Post on 19-Jan-2016
ARV Pharmacy Refill Adherence
• Robert Grossberg, MD
• Montefiore Medical Center
• Albert Einstein College of Medicine
1
Objectives
• Understand the importance of antiretroviral adherence in HIV
• Evaluate various adherence measurement methods
• Review the use of pharmacy refill adherence methodology in HIV
2
Virologic Control falls sharply with diminished adherence
0
10
20
30
40
50
60
70
80
90
95-100% 90-95% 80-90% 70-80% < 70%
Adherence, by prescription refill
% A
chie
ving
<50
0 co
pies
/mL
N = 504 pts on HAART
Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.3
0
20
40
60
80
100
>95 90-95 80–90 70-80 <70
Pat
ient
s w
ith
HIV
RN
A<
400
cop
ies/
mL
, %
Protease Inhibitor adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
Virologic Control falls sharply with diminished adherence
4
10% Adherence difference = 21% reduction in risk of AIDSAdherence and AIDS-Free Survival
Bangsberg D, et al. AIDS. 2001:15:1181
Pro
port
ion
AID
S-F
ree
Months from entry
P = .0012
0 5 10 15 20 25 30
0.00
0.25
0.50
0.75
1.00
AdherenceO 90–100%O 50–89%O 0–49%
5
Sub-Optimal Adherence Predisposes to Resistance
• Sub-optimal adherence ==> sub-therapeutic drug levels ==> incomplete viral suppression ==> generation of resistant HIV strains by selection for mutant viruses
• Association between poor adherence and antiretroviral resistance is well-documented1,2
1. Vanhove G, et al. JAMA. 1996;276:1955-1956.
2. Montaner JS, et al. JAMA. 1998;279:930-937. 6
Adherence, Antiviral Activity & Risk of Resistance Mutations
Incr
easi
ng p
roba
bili
tyof
sel
ecti
ng m
utat
ion
Increasing Adherence
Low Risk of Resistance:Inadequate Drug Exposure
Low
Risk
of Resistan
ce:C
omp
lete Viral
Su
pp
ressionHigh Risk of
Resistance:Drug
PressureSustains
Replication of Poorly Fit Virus
How do we Measure Adherence?
• Provider Estimates • Patient self-report• Diaries• Pill Count• Laboratory Markers• Electronic Devices• Prescription refill data
8
Measuring Adherence: Patient Self-Report
• patients tend to report what they think the provider wants to hear1
• patients are unlikely to misrepresent low levels of adherence3 - hence, patient-reported poor adherence is specific but not sensitive
• patient-reported adherence tends to exceed adherence by more objective measurements (such as pill count or electronic monitoring) 2
• Nevertheless, studies have documented an association between patient-reported adherence and viral outcome 4-6
• Patient-reported adherence may be a useful tool to evaluate adherence at a group level but not so much on an individual level1. 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;81:1978-1988.4 Bangsberg DR, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 93.5. Duong M, et al. 39th ICAAC; 1999; San Francisco. Abstract 20696. Demasi R, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 94.9
Measuring Adherence: Electronic Bottle Caps
MEMScaps, Aardex Corp.10
http://www.aardex.ch/QRChronology.htm
QuickRead software, for use with MEMScaps system
11
Measuring Adherence: Electronic Bottle Caps
• Advantages– more difficult for patients
to exaggerate their adherence
– reveals patterns of non-adherence (i.e., what time of day pills are taken)
– studies using these devices have documented relationship between adherence & dosing
• Disadvantages– too expensive for
routine use outside of research studies
– cannot be used for patients who use pillboxes
12
Pharmacy Refill Data
• Advantages– only choice for retrospective studies– can assess short or long-term behavior
• Disadvantages– less intra-interval variability – further removed from actual drug taking– may not capture (legitimate) prescriptions from other
sources– if automatic refills, data are useless
13
Sources of Refill Data• Automated database
–Medicaid–VA System Pharmacies–Pharmacy Benefit Managers
• Ad hoc data collection–Call pharmacies–HIPAA barriers?
14
Examples of Refill Data• Antihypertensives
–Taken chronically• Disease process over years/decades• Drugs infrequently changed
–Metric: number of refills obtained over year
• Ratio of number of refills/12
15
Examples of Refill Data• Antiretrovirals
–Taken chronically• Disease process over months/years• Drugs frequently changed
–Metric: number of days to obtain 4 refills (3 months)
• Ratio of 90 days supply/# of days to obtain supply
• Time to event approach• Allows for more variability over shorter
interval
16
Prior Work using Refills in HIV• Low-Beer et al. (Vancouver)
– 886 subjects– Median cd4 count 290 cells/cm3 (IQR 130-440)– Median viral load 130K (47K-310K)– Follow up-median 19 mo (IQR 13-24mo)– Adherence defined as
• # refills obtained/# months on therapy over 1 year
– Outcome-viral load <500 c/ml
17
Low-Beer et al. JAIDS 2000
12%
24%
47%
64%
84%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
<70% 70-<80% 80-<90% 90-<95% >95%Pro
port
ion
Und
etec
tabl
e (V
L<50
0 c/
ml)
n=n= 232 232 37 37 51 51 6464 502 502 18
Issues with Refill Data• Variety of other approaches possible–Assessment of time to refill–Assessment of duration of gaps–Others
• Limitations–Unclear how they will operate on short term–For example, 3 months of follow-up allows
only for 2, 3, or 4 fills using Low-Beer method
19
Choice of Pharmacy Metric–Metric: number of days to obtain 4 refills (3 months)
• 90 days supply/# of days to obtain supply
• Time to event approach
• Allows for more variability over shorter (clinically relevant) interval
20
Time to 4 refills (3 Time to 4 refills (3 months)months)
Fourth fill
} } }First fill Second fill Third fill
First interval Second interval Third interval
Adherence metric: Σ intervals/(4th fill date-1st fill date)
21
VA Pharmacy Refill Study
• Specific aim–To compare validity of self-reported
measure and pharmacy refill measure of adherence to antiretroviral therapy in HIV
22
VA Refill Study Design
• Observational Study (n=110) conducted in the Philadelphia VA HIV Clinic
• Outcomes– Change in HIV viral load from baseline to study date– HIV viral load undetectable or not (dichotomized)
• Exposures– Adherence measured via self-report (ACTG
measure)– Adherence measured using refill data (time to
obtaining 90 days supply)
23
Setting/Study Patients
• Subjects on therapy at least 3 months
• Philadelphia VA Medical Center–Veterans obtain all HIV Rx here–Electronic pharmacy records–Mailed medications require telephone call
24
01
23
45
0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 140
Self -reported measure Pharmacy-based measure
Change in Log Viral Load (c/ml) Fitted values
Cha
nge
in L
og V
iral
Loa
d (c
/ml)
/Fitt
ed v
alue
s
Percent Adherence
Entire cohort, N=11025
VA Pharmacy Study Results
• Spearman correlation coefficient (95% CI)• Adherence and change in viral load
Pharmacy refill = 0.22 (0.01 to 0.40)
Self-report = 0.10 (-0.08 to 0.32)
26
VA Pharmacy Study Results
Change in plasma viral loadRank sum
test
Method Study group Adherence >85% Adherence <85% p value
Pharmacy Entire cohort N=572.4 log c/ml
(IQR 1.4 - 3.2)
N=531.5 log c/ml
(IQR 0.7 - 2.4)0.005
Self-report Entire cohort N=962.1 log c/ml
(IQR 1.1 - 3.0)
N=141.4 log c/ml (IQR 0.4 -1.9)
0.04
Pharmacy 100% by self-report
N=442.4 log c/ml
(IQR 1.4 - 3.4)
N=301.5 log c/ml
( IQR 0.8 - 2.4)0.03
27
Conclusions of Refill Study• Time to refill is a valid adherence
measure–may perform better than self-report
• Generalizability outside of VA?
• Unclear function over shorter intervals (e.g., 1 or 2 months)
28
Time to 4 refills (90 days)Time to 4 refills (90 days)
Fourth fill
} } }First fill Second fill Third fill
First interval Second interval Third interval
90d
60d
60d
30d
29
Correlation of shorter interval adherence measures Correlation of shorter interval adherence measures and change in viral loadand change in viral load
Fourth fill
} } }First fill Second fill Third fill
First interval Second interval Third interval
0.250 (0.059-0.423)
0.150 (-0.045-0.334)
0.144 (-0.050-0.327)
0.229 (0.036-0.405)
0.184 (-0.007-0.362)
0.265 (0.078-0.434)
30
Correlation of shorter interval adherence measures Correlation of shorter interval adherence measures and change in viral loadand change in viral load
Fourth fill
} } }First fill Second fill Third fill
First interval Second interval Third interval
0.250 (0.059-0.423)
0.150 (-0.045-0.334)
0.144 (-0.050-0.327)
0.229 (0.036-0.405)
0.184 (-0.007-0.362)
0.265 (0.078-0.434)
31
Conclusions regarding shorter interval measurements of refill adherence
• Shorter interval measurements of refill adherence are associated with virologic outcome.
• The “upstream” interval is the best predictor of outcome.
32
Summary
• Refill adherence is a valid method for measuring adherence.
• Refill adherence correlates with outcome.• Short interval measurements of refill adherence
are valid, but only if measured 60-90 days in advance of the point of interest.
• Clinical use of refill data to inform providers about medication adherence is evolving.
33