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) • >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 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 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% 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 • 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 500-1000 copies/ml • Test may not detect “minority” mutations, those comprising <20% 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 • 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)