Adherence, Resistance and Antiretroviral Therapy

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, 2004. Retrieved
  3/3/08 www.changeproject.org/pubs/Adherence-ICIUM-
  2004.ppt

6
Adherence (1)

• gt95 adherence is necessary to achieve viral
  suppression of lt400 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, 939941.

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, 939941.

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 lt50 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 individuals belief
  that she is susceptible to HIV disease
  progression
• Perceived severity the individuals belief that
  HIV disease progression has serious consequences

18
Health Belief Model Concepts (2)

• Perceived benefits the individuals belief that
  adherence to ART would reduce susceptibility to
  HIV disease progression or disease severity
• Perceived barriers the individuals 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 individuals exposure to
  factors that prompt adherence to ART
• Self-efficacy the individuals 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 ofART
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 individuals 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 patients 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 1995-1998
• 12.4 1999-2000

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 2001-03
• Effects of pre-treatment resistance testing and
  tailored first-line HAART treatment decisions
  based on this genotype testing
• N269, 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 500-1000 copies/ml
• Test may not detect minority mutations, those
  comprising lt20 of virus population

44
Phenotyping

• 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
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
• Patients 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)
• N539 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, dont want to take pills
• Too many pills to take, instructions conflicted,
  didnt 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 (N387)
• 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