adherence, resistance and antiretroviral therapy

Adherence, Resistance and Adherence, Resistance and Antiretroviral TherapyAntiretroviral Therapy

Lucille Sanzero Eller, PhD, RNAssociate Professor

Rutgers, The State University of New Jersey College of Nursing

A Local Performance Site of the NY/NJ AETC

September 2009

Objectives Objectives (1)(1)

1. Define adherence.

2. Describe assessment of determinants of adherence to ART.

3. Discuss nursing strategies to promote adherence to ART

Objectives Objectives (2)(2)

4. Describe resistance to ART.

5. Discuss evaluation of adherence.

Primary Goals of ARTPrimary Goals of ART

Maximal and durable viral suppressionRestoration and preservation of immune

function (CD4 count)Improved quality of lifeReduced HIV-related opportunistic

infections (OIs) Reduced morbidity and mortality

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

Adherence Adherence (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.


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.


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 Determinants 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


Individual FactorsCognitive Factors

– cognitive impairment, forgetfulness, confusion Psychological Factors

– depression, anxiety, dementia, psychosisSubstance Abuse

– active drug and alcohol use

Note: Changes in appearance, behavior, eye contact, or speech may indicate any of the above


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 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


Patient-provider relationship – provider competence– trust– communication– adequacy of referrals– inclusion of patient in decision-making


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 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)

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)

Health Belief Model: Concepts Health 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


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


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 AdherenceIndividual Factors

Demographics, lifestyle, social support, mental health, substance use

Perceived susceptibilityof HIV disease progression

Perceived severity of HIV disease progression

Perceived benefitsand barriers of

ART

Likelihood to engage inadherence behavior

Self-efficacy for adherence

Perceived threat of non-adherence

Cues to action

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


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


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 counselorMental health counselor


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


Mental health and Substance Use

– Provide treatment and referral as needed for mental health and substance use before initiating therapy


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


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


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


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


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


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)


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


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?”)

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

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

Selective PressureSelective Pressure

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

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

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 )

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

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

Primary ARV Resistance Primary 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

Primary ARV Resistance Primary 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

Resistance TestingResistance Testing2 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

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

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

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

Adherence Studies Adherence Studies (1)(1)

Multicenter AIDS Cohort Study (MACS)N=539; 77% taking 3 or more medicationsReasons 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 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)


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)


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 Evaluation 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


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


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?”


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?”


Engage patient in problem-solving and alternative scenarios to address specific problems with adherence.


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?


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 AdherenceClinical Evaluation of Adherence

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

Key Points Key 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


3. Determinants of Adherence:i. Individual factorsii. ART regimen and treatment experienceiii. Disease characteristicsiv. Social supportv. Patient-provider relationshipvi. Informational resourcesvii. Health care environment


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


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. Phenotyping2. Genotyping3. Virtual phenotyping


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

adherence, resistance and antiretroviral therapy

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