Adherence to HIV Medications: An Evidence-Based Review

Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington

Adherence
[physicians] should keep aware of the fact that patients often lie when they state that they have taken certain medicines."
- Hippocrates

Drugs dont work if people dont take them.

- C. Everett Koop

Adherence and Antiretroviral Therapy

Measuring Adherence Why Adherence Matters
antiretroviral efficacy development of resistance

Factors associated with adherence Interventions to improve adherence

How do we Measure Adherence?

Provider Estimates Patient self-report Diaries Pill Count Laboratory Markers Electronic Devices

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

Clinicians Estimates of Adherence Not Much Better Than Random

Bangsberg Paterson Haubrich Steiner Bosely Charney Caron Gilbert Blowey Mushlin 2001 2000 1999 1995 1995 1967 1978 1980 1997 1977 JAIDS Annals Int Med AIDS Arch Int Med Eur Resp J Pediatrics Clin Pharmacol Can Med Assoc J Ped Nephrology Arch Int Med HAART HAART HAART AZT Inhaled terbutaline Penicillin Anatacids Digoxin Cyclosporin Hypertensive

Provider Estimate vs.Three 3-Day Patient Report Compared to Pill Count

n=45
Provider Estimate and Pill Count Adherence
100 100

Three 3-day Self Report and Pill Count Adherence

80

80

60

60

Provider Estimate

40 Patient Report

40

20 0

20

0 Pill Count

20

40

60

80

100

20

40

60

80

100

Pill Count

Provider Estimate R sq = 0.26

Bangsberg et al JAIDS 2001:26:435

Patient Report R sq = 0.72

Measuring Adherence: Patient Self-Report

patients tend to report what they think the provider wants to hear1 patients are unlikely to misrepresent high 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 monitoring2
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.

How Do Adherence Measurement Techniques Compare to One Another?

ADEPT Study; N=81 patients
100 90 80 70 60 50 40 30 20 10 0 Self-Report Clinician Estimate Pill Count Electronic bottle cap

Adherence, %

Adapted from Golin C et al. 1999; Miller L et al. 1999.

Measuring Adherence: Patient Self-Report

Nevertheless, studies have documented an association between patient-reported adherence and viral outcome1-3 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.

Measuring Adherence: Diaries

In theory, better than relying on memory in practice, not very useful
many patients do not fill them in1 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.

Measuring Adherence: Pill Counts

Advantages:
more objective than patient report correlates better with electronic bottle caps than does self-reported adherence1

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

1. Golin C, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago. Abstract 95

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

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

Measuring Adherence: Electronic Bottle Caps

caps harbor chips that register each time a bottle is opened or closed

MEMScaps, Aardex Corp.

QuickRead software, for use with MEMScaps system

http://www.aardex.ch/QRCalendar.htm

QuickRead software, for use with MEMScaps system

http://www.aardex.ch/QRChronology.htm

Measuring Adherence: Electronic Bottle Caps

Advantages
more difficult for patients to exaggerate their adherence reveals patterns of nonadherence 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

The Future of Adherence Assessment? Computer-Assisted Self-Interviewing (CASI)

Purposes of CASI
Determine patients understanding of medication regimen Determine patients adherence over 3-day period

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) http://www.edermpda.com/hivadhere/

Printed with permission from West Portal Software Corp.

Printed with permission from West Portal Software Corp.

Printed with permission from West Portal Software Corp.

Printed with permission from West Portal Software Corp.

Printed with permission from

West Portal Software Corp.

Printed with permission from West Portal Software Corp.

Printed with permission from

West Portal Software Corp.

Printed with permission from

West Portal Software Corp.

Printed with permission from West Portal Software Corp.

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)

Why is Adherence so Important for Antiretroviral Therapy?

I. Efficacy

II. Resistance

Virologic Control falls sharply with diminished adherence

% Achieving <500 copies/mL
90 80 70 60 50 40 30 20 10 0 95-100% 90-95% 80-90% 70-80% < 70%

N = 504 pts on HAART

Adherence, by prescription refill

Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.

Virologic Control falls sharply with diminished adherence

100
Patients with HIV RNA <400 copies/mL, %

80 60 40 20 0 >95 90-95

8090

70-80

<70

PI adherence, % (electronic bottle caps)

Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.

Adherence and AIDS-Free Survival

10% Adherence difference = 21% reduction in risk of AIDS
1.00

Proportion AIDS-Free

0.75

0.50

0.25 P = .0012 0.00

10

15

20

25

30

Months from entry

Bangsberg D, et al. AIDS. 2001:15:1181

Adherence O 90100% O 5089% O 049%

Adherence & Drug Resistance

HIV Reverse Transcriptase (RT) is errorprone 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

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-documented1,2

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

What Contributes to Sub-Optimal Adherence?

Reasons for Non-Adherence: Clinician vs Patient Views

60 50
Clinican Patient

value, %

40 30 20 10 0
No. of doses or pills Side Effects Meal Instructions Schedule complexity Other

Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281

Predictors of Poor Adherence

active alcohol1 or substance2 abuse work outside the home for pay1 depressed mood1 lack of perceived efficacy of HAART3 lack of advanced disease4 concern over side effects4

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.

Predictors of Poor Adherence, continued

non-caucasian race documented in some studies1-3 but not others5
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

Predictors of Poor Adherence, continued

inability to fit medications into daily schedule tid dosing, food requirements1

1. Stone VE, et al. JAIDS 2001; 28:124-131

Other Considerations
a large proportion of patients incorrectly recall their medication schedules1,2 Virologic control does not necessarily imply high levels of adherence3
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.

Factors Associated with Higher Levels of Adherence

twice-daily or once-daily regimens1,4 belief in own ability to adhere to regimen1 not living alone2 dependent on a significant other for support2 history of Opportunistic Infection or Advanced HIV disease3

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.

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.

Interventions Shown to Improve Adherence to Antiretrovirals

medication alarms1 education & counseling sessions2,3 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.

Self-Adminstered vs Directly Observed Therapy During Incarceration

N = 50 in each group
100 90 80 70 60 50 40 30 20 10 0 w4

% with VL < 50 copies/mL

DOT <50 SAT <50

w8

w16

w24

w48

w64

w72

w80

w88

p < 0.01
Fischl et al 8th CROI, 2001 abstract 528

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.

Putting it all Together

Practical Strategies to Improve Adherence

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.

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 adherencelimiting co-morbid conditions

Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

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

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

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.

Should Public Health Concerns about HIV Resistance Influence Prescribing Practices?

Are Non-Adherent Patients Responsible for Rising Levels of Antiretroviral Resistance?

N = 108 Patients Newly HIV-Infected 10 Phenotypic Data: 10-fold Resistance
8 1996-1998 1999-2000

Resistant Isolates %

7 6

6 4 2 2 1

3 2

0 NRTI NNRTI PI

From: Little SJ. JAMA 1999;282:1142-9.

Little SJ. 8th Conf Retrovirus. Abstract 756

DHS/HIV/Resistance /PP

Adherence and Viral Load Suppression

10% adherence difference : 0.33 log VL difference
7
Log10 HIV RNA copy numbers 6 5 4 3 2 1 0 0 10 20 30 40 50 60 70 80 90 100 Pill count percent adherence
Bangsberg D, et al. AIDS. 2000:14:357

High Levels of Adherence are Required to Generate Antiretroviral Resistance

7 Log10 HIV RNA copy numbers 6 5 4 3

Resistant* Sensitive
*Primary Drug Resistant Mutation IAS-USA

2
1 0 0 10 20 30 40 50 60 70 80 90 100 Pill count percent adherence

Bangsberg D, et al. AIDS. 2000:14:357

Discontinuation of HAART Leads to Rapid Decline in Resistant Strains of HIV

SG Deeks et al NEJM 344:472-480

Adherence, Antiviral Activity & Risk of Resistance Mutations

Increasing probability of selecting mutation

Low Risk of Resistance: Inadequate Drug Pressure to Sustain Poorly Fit Virus

High Risk of Resistance: Drug Pressure Sustains Replication of Poorly Fit Virus

Increasing Adherence

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

Counseling Your Patients about Adherence

An Illustrative Cartoon

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 antiHIV medications. When the medicines are taken correctly, the virus is unable to climb over the wall to get to your T-cells

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.

The Wall Goes Back Up

When you start taking the

medicine regularly again, the

wall goes back up. Sometimes,its 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.

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.