ: 0.21 95% CI 0.19, 0.23; uninfected: 0.21 95% CI
days (19 and 32%), respectively. The distribution of non- 0.20, 0.22). VACS Index discriminated risk of hospitali-
antiretroviral medication count was fairly similar among zation (HIVþ C- statistic: 0.62 95%CI 0.61, 0.63;
HIVþ and uninfected with HIVþ having slightly lower uninfected C-statistic: 0.60, 95% CI 0.60, 0.60) and
counts (Fig. 1). Median (5th and 95th) non-antiretroviral mortality (HIVþ C-statistic: 0.72, 95% CI 0.71, 0.74;
medication count was 3 (1, 10) among HIVþ, and 4 (1, uninfected C-statistic: 0.70, 95% CI 0.70, 0.71) nearly as
11) among uninfected. well among uninfected as HIVþ.

Characteristics associated with nonantiretroviral Nonantiretroviral polypharmacy and

polypharmacy hospitalization
In bivariate analyses, characteristics of HIVþ and In unadjusted analyses, more than two and at least five
uninfected individuals associated with non-antiretroviral non-antiretroviral polypharmacy was associated with
polypharmacy, whether defined as more than two or at increased risk of hospitalization (Table 3, >2: hazard ratio
least five non-antiretrovirals, were similar (Table 2). Older 1.68; 95% CI 1.63–1.73; 5: hazard ratio 1.69; 95%
age was strongly associated with polypharmacy. Those CI 1.65–1.73). Adjusting for demographic factors and
50–64 were twice as likely, and those 65 and over, nearly severity of illness, more than two and at least five non-
three times as likely, to experience non-antiretroviral antiretroviral polypharmacy remained independently
polypharmacy compared with those less than 50 years of associated with hospitalization (>2: hazard ratio 1.51;
age. Although HIVþ men were as likely as HIVþ women 95% CI 1.47–1.55: 5: hazard ratio 1.52, 95% CI 1.49–
to experience non-antiretroviral polypharmacy, unin- 1.56). Risk of hospitalization associated with polyphar-
fected men were 20–40% more likely than uninfected macy was similar by HIV status in analyses adjusted for
women to experience polypharmacy. Whites were about demographics and severity of illness (P for inter-
20% more likely than other racial groups to experience action ¼ 0.85).
non-antiretroviral polypharmacy. Conditions that more
than doubled the odds of non-antiretroviral polyphar- In unadjusted and adjusted analyses, compared with
macy in both groups included: hypertension, diabetes, those on two or fewer non-antiretroviral medications,
coronary artery disease, chronic obstructive pulmonary non-antiretroviral polypharmacy demonstrated a dose–
disease, and psychiatric diagnoses. Some common minor response association with risk of hospitalization
conditions doubled the probability of non-antiretroviral among HIVþ and uninfected (Fig. 2). Whenever non-
polypharmacy including: hyperlipidemia and gastro- antiretroviral medication count was modeled as a
esophageal reflux. Interestingly, HCV infection, alcohol, continuous variable (Table 4), we observed an 8%
and drug use disorders were more associated with incremental increased risk of hospitalization with each
744 AIDS 2018, Vol 32 No 6

Table 2. Association of characteristics with nonantiretroviral polypharmacy (more than two and at least five medications).

Polypharmacy prevalence (%) Odds ratio for polypharmacy

More than two At least five More than two At least five
Non-ARVs non-ARVs non-ARVs non-ARVs

Characteristic HIVþ Uninfected HIVþ Uninfected HIVþ Uninfected HIVþ Uninfected

All 67.2 71.2 34.1 39.3 na na na na

Age
<50 years 53.1 58.2 22.3 27.1 Ref Ref Ref Ref
50–64 years 70.6 73.6 36.7 41.8 2.1 2.0 2.0 1.9
65þ years 77.0 78.9 43.3 45.2 3.0 2.7 2.7 2.2
Sex
Female 67.3 64.2 35.7 35.5 Ref Ref Ref Ref
Male 67.2 71.4 34.1 39.4 1.0 1.4 0.9 1.2
Race
White 69.5 74.1 37.6 42.1 Ref Ref Ref Ref
Black 65.4 69.9 31.4 38.3 0.8 0.8 0.8 0.9
Hispanic 68.5 69.8 35.1 37.8 1.0 0.8 0.9 0.8
Hypertension
None 51.9 50.1 19.9 19.2 Ref Ref Ref Ref
Controlled, with Rx 83.4 85.6 50.3 54.2 4.6 5.9 4.1 5.0
Uncontrolled 71.2 72.9 35.2 38.6 2.3 2.7 2.2 2.7
Diabetes
No 63.2 65.4 29.2 32.0 Ref Ref Ref Ref
Yes 81.8 81.9 51.7 52.8 2.6 2.4 2.6 2.4
Hyperlipidemia
No 62.7 65.5 29.4 33.4 Ref Ref Ref Ref
Yes 74.3 78.9 41.5 47.3 1.7 2.0 1.7 1.8
CAD/MI
No 65.6 69.1 32.2 36.6 Ref Ref Ref Ref
Yes 88.2 89.3 59.1 61.9 3.9 3.7 3.1 2.8
COPD
No 66.4 70.0 32.9 37.6 Ref Ref Ref Ref
Yes 82.2 86.1 55.6 60.0 2.3 2.7 2.6 2.5
Cirrhosis
No 67.0 71.1 33.9 39.2 Ref Ref Ref Ref
Yes 79.9 80.5 46.2 42.4 2.0 1.7 1.7 1.1
Pain-related diagnoses
None 60.6 65.6 26.4 31.6 Ref Ref Ref Ref
Acute 69.3 70.1 35.1 38.5 1.5 1.2 1.5 1.4
Chronic 77.5 76.1 46.3 46.0 2.2 1.7 2.4 1.8
Gastroesophageal reflux disease
No 66.3 69.8 32.7 37.6 Ref Ref Ref Ref
Yes 80.5 81.6 53.6 51.6 2.1 1.9 2.4 1.8
Morbid obesity (BMI 35)
No 66.8 69.3 33.6 36.7 Ref Ref Ref Ref
Yes 75.7 79.0 44.8 50.0 1.5 1.7 1.6 1.7
Major depression
No 66.0 70.3 32.6 38.1 Ref Ref Ref Ref
Yes 80.6 82.9 50.8 54.1 2.1 2.1 2.1 1.9
Bipolar disorder
No 66.5 70.6 33.2 38.5 Ref Ref Ref Ref
Yes 79.9 80.4 50.4 50.4 2.0 1.7 2.0 1.6
PTSD
No 65.7 69.0 32.1 36.3 Ref Ref Ref Ref
Yes 85.4 83.4 57.8 56.1 3.1 2.2 2.9 2.2
Schizophrenia
No 66.8 70.4 33.6 38.2 Ref Ref Ref Ref
Yes 85.3 82.8 56.4 55.2 2.9 2.0 2.6 2.0
Any psychiatric disorder
No 63.5 66.7 29.5 33.3 Ref Ref Ref Ref
Yes 82.0 82.2 52.6 53.8 2.6 2.3 2.7 2.3
Alcohol-related diagnosis
No 66.4 70.9 33.4 39.0 Ref Ref Ref Ref
Yes 76.1 73.2 42.0 41.2 1.6 1.1 1.4 1.1
Drug abuse and dependence
No 66.3 71.0 33.3 39.1 Ref Ref Ref Ref
Yes 74.3 73.1 40.2 41.0 1.5 1.1 1.3 1.1
Smoking
Never 64.6 68.7 31.3 36.1 Ref Ref Ref Ref
Current 67.0 71.6 33.9 39.9 1.1 1.2 1.1 1.2
 Non-antiretroviral polypharmacy and adverse health outcomes Justice et al. 745

Table 2 (continued )

Polypharmacy prevalence (%) Odds ratio for polypharmacy

More than two At least five More than two At least five
Non-ARVs non-ARVs non-ARVs non-ARVs

Characteristic HIVþ Uninfected HIVþ Uninfected HIVþ Uninfected HIVþ Uninfected

Former 72.3 74.5 39.4 43.0 1.4 1.3 1.4 1.3

Hepatitis C infection
No 64.7 70.8 32.3 39.0 Ref Ref Ref Ref
Yes 72.1 73.2 37.7 40.8 1.4 1.1 1.3 1.1
Hospitalizaton
No 57.7 63.3 23.9 29.6 Ref Ref Ref Ref
Yes 74.1 77.7 41.5 47.2 2.1 2.0 2.3 2.1
Death
No 65.3 69.4 31.6 37.0 Ref Ref Ref Ref
Yes 76.8 82.5 46.7 53.5 1.8 2.1 1.9 2.0

All bivariate odds ratios significant at P < 0.001 except as noted. HIVþ, sex P ¼ 0.98, uninfected, drug abuse and dependence P ¼ 0.006. ARV,
antiretroviral therapy.

additional non-antiretroviral medication for HIVþ and five non-antiretroviral polypharmacy demonstrated a
uninfected (hazard ratio 1.08, 95% CI 1.08–1.08, P for 43% increased risk of mortality among HIVþ and
interaction ¼ 0.99). uninfected (5: hazard ratio 1.43, 95% CI 1.36–1.50,
P for interaction ¼ 0.1).
Nonantiretroviral polypharmacy and mortality
In unadjusted analyses, more than two non-antiretroviral In unadjusted and adjusted analyses, compared with those
polypharmacy was associated with 68% increased risk of on two or fewer non-antiretroviral medications, we
mortality among HIVþ (Table 3, >2: hazard ratio 1.68, observed a dose–response association between non-
95% CI 1.50–1.89) and a 99% increased risk among antiretroviral polypharmacy and risk of mortality among
uninfected individuals (hazard ratio 1.99, 95% CI 1.86– HIVþ and uninfected (Fig. 2). Whenever non-antiretro-
2.14, P for interaction ¼ 0.01). Using the at least five viral medication count was modeled as a continuous
threshold in unadjusted analysis, polypharmacy was variable (Table 4), we observed a 5% increase in risk of
associated with an 83% increased risk of mortality in mortality with each additional non-antiretroviral medi-
both HIVþ and uninfected (P for interaction ¼ 0.1, 5: cation among HIVþ (hazard ratio 1.05, 95% CI 1.03–
hazard ratio : 1.83, 95% CI 1.75–1.82). 1.06), and a 7% increase among uninfected (hazard ratio
1.07, 95% CI 1.06–1.07).
In fully adjusted models, more than two non-antiretroviral
polypharmacy was associated with a 20% increased risk of
mortality among HIVþ (>2: hazard ratio 1.20, 95% CI Discussion
1.07–1.36) and a 49% increased risk among uninfected
(>2: hazard ratio 1.49, 95% CI 1.39–1.60, P for In this large cohort of HIVþ and demographically similar
interaction ¼ 0.002). The fully adjusted model of at least uninfected individuals, non-antiretroviral polypharmacy

Table 3. Unadjusted and adjusted hazard ratios for nonantiretroviral therapies polypharmacy (more than two and at least five medications),
hospitalization, and mortality by HIV status.

Polypharmacy (more than two non-ARVs) Polypharmacy (at least five non-ARVs)

Unadjusted Fully Adjusted Unadjusted Fully Adjusted

Hazard ratio 95% CI Hazard ratio 95% CI Hazard ratio 95% CI Hazard ratio 95% CI

Combined 1.68 1.63 1.73 1.51 1.47 1.55 1.69 1.65 1.73 1.52 1.49 1.56
HIVþ 1.72 1.62 1.83 1.50 1.41 1.60 1.73 1.64 1.83 1.53 1.45 1.62
Uninfected 1.67 1.62 1.73 1.50 1.45 1.55 1.69 1.64 1.73 1.51 1.47 1.55
Combined nab nab 1.83 1.75 1.92 1.43 1.36 1.50
HIVþ 1.68 1.50 1.89 1.20 1.07 1.36 1.79 1.62 1.97 1.32 1.20 1.46
Uninfected 1.99 1.86 2.14 1.49 1.39 1.60 1.86 1.77 1.96 1.45 1.37 1.52

Hazard ratios are expressed in terms of non-ARV polypharmacy using a more than two or a at least five medication threshold. Fully adjusted models
were adjusted for VACS Index score, age, sex, and race/ethnicity. ARV, antiretroviral therapy; CI, confidence interval. aInteraction between
polypharmacy, HIV, and hospitalization was not significant in any model.
b
Interaction between polypharmacy, HIV, and mortality was significant in more than two non-ARV models (unadjusted model P ¼ 0.01, adjusted
model P ¼ 0.002), but not in at least 5 models.
746 AIDS 2018, Vol 32 No 6

Unadjusted Fully adjusted

4.0 4.0
Hospitalization
3.5 3.5

3.0 3.0

2.5 2.5

2.0 2.0

1.5 1.5

1.0
1.0 HIV+
0.5 0.5
Hazard Ratio

0.0 0.0
0 5 10 15 0 5 10 15

4.0 4.0
Mortality
3.5 3.5

3.0 3.0

2.5 2.5

2.0 2.0

1.5 1.5

1.0 1.0

0.5 0.5

0.0 0.0
0 5 10 15 0 5 10 15

Non-ARV medication count

Fig. 2. Association of nonantiretroviral medication count and adverse health outcomes. Fully adjusted estimates are adjusted for
VACS index, age, race/ethnicity, and sex. Models were stratified by HIV status. Solid circles represent HIVþ, hollow circles
represent uninfected individuals. ARV, antiretroviral.

Table 4. Unadjusted and adjusted hazard ratio of nonantiretroviral demonstrates a dose–response association with hospitali-
medication count (continuous measure), hospitalization and zation and mortality and neither severity of illness nor
mortality by HIV status.
demographic factors explain these associations. Short of a
Unadjusted Fully adjusted randomized trial, these results provide important evi-
Non-ARV medication Non-ARV medication dence that non-antiretroviral polypharmacy contributes
count count
to adverse health events among those aging with and
Hazard 95% Hazard 95% without HIV infection.
Outcome ratio CI ratio CI
Our study extends prior literature in several ways [2–5,7–
Hospitalizationa
Combined 1.10 1.09 1.10 1.08 1.08 1.08 10]. We had direct access to pharmacy-dispensing data in
HIVþ 1.10 1.09 1.10 1.08 1.07 1.09 a national system with generous pharmaceutical coverage.
Uninfected 1.12 1.09 1.15 1.08 1.07 1.08 As patients fail to fill many prescriptions, data on
Mortalityb
Combined nab nab
medication orders (prescriptions) are less informative than
HIVþ 1.11 1.10 1.11 1.05 1.03 1.06 dispensing data. We are also the first to consider the
Uninfected 1.27 1.20 1.34 1.07 1.06 1.07 association of non-antiretroviral polypharmacy with
actual clinical outcomes among HIVþ rather than
Hazard ratios are expressed in terms of risk associated with each
additional non-ARV medication. Fully adjusted models were adjusted potential drug interactions or other possible adverse
for VACS Index score, age, sex, and race/ethnicity. ARV, antiretroviral effects. We consider adverse associations with polyphar-
therapy; CI, confidence interval. macy using two potential thresholds for non-antiretrovi-
a
P for interaction between polypharmacy, HIV, and hospitalization ral polypharmacy (>2 and 5) and as a continuous
was not significant (adjusted model P ¼ 0.99).
b
P for interaction between polypharmacy, HIV, and mortality was measure (non-antiretroviral medication count). We are
significant (adjusted model P ¼ 0.04). the first to compare health outcomes associated with
 Non-antiretroviral polypharmacy and adverse health outcomes Justice et al. 747

polypharmacy among HIVþ with demographically must be taken for the rest of the patient’s life. antiretroviral
similar uninfected individuals. Our hospitalization data initiation often precipitates polypharmacy a decade earlier
is completely parallel among HIVþ and uninfected and for HIVþ than uninfected individuals [6]. Antiretrovirals
include events occurring within the VA system, fee for interact with a wide range of common medications
service, and care supported by other United States including lipid-lowering agents, antihypertensives, anti-
governmental sources (Medicare and Medicaid). Simi- depressants, proton-pump inhibitors, and prescription
larly, VA mortality data are very complete [23]. Finally, a opioids [27]. Additionally, compared with uninfected
major innovation of our study is our ability to adjust for individuals, HIVþ had higher VACS Index scores
severity of illness using a widely validated and accurate indicating increased physiologic frailty and susceptibility
physiologic index. to drug injury.

Although many have suggested that the association For example, 18% of HIVþ in our sample were on a
between polypharmacy and adverse health outcomes is proton-pump inhibitor for more than 90 days. Most
because of confounding by indication – sicker patients protease inhibitors and several nonnucleoside reverse
take more medications – our analysis suggests otherwise. transcriptase inhibitors interact with proton-pump
The VACS Index is a widely validated, highly inhibitors [5]. In most circumstances, proton-pump
discriminating, physiologic index predictive of hospitali- inhibitors should not be prescribed for more than 30
zation and mortality among veterans with and without days. Further, proton-pump inhibitors are associated with
HIV infection [16–20]. The VACS Index meets or a growing list of serious adverse effects to which HIVþ
exceeds the discrimination of prior indices validated may have increased susceptibility including fragility
among older individuals [26]. Yet, the correlation fractures, cognitive difficulties, and malabsorption [28].
between the VACS Index and non-antiretroviral poly-
pharmacy was only moderate and full adjustment for the Some might argue that comorbid conditions among
Index, age, race/ethnicity, and sex did not ‘explain’ the HIVþ on antiretrovirals are undertreated. As observed in
association between non-antiretroviral polypharmacy and this study, non-antiretroviral medications are less com-
hospitalization or mortality. After these adjustments, non- monly dispensed to HIVþ than to uninfected individuals.
antiretroviral polypharmacy remained independently For example, HIVþ were less likely to receive lipid-
associated with hospitalization and mortality in a dose– lowering therapy for indicated cardiovascular disease
response manner. Thus, although demographic factors, prevention [29]. Whether this reflects a primary focus on
especially age, and severity of illness are associated with antiretrovirals, a judicious under use related to concerns
polypharmacy and health outcomes, neither appear to be about polypharmacy; lack of comfort with non-HIV care,
major confounders of the association between poly- or clinical oversight remains to be determined. Hundreds
pharmacy and adverse health outcomes. of trials have been conducted considering whether adding
a specific medication or set of medications improves
Instead, particular diagnoses (not all of which are associated outcomes, few interventions to reduce polypharmacy
with hospitalization or mortality), individual provider (deprescribe) have been tested. Most deprescribing trials
styles, and other factors not directly related to prognosis, failed to reduce medications because they are typically
may contribute more to polypharmacy than previously required to comply with disease-specific guidelines
appreciated. For example, diagnoses of hyperlipidemia or developed without consideration of multimorbidity or
gastroesophageal reflux roughly doubled the probability of polypharmacy [30]. For every medication to treat a
non-antiretroviral polypharmacy and medication-con- symptom that the trialists stopped, medications for
trolled hypertension increased the probability of non- primary and secondary prevention of disease were added.
antiretroviral polypharmacy more than five times. Impor- Only a randomized trial can determine whether
tantly, over 6 years of observation, none of these conditions deprescribing reduces hospitalization or mortality among
conferred an increased risk of mortality independent of those exposed to polypharmacy. Our analyses offer
non-antiretroviral medication count, VACS Index score, stronger evidence than previously reported, either among
and demographic factors (data not otherwise shown). Of HIV infected or the general population, that polyphar-
note, these associations were similar by HIV status macy may cause excess hospitalization and mortality. This
suggesting similar factors drive polypharmacy among evidence may help inform the equipoise necessary for
those with and without HIV infection and suggesting randomized trials of deprescribing among patients with
potential targets for future intervention. non-antiretroviral polypharmacy.

Likely mechanisms of injury from polypharmacy among Substantial work is needed to determine how best to
HIVþ and uninfected individuals include cumulative proceed. Although many studies in uninfected populations
toxicity, side effects, and drug–drug interactions [2,3]. As cite five medications as a critical threshold, no study has
those with HIV age, the problem of adverse health established the definitive threshold for non-antiretroviral
outcomes because of non-antiretroviral polypharmacy polypharmacy. An important strength of our analyses is that
may grow. Although antiretrovirals extend survival, they we considered two thresholds for non-antiretroviral
748 AIDS 2018, Vol 32 No 6

polypharmacy (>2 and 5) as well as analyzing non- Acknowledgements

antiretroviral medication count as a continuous variable.
Our analyses suggest that harms accrue in a monotonically Funding: National Institutes of Health: NIAAA
increasing manner with three or more non-antiretroviral (U24-AA020794, U01-AA020790, U10-AA013566-
medications for HIVþ and uninfected individuals. completed, U01-AA020795, U01-AA020799, U24-
AA022001, U24 AA022007). As corresponding author,
Thresholds for injury from polypharmacy likely depend Amy Justice had full access to all the data in the study
on the specific regimen, the individual’s underlying and final responsibility for the decision to submit
physiologic injury, and genetic susceptibility. Sophisti- for publication.
cated computer models will likely be needed, incorpo-
rating knowledge such as that contained in databases of Disclosures of results before publication: Edelman EJ,
the United States Food and Drug Administration (FDA) Gordon K, Akgün K, Gibert C, Lo Re V, McNicholl I,
and the European Medicines Agency (EMA) to account Rimland D, Skanderson M, Tate J, Womack J, Wyatt C,
for what is known about drug–drug and drug and and Justice AC for the VACS Project Team. HIVþ
common substance use interactions. Current criteria individuals on ART are at risk of polypharmacy, yet more
such as Beers or START/STOPP were developed medications increases mortality. [Oral] 51st Infectious
among uninfected individuals over 65 years of age, Diseases Society of America (IDSA), San Francisco,
and evidence for the effectiveness of these criteria in California, 2–6 October, 2013.
avoiding actual adverse health outcomes is contradictory
and limited. HIVþ on lifelong antiretrovirals, may Edelman EJ, Gordon KS, Akgun KM, Gibert C, Lo Re V,
continue to use alcohol and other substances that may Rimland D, Womack J, Wyatt C, Skanderson M, Tate JP,
also interact with their medications, and may require Justice AC. Is Excess Medication Associated with
special consideration. Mortality among HIVþ and Uninfected Patients?
[Poster], 38th Annual Society of General Internal
Beyond nonrandom assignment, our findings should be Medicine (SGIM) Meeting, Toronto, Ontario, Canada,
interpreted in light of the following limitations. We did 22–25 April, 2015.
not consider specific antiretroviral classes or agents, the
number of antiretrovirals in use, or the association of Author’s contributions: All authors contributed to the
specific non-antiretroviral medication classes or individ- writing of the manuscript. A.C.J. conceived the idea and
ual non-antiretroviral medications with hospitalization or wrote all major drafts of the manuscript. A.C.J. and M.S.
mortality. We did not consider ‘potentially inappropriate’ contributed to collecting the data. K.S.G. and J.P.T
medications in light specific antiretrovirals, advanced age, analyzed the data and interpreted the results with A.C.J.
other non-antiretroviral medications or classes, or the use E.J.E. and J.P.T. contributed to study design and E.J.E.,
of alcohol. We did not study the effect of adding or K.A., C.G., V.L.R., D.R., J.W. and C.W. contributed to
subtracting a medication. Such analyses are needed, but the critical review of the manuscript.
are beyond the scope of this study. Our non-antiretroviral
medication count was based on medications dispensed Conflicts of interest
within the US Veterans Affairs Healthcare System (VA) There are no conflicts of interest.
and do not reflect outside prescriptions, over the counter,
or complimentary medications making our measures of
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