1. Adherence to HIV Medications: An Evidence-Based Review Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington

2. Adherence ”[physicians] should keep aware of the fact that patients often lie when they state that they have taken certain medicines." - Hippocrates “Drugs don’t work if people don’t take them.” - C. Everett Koop

3. Adherence and Antiretroviral Therapy Measuring Adherence Why Adherence Matters –antiretroviral efficacy –development of resistance Factors associated with adherence Interventions to improve adherence

4. How do we Measure Adherence? Provider Estimates Patient self-report Diaries Pill Count Laboratory Markers Electronic Devices

5. Current DHHS guidelines on Initiation of Antiretroviral Therapy –“The likelihood of patient adherence should be discussed and determined by the individual patient and clinician before therapy is initiated.” –“Before the first prescription is written, patient ‘readiness’ to take medication should be clearly established” August 2001 Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents

6. Clinicians’ Estimates of Adherence Not Much Better Than Random Bangsberg2001JAIDSHAART Paterson 2000Annals Int MedHAART Haubrich1999AIDSHAART Steiner1995Arch Int MedAZT Bosely 1995Eur Resp J Inhaled terbutaline Charney 1967PediatricsPenicillin Caron1978Clin PharmacolAnatacids Gilbert1980Can Med Assoc JDigoxin Blowey1997Ped NephrologyCyclosporin Mushlin1977Arch Int MedHypertensive

7. Provider Estimate vs.Three 3-Day Patient Report Compared to Pill Count Provider Estimate R sq = 0.26 Patient Report R sq = 0.72 Bangsberg et al JAIDS 2001:26:435 n=45

8. Measuring Adherence: Patient Self-Report patients tend to report what they think the provider wants to hear 1 patients are unlikely to misrepresent high levels of adherence 3 - 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 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.

9. How Do Adherence Measurement Techniques Compare to One Another? ADEPT Study; N=81 patients Adapted from Golin C et al. 1999; Miller L et al. 1999. Adherence, %

10. Measuring Adherence: Patient Self-Report Nevertheless, studies have documented an association between patient-reported adherence and viral outcome 1-3 patient-reported adherence may be a useful tool to evaluate adherence at a group level but not so much 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.

11. Measuring Adherence: Diaries In theory, better than relying on memory in practice, not very useful –many patients do not fill them in 1 –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.

12. Measuring Adherence: Pill Counts Advantages: –more objective than patient report –correlates better with electronic bottle caps than does self-reported adherence 1 1. Golin C, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95 Drawbacks: –many patients forget to bring their bottles –patients can still exaggerate adherence –time consuming –patients may find it too paternalistic –does not reveal patterns of missed doses

13. 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

14. 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

15. Measuring Adherence: Electronic Bottle Caps caps harbor chips that register each time a bottle is opened or closed MEMScaps, Aardex Corp.

16. QuickRead software, for use with MEMScaps system http://www.aardex.ch/QRCalendar.htm

17. http://www.aardex.ch/QRChronology.htm QuickRead software, for use with MEMScaps system

18. Measuring Adherence: Electronic Bottle Caps Advantages –more difficult for patients to exaggerate their adherence –reveals patterns of non- adherence –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

19. The Future of Adherence Assessment? Computer-Assisted Self-Interviewing (CASI) Advantages of CASI –Privacy may improve disclosure –Visual ARV recognition –Standardizes adherence assessment –Not 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 patient’s understanding of medication regimen –Determine patient’s adherence over 3-day period http://www.edermpda.com/hivadhere/

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29. 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)

30. Why is Adherence so Important for Antiretroviral Therapy? I. Efficacy II. Resistance

31. Virologic Control falls sharply with diminished adherence Adherence, by prescription refill % Achieving <500 copies/mL N = 504 pts on HAART Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.

32. Patients with HIV RNA <400 copies/mL, % PI 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

33. 10% Adherence difference = 21% reduction in risk of AIDS Adherence and AIDS-Free Survival Bangsberg D, et al. AIDS. 2001:15:1181 Proportion AIDS-Free Months from entry P =.0012 051015202530 0.00 0.25 0.50 0.75 1.00 Adherence O 90–100% O 50–89% O 0–49%

34. 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

35. 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 well-documented 1,2 1. Vanhove G, et al. JAMA. 1996;276:1955-1956. 2. Montaner JS, et al. JAMA. 1998;279:930-937.

36. What Contributes to Sub-Optimal Adherence?

37. Reasons for Non-Adherence: Clinician vs Patient Views Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281

38. Predictors of Poor Adherence active alcohol 1 or substance 2 abuse work outside the home for pay 1 depressed mood 1 lack of perceived efficacy of HAART 3 lack of advanced disease 4 concern over side effects 4 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.

39. Predictors of Poor Adherence, continued non-caucasian race documented in some studies 1-3 but not others 5 –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

40. Predictors of Poor Adherence, continued inability to fit medications into daily schedule tid dosing, food requirements 1 1. Stone VE, et al. JAIDS 2001; 28:124-131

41. Other Considerations a large proportion of patients incorrectly recall their medication schedules 1,2 Virologic control does not necessarily imply high levels of adherence 3 –patients with virologic control despite poor adherence may not maintain durable viral suppression 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.

42. Factors Associated with Higher Levels of Adherence twice-daily or once-daily regimens 1,4 belief in own ability to adhere to regimen 1 not living alone 2 dependent on a significant other for support 2 history of Opportunistic Infection or Advanced HIV disease 3 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. 4. Stone VE, et al. JAIDS 2001; 28:124-131

43. 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.

44. Interventions Shown to Improve Adherence to Antiretrovirals medication alarms 1 education & counseling sessions 2,3 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.

45. Self-Adminstered vs Directly Observed Therapy During Incarceration Fischl et al 8 th CROI, 2001 abstract 528 p < 0.01 N = 50 in each group

46. Interventions to Improve Adherence: Lessons from Other Disease States addressing multiple factors most effective education behavioral support from other members of the health care team Miller et al., The AIDS Reader 10(3):177-185, 2000.

47. Putting it all Together Practical Strategies to Improve Adherence

48. Improving Adherence: before Initiation of Therapy  Assess how medications fit into patient's lifestyle  Consider adherence trial with jelly beans to mesh pill taking with daily schedule  Make contingency plans for pill taking during weekends, holidays, or other changes in routine  Assess adherence and barriers to adherence in a nonjudgmental manner Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

49. Improving Adherence: before Initiation of Therapy  Assess patient's understanding and acceptance of the regimens  Determine other medical barriers to adherence  Manage or refer for management of adherence- limiting co-morbid conditions Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

50. Improving Adherence: before Initiation of Therapy Try to use simple regimens –bid or better –avoid food requirements if possible Clear & simple instructions Negotiated treatment plan

51. Improving Adherence: After Initiation of Therapy Close follow-up Ask patient to verbalize treatment regimen Education about adherence –re-emphasize importance of adherence at each visit, even in patients with good virologic control –review incidence & management of adverse effects often

52. Improving Adherence: After Initiation of Therapy consider cues to remind patients of dosing other reminders: alarms, watches, pagers consider recruiting family/friends as support referral to community support groups involve other members of the health care team formal recognition of adherence as a job responsibility Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

53. Should Public Health Concerns about HIV Resistance Influence Prescribing Practices?

55. DHS/HIV/Resistance /PP Are Non-Adherent Patients Responsible for Rising Levels of Antiretroviral Resistance? From: Little SJ. JAMA 1999;282:1142-9. Little SJ. 8th Conf Retrovirus. Abstract 756 N = 108 Patients Newly HIV-Infected Phenotypic Data: 10-fold Resistance

56. Adherence and Viral Load Suppression 10% adherence difference : 0.33 log VL difference Pill count percent adherence Bangsberg D, et al. AIDS. 2000:14:357 Log 10 HIV RNA copy numbers 7 0 1 2 3 4 5 6 0102030405060708090100

57. High Levels of Adherence are Required to Generate Antiretroviral Resistance Pill count percent adherence Log 10 HIV RNA copy numbers 7 0 1 2 3 4 5 6 0102030405060708090100 Resistant* Sensitive *Primary Drug Resistant Mutation IAS-USA Bangsberg D, et al. AIDS. 2000:14:357

58. Discontinuation of HAART Leads to Rapid Decline in Resistant Strains of HIV SG Deeks et al NEJM 344:472-480

59. Adherence, Antiviral Activity & Risk of Resistance Mutations Increasing probability of selecting mutation Increasing Adherence Low Risk of Resistance: Inadequate Drug Pressure to Sustain Poorly Fit Virus Low Risk of Resistance: Complete Viral Suppression High Risk of Resistance: Drug Pressure Sustains Replication of Poorly Fit Virus

60. Hypothesis Prescribing HIV antiretroviral therapy to patients with marginal adherence will not accelerate the rise in population levels of drug resistance –Nonadherence is associated with insufficient drug pressure to select or sustain resistant virus –It is the patients with higher levels of adherence that may be generating resistant strains

61. Counseling Your Patients about Adherence An Illustrative Cartoon

62. How Resistance Develops to HIV  This is the virus known as HIV. The only thing that matters to him in his short, nasty life is to destroy T-Cells. To do this, he must somehow get over this wall.  The wall is created by taking anti- HIV medications. When the medicines are taken correctly, the virus is unable to climb over the wall to get to your T-cells

63. Sometimes the Wall Comes Down  When you forget to take your evening dose, or only take 2 of your anti-HIV medicines, the strong wall comes down  The virus breaks free and is able to get over the wall.  When he gets to the other side, he discovers a way to get over the wall in the future. This is called resistance. He finds a spring that will give him a little more bounce.

64. The Wall Goes Back Up  When you start taking the medicine regularly again, the wall goes back up.  Sometimes,it’s too late and the virus uses the spring to jump over the wall. At this point, it is a resistant virus The drugs may not be able to keep the wall high enough to stop the springing virus.

65. Lessons to Be Learned  It is better to not take anti-HIV drugs at all than to take them only some of the time.  If you think you may be missing doses often, please tell your health care provider or pharmacist! We promise not to tell your mother.