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Adherence to HIV Medications:An Evidence-Based Review
Christopher Behrens, MD
Northwest AIDS Education &Training Center
University of Washington
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Adherence
[physicians] should keep aware of the fact that
patients often lie when they state that they havetaken certain medicines."
- Hippocrates
Drugs dont work if people dont take them.- C. Everett Koop
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Adherence and Antiretroviral
Therapy
Measuring Adherence
Why Adherence Matters
antiretroviral efficacy
development of resistance
Factors associated with adherence
Interventions to improve adherence
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Current DHHS guidelines on
Initiation of Antiretroviral Therapy
The likelihood of patient adherence should be
discussed and determined by the individual patientand clinician before therapy is initiated.
Before the first prescription is written, patient
readiness to take medication should be clearlyestablished
August 2001 Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents
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Clinicians Estimates of Adherence
Not Much Better Than Random
Bangsberg 2001 JAIDS HAART
Paterson 2000 Annals Int Med HAART
Haubrich 1999 AIDS HAART
Steiner 1995 Arch Int Med AZT
Bosely 1995 Eur Resp J Inhaled terbutaline
Charney 1967 Pediatrics Penicillin
Caron 1978 Clin Pharmacol Anatacids
Gilbert 1980 Can Med Assoc J Digoxin
Blowey 1997 Ped Nephrology Cyclosporin
Mushlin 1977 Arch Int Med Hypertensive
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Provider Estimate vs.Three 3-Day Patient
Report Compared to Pill Count
Three 3-day Self Report and Pill Count Adherence
Pill Count
100806040200
Pa
tientReport
100
80
60
40
20
0
Provider Estimate and Pill Count Adherence
Pill Count
100806040200ProviderEstimate
100
80
60
40
20
0
Provider Estimate
R sq = 0.26Patient Report
R sq = 0.72Bangsberg et al JAIDS 2001:26:435
n=45
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Measuring Adherence:
Patient Self-Report
patients tend to report what they think the provider
wants to hear1
patients are unlikely to misrepresent high levels ofadherence3- hence, patient-reported poor
adherence is specific but not sensitive
patient-reported adherence tends to exceed
adherence by more objective measurements, suchas pill count or electronic monitoring2
1. DiMatteo MR, DiNicola DD, eds. Achieving Patient Compliance. New York: Pergamon Press; 1982:1-28.
2. Golin C et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95.
3. Bond W, Hussar DA, Am J Public Health 1991;81:1978-1988.
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How Do Adherence Measurement
Techniques Compare to One Another?
0
10
20
30
40
50
60
7080
90
100
Self-Report Clinician
Estimate
Pill Count Electronic
bottle cap
ADEPT Study; N=81 patients
Adapted from Golin C et al. 1999; Miller L et al. 1999.
Adh
erence,
%
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Measuring Adherence:
Patient Self-Report
Nevertheless, studies have documented an
association between patient-reported adherenceand viral outcome1-3
patient-reported adherence may be a useful tool to
evaluate adherence at a group level but not somuch on an individual level
1. Bangsberg DR, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 93.
2. Duong M, et al. 39th ICAAC; 1999; San Francisco. Abstract 2069
3. Demasi R, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 94.
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Measuring Adherence: Diaries
In theory, better than relying on memory
in practice, not very useful
many patients do not fill them in1
those that do may do so immediately before
office visit
1. Golin C, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95.
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Measuring Adherence:
Pill Counts
Advantages:
more objective than
patient report correlates better with
electronic bottle caps
than does self-reported
adherence1
1. Golin C, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95
Drawbacks:
many patients forget to
bring their bottlespatients can still
exaggerate adherence
time consuming
patients may find it toopaternalistic
does not reveal patterns
of missed doses
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Measuring Adherence:
Laboratory Markers
many antiretroviral agents associated with
changes in laboratory parameters
AZT, d4T produce macrocytosis
indinavir associated with hyperbilirubinemia
didanosine changes urinary uric acid levels
drug levels could also potentially be used to
monitor adherence
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Laboratory Markers to Assess
Adherence: Drawbacks
lab markers not highly sensitive nor specific
do not give any information regarding the pattern
of non-adherence
patients who take their medications immediately
before having blood levels drawn could
exaggerate their adherence
measurement of drug levels has not been
standardized
other factors besides adherence can affect drug
levels
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Measuring Adherence:
Electronic Bottle Caps
caps harbor chips that register each time a
bottle is opened or closed
MEMScaps, Aardex Corp.
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QuickRead software, for use with MEMScaps system
http://www.aardex.ch/QRCalendar.htm
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QuickRead software, for use with MEMScaps system
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Measuring Adherence:
Electronic Bottle Caps
Advantages
more difficult for
patients to exaggeratetheir adherence
reveals patterns of non-
adherence
studies using thesedevices have
documented
relationship between
adherence & dosing
Disadvantages
too expensive for
routine use outside ofresearch studies
cannot be used for
patients who use
pillboxes
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The Future of Adherence Assessment?
Computer-Assisted Self-Interviewing (CASI)
Advantagesof CASI
Privacy may improve disclosure
Visual ARV recognition
Standardizes adherence assessmentNot personnel intensive
Could be administered in waiting
room or at home
via the web
Bangsberg D et al. AIDS Care, 2002 (in press)
Purposes of CASI
Determine patients understanding of medication regimen
Determine patients adherence over 3-day period
http://www.edermpda.com/hivadhere/
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Printed with permission from
West Portal Software Corp.
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West Portal Software Corp.
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West Portal Software Corp.
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Printed with permission from
West Portal Software Corp.
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Pilot CASI Adherence Measurement
111 patients, 11 providers in study
over 50% of patients made at least one error in
describing their regimen
providers missed 76% of non-adherent patients
patients reports of adherence significantly
associated with viral load counts 65% of patients reported that CASI made them
think more about how they take their medications
Bangsberg, Bronstone & Hoffman AIDS Care 2002 (in press)
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Why is Adherence so Importantfor Antiretroviral Therapy?
I. Efficacy
II. Resistance
V l C l f ll h l h
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Virologic Control falls sharply with
diminished adherence
0
10
20
30
40
5060
70
80
90
95-100% 90-95% 80-90% 70-80% < 70%
Adherence, by prescription refill
%A
chie
ving95 90-95 8090 70-80
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10% Adherence difference = 21% reduction in risk of AIDS
Adherence and AIDS-Free Survival
Bangsberg D, et al. AIDS. 2001:15:1181
ProportionA
IDS-Free
Months from entry
P= .0012
0 5 10 15 20 25 30
0.00
0.25
0.50
0.75
1.00
Adherence
O 90100%
O 5089%
O 0
49%
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Adherence & Drug Resistance
HIV Reverse Transcriptase (RT) is error-
prone
on average, HIV RT generates one mutation
in each copy of HIV produced
billions of HIV virions produced daily in
untreated patients
some HIV mutations associated with drug
resistance
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Sub-Optimal Adherence Predisposes
to Resistance
Sub-optimal adherence ==> sub-therapeutic
drug levels ==> incomplete viral
suppression ==> generation of resistantHIV strains by selection for mutant viruses
association between poor adherence andantiretroviral resistance well-documented1,2
1. Vanhove G, et al. JAMA. 1996;276:1955-1956.2. Montaner JS, et al. JAMA. 1998;279:930-937.
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What Contributes toSub-Optimal Adherence?
f dh
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Reasons for Non-Adherence:
Clinician vs Patient Views
0
10
20
30
40
50
60
value,%
No. of doses or
pills
Side Effects Meal Instructions Schedule
complexity
Other
Clinican
Patient
Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281
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Predictors of Poor Adherence
active alcohol1or substance2abuse
work outside the home for pay1
depressed mood1
lack of perceived efficacy of HAART3
lack of advanced disease4
concern over side effects4
1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281.
2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.
3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588.4. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
P d f P Adh
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Predictors of Poor Adherence,
continued
non-caucasian race documented in some
studies1-3but not others5
association of race with adherence not found in
other disease states
lower literacy rate a confounder?4
1. Paterson, et al.6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL. Abstract 92.
2. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL. Abstract 98.
3. Mar-Tang M, et al. J Gen Intern Med. 1999;14(suppl 2):53.
4. Kalichman SC, et al. J Gen Intern Med. 1999;14:267-273.5. Stone VE, et al. JAIDS 2001; 28:124-131
P di f P Adh
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Predictors of Poor Adherence,
continued
inability to fit medications into daily
schedule
tid dosing, food requirements1
1. Stone VE, et al. JAIDS 2001; 28:124-131
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Other Considerations
a large proportion of patients incorrectly
recall their medication schedules1,2
Virologic control does not necessarily imply
high levels of adherence3
patients with virologic control despite poor
adherence may not maintain durable viralsuppression without improved adherence
1. Chesney MA, International AIDS Society USA Meeting, 1998; Los Angeles.
2. Kravitz RL, et al. Arch Intern Med. 1993;153:1869-1878.
3. Kaplan A, et al. 6th Conference on Retro-viruses and Opportunistic Infections; 1999; Chicago. Abstract 96.
F A i d i h Hi h
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Factors Associated with Higher
Levels of Adherence
twice-daily or once-daily regimens1,4
belief in own ability to adhere to regimen1
not living alone2
dependent on a significant other for support2
history of Opportunistic Infection or AdvancedHIV disease3
1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.
2. Morse EV et al, Soc Sci Med 1991;32:1161-1167.3. Singh N, et al, AIDS Care 1996;8:261-269.
F A i d i h Hi h
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Factors Associated with Higher
Levels of Adherence
Belief in efficacy of antiretroviral therapy
Belief that non-adherence will lead to viral
resistance
Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
I i Sh I
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Interventions Shown to Improve
Adherence to Antiretrovirals
medication alarms1
education & counseling sessions2,3
Directly Observed Therapy (DOT)4,5
1. Samet JH, et al. Am J Med. 1992;92:495-502.
2. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.
3. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595.
4. Sorensen JL, et al. AIDS Care. 1998;10:297-312.
5. Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.
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Self-Adminstered vs Directly Observed
Therapy During Incarceration
0
10
20
30
40
50
60
70
80
90
100
%w
ithVL
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