1. ADHERENCE Patrick Desmet HIV / Therapycounselor

4. PALELLA, NEJM 1998

5. WAC, Geneva 1998

6. 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

7. 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 Conclusion Adherent= SIMILAR MORTALITY RATES CD4: 200-349 and greater (p > 0.2) (p=0.004) Non-Adherent = increased mortality rate CD4 range: >200-349

8. 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

9. 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 45 33 29 18 0 25 50 75 100 >95%90%-95%80%-90%70%-80%<70% Patients Reaching Undetectable HIV RNA LOQ 400 (%) P = <0.001 Greatest danger zone for developing resistance

10. Adherence levels over time impact on virological response Adherence levels at 6 months and virological response 0 10 20 30 40 50 60 Percentage of patients <200 copies/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

11. ADHERENCE

12. Health Care Team MULTIDISCIPLINARY TEAM EFFORT HIV-CARE TEAMCOMMUNITY-CARE HIV-SPECIALIST NURSE / THERAPY COUNSELOR SOCIAL WORKER PSYCHOLOGIST PHARMACIST DIETICIAN GP VOLUNTEERS HOME BASED CARE PATIENT ORGANISATIONS

13. HEALTHCARE FACTORS STAFF TRAINING INSUFFICIENT STAFF & SPACE for COUNSELLING CONFIDENTIALITY POOR ORGANIZATION OF DAILY CARE AUTHORITARIAN AND JUDGEMENTAL ATTITUDE CONFLICTING PATIENT-INFORMATION (EDUCATION)

14. PATIENT FACTORS PATIENT EMPOWERMENT BASIC KNOWLEDGE SKILLS & MOTIVATION HEALTH BELIEFS & CULTURAL / SOCIO-ECONOMIC STATUS

15. 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

16. 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

17. 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

18. MOTIVATION ESTABLISH : READINESS COMMITMENT ASYMPTOMATIC vs.SYMPTOMATIC MOTIVATION Preventive Measures ART-SE Distress ART Stop = SE Relief Reinforce the Necessity OI-status, Pill Burden, Drug-drug Interactions LONG-TERM TREATMENT

19. 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

20. What’s the Virologic Impact of Pill Burden? Number of Antiretroviral Pills Prescribed Per Day Bartlett. 13th IAC; 2000; Durban. Abstract 4998. 80 60 40 20 0 5101520 HIV RNA  50 at 48 weeks PI NRTI NNRTI (r = –0.57, P =.0085) Size of symbol is directly proportional to weight of the data point in the analysis. 100 Meta-analysis of 22 clinical trials / 3257 patients first line HAART 48 weeks of follow up

21. * Indicates group “Taking all medication on time according to food restriction” not assessed Nieuwkerk 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 + NRTIsNFV + NRTIsRTV/SQV + NRTIs NVP + NRTIs Patients (%) 100 Taking all medications on time according to food restrictions * N=224

22. SIMPLIFIED PILL BURDEN FREQUENCY DIET RESTRICTIONS AVOID SUB-OPTIMAL ADHERENCE SIMPLIFY FREQUENCY QD+BID = COMPLEXITY  PILL BURDEN > 6 PILLS SEPARATE TIMING = DIET

23. Frequency of dosing and forgetting medication Moyle G et al. 6th ICDTHI, Glasgow, UK, 17-21 November 2002. Poster 99 40% N=504 across Europe 63% 66% 71%

24. 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=133 52 46 45 27 20 19 18 17 16 14 13 10 9 0 2030405060 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

25. 1 10 100 1000 10000 Log concentration (ng/mL) day 1day 2day 3day 4day 5 dose miss EC 50 Even 48 hours post-dose, plasma levels remain above EC50 Half life: >12 hours Examples: EFV, TDF, ddI, Atazanavir The Weakest Link !!!

26. MEASUREMENT DOT PHARMACY BASED RECORDS CLINICAL JUDGEMENT SELF REPORT BIOCHEMICAL PARAMETERS ELECTRONIC EVENT MONITORING (MEMS®) HOW ? PILL COUNTS PLASMA LEVELS / TDM

27. 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

28. PRISONERS 0 20 40 60 80 100 481624486472 Weeks on therapy HIV RNA <400, % SELF ADMINISTERED THERAPY VS. M.Fishl CROI 2001

29. 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

30. 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?

31. 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

32. 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

33. 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,

34. 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

35. 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…

36. Electronic Event Monitoring (MEMS ® ) UZ Leuven Fabienne Dobbels

37. 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

38. CONCLUSION NO DECISIVE TOOL and/or METHOD TO MEASURE PATIENT SELF - EFFICACY ADHERENCE

39. Flow Chart Counseling New HIV+  TRUST  KNOWLEDGE  LIFESTYLE  Potential 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

40. 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

41. 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 READINESS COMMITMENT

42. Medication schedule UZ Leuven

43. Pillbox and reminder system UZ Leuven

44. Vibrating alarms, watches, cell-phone alarm, SMS

45. ADHERENCE COUNSELLING MULTIDISCIPLINARY TEAM EFFORT NEGOTIATION INFORMATION EDUCATION BEFORE, DURING and AFTER START of ART