Author: Lucille Sanzero Eller, PhD, RN Associate Professor Rutgers, The State University of New Jersey College of Nursing A Local Performance Site of the NY/NJ AETC See: http://AIDSETC.org

1. Adherence, Resistance andAdherence, Resistance and
Antiretroviral TherapyAntiretroviral Therapy
Lucille Sanzero Eller, PhD, RN
Associate Professor
Rutgers, The State University of New Jersey
College of Nursing
A Local Performance Site of the NY/NJ AETC
September 2009

2. ObjectivesObjectives (1)(1)
1. Define adherence.
2. Describe assessment of determinants of
adherence to ART.
3. Discuss nursing strategies to promote
adherence to ART

3. ObjectivesObjectives (2)(2)
4. Describe resistance to ART.
5. Discuss evaluation of adherence.

4. Primary Goals of ARTPrimary Goals of ART
Maximal and durable viral suppression
Restoration and preservation of immune
function (CD4 count)
Improved quality of life
Reduced HIV-related opportunistic
infections (OIs)
 Reduced morbidity and mortality

5. Adherence: DefinitionAdherence: Definition
 Right drug
 Right amount
dose (formulation), total duration, intervals
 Right circumstances
e.g., with or without food, not with certain
other drugs
Adapted from Second International Conference on Improving Use
of Medicines, 2004. Retrieved 3/3/08
www.changeproject.org/pubs/Adherence-ICIUM-2004.ppt

6. AdherenceAdherence (1)(1)
>95% adherence is necessary to
achieve viral suppression of <400
copies/mL on unboosted PI therapy,
but more-potent NNRTI regimens lead
to viral suppression at moderate levels
of adherence
Bangsberg, D.R. (2006). Less Than 95% Adherence to
Nonnucleoside Reverse-Transcriptase Inhibitor Therapy Can
Lead to Viral Suppression. Clinical Infectious Diseases. 43,
939–941.

7. AdherenceAdherence (2)(2)
 Although viral suppression may be
possible with moderate adherence, the
probability of viral suppression and
reduced disease progression and
mortality improves with every increase
in adherence level
Bangsberg, D.R. (2006). Less Than 95% Adherence to
Nonnucleoside Reverse-Transcriptase Inhibitor Therapy Can
Lead to Viral Suppression. Clinical Infectious Diseases. 43,
939–941.

8. AdherenceAdherence (3)(3)
Assess the determinants of adherence
– prior to initiation of ART
– within first few days of initiation of ART
– at each visit to assess any change in
determinants

9. Determinants of AdherenceDeterminants of Adherence (1)(1)
Individual Factors
 Sociodemographics
– Basic Needs
 food, shelter, heating, cooling, refrigeration
– Economic Factors
 health insurance, prescription coverage, employment
status, disability insurance, income
– Education
 language, literacy, health literacy
– Cultural beliefs, values, practices

10. Determinants of AdherenceDeterminants of Adherence (2)(2)
Individual Factors
Cognitive Factors
– cognitive impairment, forgetfulness, confusion
Psychological Factors
– depression, anxiety, dementia, psychosis
Substance Abuse
– active drug and alcohol use
Note: Changes in appearance, behavior, eye contact,
or speech may indicate any of the above

11. Determinants of AdherenceDeterminants of Adherence (3)(3)
ART Regimen and Treatment
Experience
– adverse drug effects
– early toxicity
– treatment fatigue
– complexity of regimen (pill burden, dosing
frequency, food requirements)
– difficulty taking meds (swallowing pills, daily
scheduling issues)
– history of reasons for non-adherence
– history of missed medical appointments

12. Determinants of AdherenceDeterminants of Adherence (4)(4)
Disease characteristics
– symptoms
– immune status
– illness severity
Social support
– disclosure status with friends & family
– support from friends
– family support
– partner support

13. Determinants of AdherenceDeterminants of Adherence (5)(5)
Patient-provider relationship
– provider competence
– trust
– communication
– adequacy of referrals
– inclusion of patient in decision-making

14. Determinants of AdherenceDeterminants of Adherence (6)(6)
Informational resources
– Education and information about ARVs, side
effects and their management
Health care environment
– Access- insurance, transportation, etc.
– Convenience
– Confidentiality
– Adherence services at site of medical care

15. Determinants of AdherenceDeterminants of Adherence (7)(7)
Health beliefs
– purpose of treatment
– effectiveness of treatment
– treatment experiences
– self-efficacy
Poorest adherers: <50 years old, cognitively
impaired, substance abusers
(Levine et al., 2005)

16. Patient Readiness for HAARTPatient Readiness for HAART
Health Belief Model can be used to assess
readiness and likelihood of adherence to
Highly Active Antiretroviral Therapy
(HAART)

17. Health Belief Model: ConceptsHealth Belief Model: Concepts (1)(1)
Perceived susceptibility: the individual’s
belief that she is susceptible to HIV disease
progression
Perceived severity: the individual’s belief
that HIV disease progression has serious
consequences

18. Health Belief Model: ConceptsHealth Belief Model: Concepts (2)(2)
Perceived benefits: the individual’s belief
that adherence to ART would reduce
susceptibility to HIV disease progression or
disease severity
Perceived barriers: the individual’s belief
that the materials, physical and
psychological costs of adhering to ART
outweigh the benefits

19. Health Belief Model: ConceptsHealth Belief Model: Concepts (3)(3)
Cues to action: the individual’s exposure
to factors that prompt adherence to ART
Self-efficacy: the individual’s confidence
in her ability to successfully adhere to ART

20. Health Belief Model and Adherence
Individual Factors
Demographics, lifestyle, social support,
mental health,
substance use
Perceived susceptibility
of HIV disease
progression
Perceived severity of
HIV disease progression
Perceived benefits
and barriers of
ART
Likelihood to engage in
adherence behavior
Self-efficacy for
adherence
Perceived threat of
non-adherence
Cues to action

21. Strategies to Promote AdherenceStrategies to Promote Adherence (1)(1)
Lifestyle
– Identify instances when med side effects might
interfere with lifestyle (job, family)
– Fit regimen to lifestyle, preference and priorities
 consider daily schedule, weekly or monthly changes
in schedule
– Balance dosing ease with strength of regimen
 ideal is highest potential viral suppression
acceptable to patient

22. Strategies to Promote AdherenceStrategies to Promote Adherence (2)(2)
Social support/Provider support
– Establish therapeutic/trusting, non-
judgmental/confidential patient-provider
relationship prior to initiating therapy
– Identify & reinforce sources of emotional and
social support
– Educate patient and support persons, if
available, on the regimen prescribed
 Dosage, side effects, side effect management, food
requirements

23. Strategies to Promote AdherenceStrategies to Promote Adherence (3)(3)
Social support/Provider support (cont.)
– Utilize community resources
Support groups, peer mentors
– Collaborate with multidisciplinary team
and refer as needed
Case management for entitlements,
transportation
Substance abuse counselor
Mental health counselor

24. Strategies to Promote AdherenceStrategies to Promote Adherence (4)(4)
Social support/Provider support (cont.)
– Provide contact information to reach
health care provider
 Reinforce seeking expert advice when stopping ARV
– Formulate an individual plan of care for
follow-up visits and phone calls
 Assess side effects of therapy within first few days of
initiation of therapy
 Assess accuracy of understanding of regimen
within first few days of initiation of therapy

25. Strategies to Promote AdherenceStrategies to Promote Adherence (5)(5)
Mental health and Substance Use
– Provide treatment and referral as needed for
mental health and substance use before
initiating therapy

26. Strategies to Promote AdherenceStrategies to Promote Adherence (6)(6)
Perceived susceptibility
– Provide culturally and linguistically appropriate
education and counseling on disease process of
HIV
– Assist patient in developing accurate perception
of risk of non-adherence
– Tailor risk information to individual’s beliefs,
values
Perceived severity
– Explain adherence in reference to
resistance

27. Strategies to Promote AdherenceStrategies to Promote Adherence (7)(7)
Perceived benefits
– Provide specific information re dose, schedule
and dietary requirements of ART and potential
benefits of adherence
– Graph patient’s viral load and CD4+ count
before and throughout treatment to trend
response for reinforcement of benefits of
adherence
– Utilize team approach with nurses, physicians,
pharmacists and peer counselors

28. Strategies to Promote AdherenceStrategies to Promote Adherence (8)(8)
Perceived barriers
– Address patient questions and concerns with
specific information and strategies to address
barriers (e.g., regimen complexity, dietary
restrictions, short and long term side effects)
– Provide incentives for adherence
– Provide ongoing support and reassurance
– Provide and instruct patient how maintain a
daily pill diary to identify barriers to adherence

29. Strategies to Promote AdherenceStrategies to Promote Adherence (9)(9)
Perceived barriers (cont.)
– Anticipate and discuss potential side effects,
their duration and management
– Simplify regimens, dosing and food
requirements
– Include patient in development of plan of
care/decision-making process
– Establish readiness to start therapy

30. Strategies to Promote AdherenceStrategies to Promote Adherence (10)(10)
Cues to action
– Provide detailed, specific, easily understood
information re when and how to take medication
– Provide and instruct patient in the use of tools
to foster and reinforce adherence
 beepers, watches, pill organizers, stickers, telephone
reminders, medication planner, written instructions,
instruct to place medications in location where they
will be seen
– Utilize educational aids including charts,
cartoons, written information

31. Strategies to Promote AdherenceStrategies to Promote Adherence (11)(11)
Cues to action (cont.)
– Provide adherence assessment and counseling
at routine medical visits
– Enlist friends/family/partner to provide
motivation and remind patient to take
medications
– Collaborate with patient to choose a regular
daily activity as a cue to take medication
(getting out of bed, making breakfast or dinner)

32. Strategies to Promote AdherenceStrategies to Promote Adherence (12)(12)
Self-efficacy
– Provide skill building for adherence
 role-playing (e.g. patient-provider communication
skills; use of jelly beans to practice taking
medications on schedule)
 problem solving (what to do for late or missed dose)
 planning ahead for refills
 management of medications during changes in daily
schedule
 potential side effects, self-management strategies,
when to call the health care provider

33. Strategies to Promote AdherenceStrategies to Promote Adherence (13)(13)
Self-efficacy (cont.)
• Collaborate with patient on potential solutions
for patient-identified barriers to adherence.
• Provide positive reinforcement for adherence.
• Contract with patient for adherence.
• Utilize role models with adherent behavior
• Utilize the problem-solving process (e.g. ask the
patient “Think of a time when you might miss a
dose of your medication. What would you do
then?”)

34. ResistanceResistance
The ability of HIV to enter the cell and
replicate despite presence of antiretroviral
drugs
Can lead to increasing viral load, ongoing
damage to immune system, progression of
HIV disease

35. Reasons for ResistanceReasons for Resistance
High rate of HIV replication (109
to 1010
virions/person/day)
Error prone HIV polymerase
Selective pressure and mutant viral strains
are cause of resistance

36. Selective PressureSelective Pressure
ARTs suppress replication of wild type
(original) virus while ART-resistant mutant
virus continues to replicate

37. Cross-resistanceCross-resistance
Development of resistance to a drug in a
particular class may transfer to drugs in the
same class
Limits options for ART

38. Adherence/Resistance RelationshipAdherence/Resistance Relationship
Highly Active Antiretroviral Therapy
(HAART) Observational Medical Evaluation
and Research (HOMER) study
1191 ARV naïve adults receiving 2 NRTIs
plus a PI or NNRTI
Found bell-shaped relationship between
level of adherence and drug-resistance
mutations
(Harrigan et al., 2005 )

39. Adherence/Resistance Relationship
(Harrigan et al., 2005)

40. Primary ARV ResistancePrimary ARV Resistance (1)(1)
Patient who is ARV naïve is infected with
ARV-resistant virus
Single or multi-class drug resistance
increasing
Primary resistance in 10 North American
cities (Little et al. 2002)
– 3.4% 1995-1998
– 12.4% 1999-2000

41. Primary ARV ResistancePrimary ARV Resistance (2)(2)
Prevalence of primary drug resistant HIV
mutations varies geographically (Wolf, 2006)
– San Francisco 26%
– Spain 19%
– European multicenter study 10%
Guidelines recommend resistance testing
prior to ART initiation (USDHHS, 2004; EuroGuidelines
Group for HIV Resistance, 2001

42. Primary ARV ResistancePrimary ARV Resistance (3)(3)
RESINA project – Germany 2001-03
– Effects of pre-treatment resistance testing and
tailored first-line HAART treatment decisions
based on this genotype testing
– N=269, 48 weeks after initiation of genotype-
guided HAART
Comparable efficacy of first-line HAART in
groups with resistant HIV and wild-type HIV

43. Resistance TestingResistance Testing
2 Types of assays
– Phenotypic
– Genotypic
Both types of assay require presence of a
minimum amount of HIV
– Tests may not detect resistance at viral load
below 500-1000 copies/ml
– Test may not detect “minority” mutations, those
comprising <20% of virus population

44. PhenotypingPhenotyping
Direct quantification of drug sensitivity
– Increasing concentrations of drug added to
patient HIV cultures
– Viral replication compared to that of wild-type
virus
– The IC50 is concentration of drug that inhibits
viral replication by 50%
Disadvantages
– Lengthy procedure
– Costly

45. GenotypingGenotyping
Indirect measure of drug resistance
– Genetic code of patient virus is compared to
that of wild-type virus
– Resistance is defined by number of known
resistant mutations (those associated with
reduced drug sensitivity) present in patient
sample at time of test

46. Virtual PhenotypingVirtual Phenotyping
Predicts the phenotype from the genotype
– Patient’s genotypic mutations are compared
with a database of samples of paired genotypic
and phenotypic data
– IC50 of matching viruses are averaged, and the
likely phenotype of patient virus identified
Advantages
– requires less time than phenotyping
– less costly than phenotyping

47. Adherence StudiesAdherence Studies (1)(1)
Multicenter AIDS Cohort Study (MACS)
N=539; 77% taking 3 or more medications
Reasons for non-adherence by frequency
– Forgot, change in daily routine, busy, away from
home
– To avoid side effects, slept, ran out of meds, felt
depressed or ill, felt the drug was toxic/harmful,
don’t want to take pills
– Too many pills to take, instructions conflicted,
didn’t want others to notice, had problem taking
pills (Kleeberger et al, 2001)

48. Adherence StudiesAdherence Studies (2)(2)
Most patients willing to tolerate severe side
effects, large pill burden, inconvenience for
higher potency of ART
(Miller et al., 2002; Sherer et al., 2005)

49. Adherence StudiesAdherence Studies (3)(3)
 Phone interviews for patient preferences
and priorities re ART (N=387)
– Lower viral load, higher CD4, durability of viral
suppression were more important than
resistance profile, GI side effects, dosing
frequency and pill burden
– 92% preferred more effective, 89% preferred
more durable 2X day regimen to more
convenient 1X day
(Sherer et al., 2005)

50. Adherence StudiesAdherence Studies (4)(4)
Review of 24 ART adherence
interventions
– The most effective adherence interventions
targeted patients with known or anticipated
adherence problems
– improvements held over time
(Amico, Harman & Johnson, 2006)

51. Evaluation of AdherenceEvaluation of Adherence (1)(1)
Adherence to ART declines over time
Ongoing assessment and intervention
critical
Self-report is primary means of
assessment; pharmacy records and pill
counts can also be used as adjuncts

52. Evaluation of AdherenceEvaluation of Adherence (2)(2)
 Use non-judgmental language and tone of
voice.
 the patient who senses disapproval and is
shamed for non-adherence is less likely to
provide accurate information
 Be aware of non-verbal communication.
 facial expression, posture, tone of voice,
seating arrangement, use of personal space

53. Evaluation of AdherenceEvaluation of Adherence (3)(3)
 Ask questions in a way that gives
permission for missed doses.
 “Which doses are the hardest to remember to
take?” “Which doses did you miss?”
 Use open-ended questions.
 “Can you tell me about how you take your
medicines on a typical weekday?”
 “How do you take your medicines on a weekend
day?”

54. Evaluation of AdherenceEvaluation of Adherence (4)(4)
 Communicate the understanding that
problems with adherence are expected.
 Normalization of adherence problems opens
door for honest communication.
 “Many people have difficulty sticking to their
medication schedule. What problems have you
had with taking your medications?”

55. Evaluation of AdherenceEvaluation of Adherence (5)(5)
Engage patient in problem-solving and
alternative scenarios to address
specific problems with adherence.

56. Evaluation of AdherenceEvaluation of Adherence (6)(6)
 Ask permission to provide information and
feedback to lower patient resistance to the
information.
 “Can I give you some suggestions that may help
with that problem?”
 “Can I tell you how taking your medications on
time can keep you healthy?

57. Evaluation of AdherenceEvaluation of Adherence (7)(7)
 When providing information, keep it simple.
 Stress and anxiety lower the ability to
assimilate new information.
 Assess understanding of new information
by asking patients to repeat it in their own
words.

58. Clinical Evaluation of AdherenceClinical Evaluation of Adherence

Level of HIV RNA in plasma

CD4+ lymphocyte count

Clinical condition of patient

Resistance testing

59. Key PointsKey Points (1)(1)
1. Adherence:
 Right drug
 Right amount
 dose (formulation), total duration, intervals
 Right circumstances
2. Optimal adherence to ART = 95% or more
of all prescribed doses taken on time

60. Key PointsKey Points (2)(2)
3. Determinants of Adherence:
i. Individual factors
ii. ART regimen and treatment experience
iii. Disease characteristics
iv. Social support
v. Patient-provider relationship
vi. Informational resources
vii. Health care environment

61. Key PointsKey Points (3)(3)
4. Health Belief Model can be used to assess
readiness for ART and develop strategies to
promote adherence:
 Perceived susceptibility
 Perceived severity
 Perceived benefits
 Perceived barriers
 Cues to action
 Self-efficacy

62. Key PointsKey Points (4)(4)
5. Resistance- the ability of HIV to enter the
cell and replicate in the presence of ARVs
6. Resistance testing- identifies drugs to
which the virus is not resistant
1. Phenotyping
2. Genotyping
3. Virtual phenotyping

63. Key PointsKey Points (5)(5)
7. Evaluation of adherence
 Adherence declines over time
 Ongoing evaluation and intervention critical
 Self-report is primary means of evaluation
8. Clinical evaluation of adherence
 Level of HIV RNA
 CD4+ lymphocyte count
 Clinical condition of patient
 Resistance testing