Transcript adherence

ADHERENCE
Patrick Desmet
HIV / Therapycounselor
Mortality vs HAART Utilization
40
100
USE OF HAART
30
25
75
DEATHS
20
50
15
10
25
5
0
1995
0
1996
PALELLA, NEJM 1998
1997
1998
1999
2000
2001
Patient-Days on HAART, %
Deaths per 100 Person-Years
35
WAC, Geneva 1998
Definition Adherence
The medication adherence is the ability of the patient
to be involved in:
choosing , starting, managing and maintaining
a given therapeutic combination regimen
to control viral replication and improve the immune
function.
Jane M.Simoni Ph D
ADHERENCE vs. SURVIVAL
Objective:
Effect of baseline CD4-count and adherence to
HAART on survival rate
Methods :• 1422 HIV patients
• 2-6 years follow-up
• Adherence : first 48 weeks pharmacy refills
• 2 categories:>75% and >95% adherent refills
• CD4 ranges: >200-349 cells or ≥350 cells
Conclusion
Adherent=
SIMILAR MORTALITY RATES
CD4: 200-349 and greater (p > 0.2)
Non-Adherent = increased mortality rate
CD4 range: >200-349
Evan Wood 2003 / Annals of Internal Medicine
(p=0.004)
ADHERENCE vs. SURVIVAL
CONCLUSION:
In HIV-infected individuals, adherence, rather
than when therapy is initiated above a CD4count of 200 cells may be the most important
determinant of survival
Evan Wood 2003 / Annals of Internal Medicine
How Much Adherence Required
Patients Reaching Undetectable
HIV RNA LOQ 400 (%)
Relationship of adherence (measured by
MEMS® 81 patients / 45397 doses /
6 months of FU ) to virologic success
100
Mean adherence rate
78
P = <0.001
75
45
50
33
29
25
18
0
>95%
90%-95% 80%-90% 70%-80%
<70%
Greatest danger zone for developing resistance
Adapted from: Paterson DL et al. Ann Intern Med 2000;133: 21-30
Adherence levels over time impact on
virological response
Adherence levels at 6 months and virological
response
Percentage of patients
<200 copies/ml
N=3004 / 69 centers
60
50
40
52%
35%
20%
30
20
10
0
Level of adherence
Casado JL et al. 42nd ICAAC, San Diego CA, September 2002. Abs H-1707
18%
90-95%
70-89%
40-69%
<40%
ADHERENCE
Health Care Team
MULTIDISCIPLINARY TEAM EFFORT
HIV-CARE TEAM
•HIV-SPECIALIST
•NURSE / THERAPY
•COUNSELOR
•SOCIAL WORKER
•PSYCHOLOGIST
•PHARMACIST
•DIETICIAN
COMMUNITY-CARE
•GP
•VOLUNTEERS
•HOME BASED CARE
•PATIENT
ORGANISATIONS
HEALTHCARE FACTORS
• STAFF TRAINING
• INSUFFICIENT STAFF & SPACE for COUNSELLING
• CONFLICTING PATIENT-INFORMATION (EDUCATION)
• CONFIDENTIALITY
• POOR ORGANIZATION OF DAILY CARE
•AUTHORITARIAN AND JUDGEMENTAL ATTITUDE
PATIENT FACTORS
BASIC KNOWLEDGE
PATIENT
HEALTH
BELIEFS
&
CULTURAL /
SOCIO-ECONOMIC
STATUS
EMPOWERMENT
SKILLS
&
MOTIVATION
PATIENT FACTORS
BASIC KNOWLEDGE
WHAT ?
•HIV vs. AIDS
•CD4 / CD4 % / VL
• ART / ACTION
WHEN ?
WHY ?
•RISKS & BENEFITS
of
EARLY / DELAYED
ART
• ADHERENCE
•ADHERENCE
• EXPECTATIONS :
GOLDEN STANDARD
• LIFELONG
TREATMENT
&
ART
RESTRICTIONS
PATIENT FACTORS
HEALTH BELIEFS & FEARS
•Denial HIV- status
•Negative beliefs (expectation of benefit ART)
•Fear of Short or Longterm - Side Effects
•Lack off trust towards Health-Care team
Cultural and Socio-economic
Status
•Welfare status: housing, financial support…
•Fear of Disclosure : ARV > trigger HIV-Status
•Stigmatisation : cultural / religious beliefs
•Drug and Alcohol use
MOTIVATION
ESTABLISH : READINESS
COMMITMENT
ASYMPTOMATIC
MOTIVATION
vs.
LONG-TERM
TREATMENT
SYMPTOMATIC
• Preventive Measures
MOTIVATION
• Reinforce the Necessity
• ART-SE Distress
ART Stop = SE Relief
• OI-status, Pill Burden,
Drug-drug Interactions
TREATMENT FACTORS
• DRUG TOXICITIES: SHORT AND LONGTERM SE
• COMPLEX REGIMEN / PILL BURDEN
• DOSING FREQUENCY / DRUG INTERACTIONS
• DIETARY RESTRICTIONS
• LOGISTICAL : APPROVALS / AVAILABILITY OF DRUGS
• CONCOMITANT /ALTERNATIVE MEDICINE
• ACCUMULATIVE TREATMENT CHANGES
What’s the Virologic
Impact of Pill Burden?
Meta-analysis of 22 clinical trials / 3257 patients first line HAART
48 weeks of follow up
HIV RNA 50 at 48 weeks
100
(r = –0.57, P = .0085)
80
60
40
PI
NRTI
NNRTI
20
Size of symbol is directly proportional to weight of the data point in the analysis.
0
5
10
15
Number of Antiretroviral Pills Prescribed Per Day
Bartlett. 13th IAC; 2000; Durban. Abstract 4998.
20
As Regimen Complexity Increases
Adherence Rates Decrease
Taking all medications
Taking all medications on time
Taking all medications on time according to food restrictions
N=224
Patients (%)
100
80
60
40
*
20
0
IDV + NRTIs
NFV + NRTIs
RTV/SQV +
NRTIs
NVP + NRTIs
* Indicates group “Taking all medication on time according to food restriction” not assessed
Nieuwkerk PT et al. Arch Int Med 2001,161: 1962-1968
SIMPLIFIED
PILL BURDEN
FREQUENCY
DIET RESTRICTIONS
QD+BID = COMPLEXITY 
SIMPLIFY
FREQUENCY
PILL BURDEN > 6 PILLS
SEPARATE TIMING = DIET
AVOID
SUB-OPTIMAL
ADHERENCE
% of patients ever forgetting to
take HIV medication
Frequency of dosing and
forgetting medication
N=504
across
Europe
100
80
63% 66%
60
40
71%
40%
20
0
Moyle G et al. 6th ICDTHI, Glasgow, UK, 17-21 November 2002. Poster 99
Once daily
Twice daily
3 times daily
>3 times daily
Why do Patients Miss Doses?
%
0
10
20
30
40
50
52
Too busy/simply forgot
46
Away from home
27
Felt depressed/overwhelmed
Took drug holiday/medication break
20
Ran out of medication
20
Too many pills
19
Worried about becoming 'immune'
19
Reasons given for missing
antiretroviral doses
(structured questionnaire)
18
Felt drug was too toxic
Wanted to avoid side effects
17
Didn't want others to notice
17
16
Reminder of HIV infection
14
Confused about dosage direction
13
Didn't think it was improving health
Were told the medicine is no good
n=133
45
Change in daily routine
To make it last longer
60
10
9
Adapted from: Gifford AL et al. JAIDS 2000; 23: 386-395
possible interventions
simplify dosing schedule
decrease pill burden
other
The Weakest Link !!!
Log concentration (ng/mL)
10000
1000
Half life: >12 hours
100
Even 48 hours post-dose, plasma levels remain above EC50
10
1
day 1
dose
day 2
dose
day 3
dose
day 4
miss
Examples: EFV, TDF, ddI, Atazanavir
day 5
dose
EC50
MEASUREMENT
HOW ?
• DOT
• CLINICAL JUDGEMENT
• BIOCHEMICAL PARAMETERS
• PLASMA LEVELS / TDM
• PILL COUNTS
• PHARMACY BASED RECORDS
• SELF REPORT
• ELECTRONIC EVENT MONITORING (MEMS®)
Direct Observed Therapy
PRO
• May theoretically be justified:
> 100 % levels of adherence
CONTRA
• Labor intensive:
>only for QD-BID dosing
> can be used for observational
limited time
• Expensive
• Restricted to institutional setting:
> targetted patient population
prisons, etc..
• Confidentiality
PRISONERS VS.
SELF ADMINISTERED THERAPY
HIV RNA <400, %
100
80
60
40
20
0
4
M.Fishl CROI 2001
8
16
24
Weeks on therapy
48
64
72
Clinician/Nurses-Estimated Adherence
PRO
•Phrasing Questions
in specific terms
> dosing
> timing
> anticipating
> diet
• Cheap
CONTRA
• Open-ended
questions
• Slightly better than a
coin toss !
• Paterson et al.: prediction
>80% adherence
physician 41% incorrect
nurses 30% incorrect
White coat-effect !?
Adherence = phrasing questions in specific terms
ex. Timing : How and When did your demanding job
influence your ARV- timing schedule? Could you combine
your Kaletra with your dinner?
ex. Anticipating : Seeing your parents this week-end, how did
you to plan ahaed your ARV’s in order not to disclose your
HIV-status?
Adherence= avoid open-ended questions
ex. Looking at your labresults I suppose you didn’t
have any problems taking your medications?
BIOCHEMICAL PARAMETERS
VIRAL LOAD : Standard assay
> can be objective if combined with patient self-reports
CD4 / CD4% : Ojective measure , good correlation
MCV- increase reflects AZT-intake, poor correlation
Genotypic Resistance testing: marker of non-adherence
! Only absolute non-adherent patients
!Assay misleading if patient is no longer on drug
> 3TC failing patients still susceptible for the RT184 mutation
Pill Counts
PRO
• Cheap
• Useful adjunct to
self-report
CONTRA
• Overestimates
adherence
– “Pill dumping” > hospital
flowerbeds
• Time consuming
• Rather in research
setting> structured dosing
schedules
• Counsellor = medication
monitor > threatening
Pharmacy Records / Refills
PRO
• Cheap
• Useful adjunct to
self-report
CONTRA
• 1 patient vs. many
pharmacies
• Refilling doesn’t mean
drugtaking
• Patient may have different
sources of medications:
free samples, pill sharing,
ADHERENCE vs. PHARMACY REFILLS
Objective : HIV-disease progression / AIDS vs. Adherence
Methods :
• 950 patients ARV naive
• (85% PI and 15%NNRTI) + 2NRTI
• Median follow-up 13 months
• Pharmacy based records, refills
Conclusion
For each 10% decline in adherence
16% increase in mortality
Hogg et al.7th CROI 2000/abs73.
Self-Report
PRO
• Cheap
• Correlated with
virologic outcomes.
CONTRA
• Overestimates
adherence
• Accuracy can be
improved by gathering
and averaging
information over time
• Diaries: easily neglected
and lost…
Electronic Event Monitoring (MEMS®)
24:00
Time
20:00
16:00
12:00
08:00
04:00
6
10
14 18 22 26 30
September
4
8
12 16 20 24 28
October
Fabienne Dobbels
UZ Leuven
Electronic Monitoring (MEMS®)
PRO
CONTRA
• Best correlation with • Expensive : 125€
/drug/patient
virologic outcomes
• Data is available in
• Not for routine daily
a computer
practice > limited to
accessible format
research settings
• Allows more
> Poor patient acceptance
detailed view of the
• Not infallible (patients can
dynamics of drug
open bottle and not take
intake.
pill)
CONCLUSION
NO DECISIVE TOOL and/or METHOD TO MEASURE
ADHERENCE
PATIENT SELF - EFFICACY
Flow Chart Counseling New HIV+
3 STEP APPROACH = a stepwise informationflow
OPTIMISING HAART
TRUST
KNOWLEDGE
LIFESTYLE
Potential ADHERENCE
and ARV-BARRIERS
DYNAMIC MONITORING
PEOPLES LIVES
= VARIABLE BEHAVIOR
IMPACT from ENVIRONMENT
 SOCIAL FACTORS
 NEW DIAGNOSES
2 visits
Counseltopics
Counseltopic(s): naive patients
• Sec.Prevention:Safe sex,blood
•Evaluation 2 ARV proposals
•HIV virus basics
Lifestyle:Diet, work, co-medication…
•Social:partner,disclosure
Potential Adherence and Therapy
barriers
•CD4 & VL-interpretation
•Side-effects: short and longterm
•Video
Social status check !
Drug specific Side effects
•Initiate Dummy Run
•ARV support
•Adherence: 4 markers
• Resistance
Initiation Haart and follow- up
READINESS
COMMITMENT
Counseltopics
Counseltopics
•Drugplanning: optimizing
drugintake, identify ARVreminders, ARV-storage, food
recommendations….
•Telephone call patient / counselor
•Patient rehearses
drugplanning and potential SE
= Timing , dosing, diet,anticipation,
ARV_storage.
•Drug specific SEffects
•Reasons for non-adherence
• Supportive Tools
•Anticipate SEffects cf Dr.
•Adherence check:
Medication schedule
Medication
Frequ.
Hours
Nutrition
Remarks
1 co Retrovir® 300 mg
2x/day
1 caps Videx® EC 400 mg
1x/day
On an empty stomach = take 1 hour before
a meal or 2 hours after a meal
1 caps Stocrin® 600mg
1x/day
Do not take after a fatty meal
4 caps Kaletra® 133.3/33.3mg
2x/day
Store bottle at room temperature for max.
42 days
Store reserve in refrigerator
UZ Leuven
Pillbox and reminder system
UZ Leuven
Vibrating alarms, watches,
cell-phone alarm, SMS
ADHERENCE COUNSELLING
MULTIDISCIPLINARY TEAM EFFORT
INFORMATION
EDUCATION
NEGOTIATION
BEFORE, DURING and AFTER START of ART