Adherence to HIV Medications: An EvidenceBased Review

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 dont work if people dont 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

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

7
Provider Estimate vs.Three 3-Day Patient Report
Compared to Pill Count
n45
Provider Estimate R sq 0.26
Patient Report R sq 0.72
Bangsberg et al JAIDS 200126435
8
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
19821-28. 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 1991811978-1988.
9
How Do Adherence Measurement Techniques Compare
to One Another?
ADEPT Study N81 patients
Adherence,
Adapted from Golin C et al. 1999 Miller L et al.
1999.
10
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.
11
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.
12
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
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
QuickRead software, for use with MEMScaps system
http//www.aardex.ch/QRChronology.htm
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)

• 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/
20
Printed with permission from West Portal
Software Corp.
21
Printed with permission from West Portal
Software Corp.
22
Printed with permission from West Portal
Software Corp.
23
Printed with permission from West Portal
Software Corp.
24
Printed with permission from West Portal
Software Corp.
25
Printed with permission from West Portal
Software Corp.
26
Printed with permission from West Portal
Software Corp.
27
Printed with permission from West Portal
Software Corp.
28
Printed with permission from West Portal
Software Corp.
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
N 504 pts on HAART
Achieving lt500 copies/mL
Adherence, by prescription refill
Montessori, V, et al. XII International
Conference on AIDS, Durban, South Africa, 2000.
Abstract MoPpD1056.
32
Virologic Control falls sharply with diminished
adherence
Patients with HIV RNAlt400 copies/mL,
PI adherence, (electronic bottle caps)

Paterson, et al. 6th Conference on Retroviruses
and Opportunistic Infections 1999 Chicago, IL.
Abstract 92.
33
Adherence and AIDS-Free Survival
10 Adherence difference 21 reduction in risk
of AIDS
1.00
0.75
Proportion AIDS-Free
0.50
0.25
P .0012
0.00
0
5
10
15
20
25
30
Months from entry
Bangsberg D, et al. AIDS. 2001151181
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 gt sub-therapeutic drug
  levels gt incomplete viral suppression gt
  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. 19962761955-1956. 2.
Montaner JS, et al. JAMA. 1998279930-937.
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 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 Oct1(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 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.
199914(suppl 2)53. 4. Kalichman SC, et al. J
Gen Intern Med. 199914267-273. 5. Stone VE, et
al. JAIDS 2001 28124-131
40
Predictors of Poor Adherence, continued

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

1. Stone VE, et al. JAIDS 2001 28124-131
41
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. 19931531869-1878. 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 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 199818117-125. 2. Morse EV et
al, Soc Sci Med 1991321161-1167. 3. Singh N,
et al, AIDS Care 19968261-269. 4. Stone VE, et
al. JAIDS 2001 28124-131
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 alarms1
• education counseling sessions2,3
• Directly Observed Therapy (DOT)4,5

1. Samet JH, et al. Am J Med. 199292495-502.
2. Malow RW, et al. Alcohol Drug Abuse
1998491021-4. 3. Tuldra A, et al. 39th
Interscience Conference on Antimicrobial Agents
and Chemotherapy 1999 Abstract 595. 4. Sorensen
JL, et al. AIDS Care. 199810297-312. 5. Wall
TL, et al. Drug Alcohol Depend. 199537261-269.
45
Self-Adminstered vs Directly Observed Therapy
During Incarceration
N 50 in each group
p lt 0.01
Fischl et al 8th CROI, 2001 abstract 528
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?
54
(No Transcript)
55
Are Non-Adherent Patients Responsible for Rising
Levels of Antiretroviral Resistance?
N 108 PatientsNewly HIV-Infected Phenotypic
Data 10-fold Resistance
From Little SJ. JAMA 19992821142-9.Little
SJ. 8th Conf Retrovirus. Abstract 756
DHS/HIV/Resistance /PP
56
Adherence and Viral Load Suppression10
adherence difference 0.33 log VL difference
Pill count percent adherence
Bangsberg D, et al. AIDS. 200014357
57
High Levels of Adherence are Required to Generate
Antiretroviral Resistance
Resistant
Sensitive
Primary Drug Resistant Mutation IAS-USA
Pill count percent adherence
Bangsberg D, et al. AIDS. 200014357
58
Discontinuation of HAART Leads to Rapid Decline
in Resistant Strains of HIV
SG Deeks et al NEJM 344472-480
59
Adherence, Antiviral Activity Risk of
Resistance Mutations
High Risk of Resistance Drug Pressure Sustains R
eplication of Poorly Fit Virus
Low Risk of Resistance Complete Viral Suppression
Low Risk of Resistance Inadequate Drug
Pressure to Sustain Poorly Fit Virus
Increasing probability of selecting mutation
Increasing Adherence
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,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.

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.