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

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

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

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

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

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.

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.

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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?”)

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

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

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

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

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 )

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

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

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

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

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

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

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

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

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)

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)

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)

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)

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

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

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?”

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?”

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

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?

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.

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

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

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

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

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

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