ADHERENCE

Patrick Desmet HIV / Therapycounselor

0

5

10

15

20

25

30

35

40

1995 1996 1997 1998 1999 2000 2001

Dea

ths

per

100

Per

son

-Yea

rs

0

25

50

75

100

DEATHS

USE OF HAART

Mortality vs HAART UtilizationP

atient-Days o

n HA

AR

T, %

PALELLA, NEJM 1998

WAC, Geneva 1998

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

Definition Adherence

Objective: Effect of baseline CD4-count and adherence to HAART on survival rate

ADHERENCE vs. SURVIVAL

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

Evan Wood 2003 / Annals of Internal Medicine

ConclusionAdherent=SIMILAR MORTALITY RATES

CD4: 200-349 and greater (p > 0.2)

(p=0.004)Non-Adherent = increased mortality rateCD4 range: >200-349

ADHERENCE vs. SURVIVAL

CONCLUSION:

In HIV-infected individuals, adherence, rather than when therapy is initiated above a CD4-count of 200 cells may be the most important determinant of survival

Evan Wood 2003 / Annals of Internal Medicine

How Much Adherence Required

Adapted from: Paterson DL et al. Ann Intern Med 2000;133: 21-30

Mean adherence rate

Relationship of adherence (measured by MEMS® 81 patients / 45397 doses /

6 months of FU ) to virologic success

78

4533

2918

0

25

50

75

100

>95% 90%-95% 80%-90% 70%-80% <70%

Pat

ien

ts R

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g U

nd

etec

tab

le

HIV

RN

A L

OQ

400

(%

)

P = <0.001

Greatest danger zone for developing resistance

Adherence levels over time impact on virological response

Adherence levels at 6 months and virological response

0

10

20

30

40

50

60

Per

cen

tag

e o

f p

atie

nts

<

200

cop

ies/

ml

90-95%

52%

70-89%

35%

40-69%

20%

<40%

18%

N=3004 / 69 centers

Casado JL et al. 42nd ICAAC, San Diego CA, September 2002. Abs H-1707

Level of adherence

ADHERENCE

Health Care Team

MULTIDISCIPLINARY TEAM EFFORT

HIV-CARE TEAM COMMUNITY-CARE•HIV-SPECIALIST

•NURSE / THERAPY •COUNSELOR •SOCIAL WORKER•PSYCHOLOGIST•PHARMACIST•DIETICIAN

•GP•VOLUNTEERS•HOME BASED CARE•PATIENT ORGANISATIONS

HEALTHCARE FACTORS

• STAFF TRAINING

• INSUFFICIENT STAFF & SPACE for COUNSELLING

• CONFIDENTIALITY

• POOR ORGANIZATION OF DAILY CARE

•AUTHORITARIAN AND JUDGEMENTAL ATTITUDE

• CONFLICTING PATIENT-INFORMATION (EDUCATION)

PATIENT FACTORS

PATIENT

EMPOWERMENT

BASIC KNOWLEDGE

SKILLS &MOTIVATION

HEALTHBELIEFS &CULTURAL /SOCIO-ECONOMICSTATUS

BASIC KNOWLEDGE

WHAT ? WHEN ? WHY ?

•CD4 / CD4 % / VL

•EXPECTATIONS :GOLDEN STANDARD

•ADHERENCE

•RISKS & BENEFITS of EARLY / DELAYED ART

• ADHERENCE

• LIFELONG TREATMENT & ART RESTRICTIONS

•HIV vs. AIDS

• ART / ACTION

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

PATIENT FACTORS

Cultural and Socio-economic Status

•Drug and Alcohol use

•Fear of Disclosure : ARV > trigger HIV-Status

•Welfare status: housing, financial support…

•Stigmatisation : cultural / religious beliefs

MOTIVATION

ESTABLISH : READINESS COMMITMENT

ASYMPTOMATIC vs. SYMPTOMATIC

MOTIVATION MOTIVATION

• Preventive Measures

• ART-SE Distress ART Stop = SE Relief

• Reinforce the Necessity

• OI-status, Pill Burden, Drug-drug Interactions

LONG-TERM TREATMENT

TREATMENT FACTORS

• CONCOMITANT /ALTERNATIVE MEDICINE

• DRUG TOXICITIES: SHORT AND LONGTERM SE

• COMPLEX REGIMEN / PILL BURDEN

• DOSING FREQUENCY / DRUG INTERACTIONS

• DIETARY RESTRICTIONS

• LOGISTICAL : APPROVALS / AVAILABILITY OF DRUGS

• ACCUMULATIVE TREATMENT CHANGES

What’s the VirologicImpact of Pill Burden?

Number of Antiretroviral Pills Prescribed Per Day

Bartlett. 13th IAC; 2000; Durban. Abstract 4998.

80

60

40

20

05 10 15 20

HIV

RN

A

50 a

t 48

wee

ks

PI

NRTI

NNRTI

(r = –0.57, P = .0085)

Size of symbol is directly proportional to weight of the data point in the analysis.

100Meta-analysis of 22 clinical trials / 3257 patients first line HAART

48 weeks of follow up

* Indicates group “Taking all medication on time according to food restriction” not assessedNieuwkerk PT et al. Arch Int Med 2001,161: 1962-1968

As Regimen Complexity Increases Adherence Rates Decrease

Taking all medications

Taking all medications on time

0

20

40

60

80

IDV + NRTIs NFV + NRTIs RTV/SQV +NRTIs

NVP + NRTIs

Pat

ien

ts (

%)

100

Taking all medications on time according to food restrictions

*

N=224

SIMPLIFIED

PILL BURDEN FREQUENCY DIET RESTRICTIONS

AVOIDSUB-OPTIMALADHERENCE

SIMPLIFYFREQUENCY

QD+BID = COMPLEXITY

PILL BURDEN > 6 PILLS

SEPARATE TIMING = DIET

Frequency of dosing and forgetting medication

0

20

40

60

80

100

% o

f pat

ients

eve

r fo

rget

ting t

o

take

HIV

med

icat

ion

Once dailyTwice daily3 times daily>3 times daily

Moyle G Moyle G et alet al. 6th ICDTHI, Glasgow, UK, 17-21 November 2002. Poster 99. 6th ICDTHI, Glasgow, UK, 17-21 November 2002. Poster 99

40%

N=504 across Europe

63% 66% 71%

Why do Patients Miss Doses?

Adapted from: Gifford AL et al. JAIDS 2000; 23: 386-395

Reasons given for missing antiretroviral doses

(structured questionnaire)

possible interventions

simplify dosing schedule

decrease pill burden

other

%

n=13352

46

45

27

20

20

19

19

18

17

17

16

14

13

10

9

0 10 20 30 40 50 60

Too busy/simply forgot

Away from home

Change in daily routine

Felt depressed/overwhelmed

Took drug holiday/medication break

Ran out of medication

Too many pills

Worried about becoming 'immune'

Felt drug was too toxic

Wanted to avoid side effects

Didn't want others to notice

Reminder of HIV infection

Confused about dosage direction

Didn't think it was improving health

To make it last longer

Were told the medicine is no good

1

10

100

1000

10000L

og

co

nce

ntr

atio

n (

ng

/mL

)

day 1 day 2 day 3 day 4 day 5

dose dose dose missmiss dose

EC50Even 48 hours post-dose, plasma levels remain above EC50

Half life: >12 hours

Examples: EFV, TDF, ddI, Atazanavir

The Weakest Link !!!

MEASUREMENT

• DOT

• PHARMACY BASED RECORDS

• CLINICAL JUDGEMENT

• SELF REPORT

• BIOCHEMICAL PARAMETERS

• ELECTRONIC EVENT MONITORING (MEMS®)

HOW ?

• PILL COUNTS

• PLASMA LEVELS / TDM

Direct Observed Therapy

PRO CONTRA

• May theoretically be justified:> 100 % levels of adherence

• 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

PRISONERSPRISONERS

00

2020

4040

6060

8080

100100

44 88 1616 2424 4848 6464 7272

Weeks on therapyWeeks on therapy

HIV

RN

A <

400,

%

HIV

RN

A <

400,

%

SELF ADMINISTERED THERAPYSELF ADMINISTERED THERAPYVS.

M.Fishl CROI 2001

PRO CONTRA

Clinician/Nurses-Estimated Adherence

• Open-ended questions• Slightly better than a coin

toss !• Paterson et al.: prediction

>80% adherence

physician 41% incorrect

nurses 30% incorrect

White coat-effect !?

• Cheap

•Phrasing Questions in specific terms > dosing > timing > anticipating > diet

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’thave any problems taking your medications?

VIRAL LOAD : Standard assay> can be objective if combined with patient self-reports

BIOCHEMICAL PARAMETERS

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

PRO CONTRA

Pill Counts

• Cheap• Useful adjunct to

self-report

• Overestimates adherence– “Pill dumping” > hospital

flowerbeds

• Time consuming• Rather in research setting>

structured dosing schedules• Counsellor = medication

monitor > threatening

PRO CONTRA

Pharmacy Records / Refills

• Cheap• Useful adjunct to

self-report

• 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

Hogg et al.7th CROI 2000/abs73.

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

PRO CONTRA

Self-Report

• Cheap• Correlated with

virologic outcomes.

• Overestimates adherence

• Accuracy can be improved by gathering and averaging information over time

• Diaries: easily neglected and lost…

Electronic Event Monitoring (MEMS®)

6 10 14 18 22 26 30 4 8 12 16 20 24 28

04:00

08:00

12:00

16:00

20:00

24:00

September October

Tim

e

UZ LeuvenFabienne Dobbels

Electronic Monitoring (MEMS®)

• Best correlation with virologic outcomes

• Data is available in a computer accessible format

• Allows more detailed view of the dynamics of drug intake.

• Expensive : 125€ /drug/patient

• Not for routine daily practice > limited to research settings

> Poor patient acceptance

• Not infallible (patients can open bottle and not take pill)

PRO CONTRA

CONCLUSION

NO DECISIVE TOOL and/or METHOD TO MEASURE

PATIENT SELF - EFFICACY

ADHERENCE

Flow Chart Counseling New HIV+

TRUST KNOWLEDGELIFESTYLEPotential ADHERENCE and ARV-BARRIERS

OPTIMISING HAART

PEOPLES LIVES = VARIABLE BEHAVIOR

IMPACT from ENVIRONMENT SOCIAL FACTORS NEW DIAGNOSES

DYNAMIC MONITORING

3 STEP APPROACH = a stepwise informationflow

Counseltopics

• Sec.Prevention:Safe sex,blood

•HIV virus basics

•Social:partner,disclosure

•CD4 & VL-interpretation

•Side-effects: short and long-term

•Video

Counseltopic(s): naive patients

•Evaluation 2 ARV proposals

Lifestyle:Diet, work, co-medication…

Potential Adherence and Therapy barriers

Social status check !

Drug specific Side effects

•Initiate Dummy Run

•ARV support

•Adherence: 4 markers

• Resistance

2 visits

Counseltopics

•Drugplanning: optimizing drugintake, identify ARV-reminders, ARV-storage, food recommendations….

•Patient rehearses drugplanning and potential SE

•Drug specific SEffects

• Supportive Tools

Counseltopics

•Telephone call patient / counselor

•Anticipate SEffects cf Dr.

•Adherence check:

= Timing , dosing, diet,anticipation, ARV_storage.

•Reasons for non-adherence

Initiation Haart and follow- up

READINESSCOMMITMENT

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 beforea 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 daysStore reserve in refrigerator

UZ Leuven

Pillbox and reminder system

UZ Leuven

Vibrating alarms, watches,

cell-phone alarm, SMS

ADHERENCE COUNSELLING

MULTIDISCIPLINARY TEAM EFFORT

NEGOTIATIONINFORMATION EDUCATION

BEFORE, DURING and AFTER START of ART