1. Adherence, Resistance and Antiretroviral 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. Objectives (1) 1. Define adherence.
2. Describe assessment of determinants of adherence to ART.
3. Discuss nursing strategies to promote adherence to ART

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

4. Primary 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: 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, Retrieved 3/3/08

6. Adherence (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. Adherence (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. Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (5)
Patient-provider relationship
provider competence
trust
communication
adequacy of referrals
inclusion of patient in decision-making

14. Determinants of Adherence (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 Adherence (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 HAART
Health Belief Model can be used to assess readiness and likelihood of adherence to Highly Active Antiretroviral Therapy (HAART)

17. Health Belief Model: Concepts (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: Concepts (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: Concepts (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 benefits
and barriers of ART
Perceived susceptibility
of HIV disease
progression
Perceived severity of
HIV disease progression
Perceived threat of
non-adherence
Likelihood to engage in
adherence behavior
Cues to action
Self-efficacy for
adherence

21. Strategies to Promote Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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. Resistance
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 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 Pressure
ARTs suppress replication of wild type (original) virus while ART-resistant mutant virus continues to replicate

37. Cross-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 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 Resistance (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%
12.4%

41. Primary ARV Resistance (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 Resistance (3)
RESINA project – Germany
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 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 copies/ml
Test may not detect “minority” mutations, those comprising <20% of virus population

44. Phenotyping Direct quantification of drug sensitivity Disadvantages
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. Genotyping 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 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 Studies (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 Studies (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 Studies (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 Studies (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 Adherence (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 Adherence (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 Adherence (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 Adherence (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 Adherence (5)
Engage patient in problem-solving and alternative scenarios to address specific problems with adherence.

56. Evaluation of Adherence (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 Adherence (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 Adherence
Level of HIV RNA in plasma
CD4+ lymphocyte count
Clinical condition of patient
Resistance testing

59. Key Points (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 Points (2) 3. Determinants of Adherence: Individual factors
ART regimen and treatment experience
Disease characteristics
Social support
Patient-provider relationship
Informational resources
Health care environment

61. Key Points (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 Points (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
Phenotyping
Genotyping
Virtual phenotyping

63. Key Points (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