Adherence to Antiretroviral
Therapy for Pediatric HIV Infection:
A Review with Recommendations
for Research and Clinical
Jane M. Simoni
University of Washington
NIMH/IAPAC International Conference
on HIV Treatment Adherence
Jersey City, New Jersey March 8-10, 2006
• Arianna Montgomery, CDC
• Erin Martin, Children’s National Medical
• Michelle New, Children’s National Medical
• Penny Demas, Montefiore Medical Center
• Sohail Rana, Howard University
• Combination highly active antiretroviral therapy
– Suppress HIV
– Improve immune function
– Reduce morbidity and mortality
• Viral suppression requires
– High levels of adherence to therapy
• Most research has been conducted with adults
– Different approaches to the study of adherence and
interventions to improve adherence are required
– Unique psychosocial, developmental, and pharmacologic
issues in children and adolescents
Aims of the Review
1. Describe the advantages and disadvantage of
various adherence assessment methodologies
(with a focus on factors that impact pediatric
2. Summarize the empirical findings regarding
estimates of adherence among pediatric
3. Review the findings on correlates of
4. Describe empirically tested interventions to
Data Sources for the Review
• A thorough search: published journal articles,
abstracts, books, and ongoing studies on pediatric
adherence to antiretroviral therapy (Pubmed, PsycINFO,
Medline, AIDSLINE, and CRISP
• Combinations of the search terms (HIV/AIDS and
pediatric/children and compliance/adherence) were used
• Through December, 2005.
• Hand searched references for relevant articles
• Input from colleagues
• Three reviewers narrowed down 252 citations to 53
relevant to the objectives.
1. Adherence Assessment
• Range of methodologies for capturing antiretroviral
– Direct methods:
• biological assays of active drug, metabolite or other markers in
– Indirect methods:
• self-report; caregiver report; clinician assessment; medical chart
review; clinic attendance; pill count; pharmacy refill records;
electronic drug monitoring (EDM); behavioral observation
(directly observed therapy); and therapeutic impact (HIV-1 RNA
viral load (VL), CD4 lymphocyte count), Centers for Disease
Control-defined stage of disease progression, and mortality.
• Assessing adherence in pediatric populations
poses specific challenges (Brakis-Cott & Mellins (2003) ; Dolezal
et al., 2003.; (Matsui, 2000).
– Medications only available in liquid form (precludes
pill counts and EDM)
– Pre-packaged pill boxes or syringes
– Self-report : cognitive abilities and developmental level
– Caregiver report: vantage point varies depending on
role (parent or guardian, other family member,
babysitter, home health aide, or school nurse). Each
may have incomplete information about the specifics
of medication taking.
– No one individual is consistently the most reliable
2. Estimates of Adherence
• Twenty-five studies reporting empirical data on pediatric
• Articles were mostly based on studies in the U.S.
• Sample sizes ranged from 6 to 161 participants (3 months to
24 years of age).
• Most participants were infected perinatally.
• Adherence estimates varied widely but were generally
• Comparisons complicated by different assessment methods
• Data on adherence estimates were collected mainly from
patient and caregiver reports
• Few studies employed purportedly more objective methods
such as EDM.
Estimates of Adherence (cont)
• Comparison of assessment strategies (Wiener et al., 2004)
– Provider (i.e., clinical nurse) overestimated adherence.
– Self-reported adherence higher than provider ratings (social
– Patients who reported even one missed dose in the last
week were at greater risk for of having a VL > 10,000.
– Face-to-face interviews, quick and easy to administer.
– Intensive daily phone diary had similar validity to the self-
report interview (VL), but expensive and burdensome
– VL is not a perfect indicator of adherence
3. Factors Related to Adherence
• Adult typologies note variables related to the patient,
disease, treatment regimen, patient-provider
relationship, and clinical setting (Ickovics & Meisler 1997 )
• But, for pediatric populations?
» Role of the caregiver
» Developmental challenges
Factors Related to Adherence (cont)
– May also be HIV-positive
– May have other co-morbidities and stressors
– Stigma associated with the diagnosis of HIV
and the caregiver’s often inadequate resources
to cope with the disease often mean taking
medications and attending clinic appointments
remain very low in the hierarchy of daily
priorities in the life of the family
Factors Related to Adherence (cont)
• Adolescents’ unique factors
– Marhefka et al. 2004. Adolescents have same
difficulties as adults, but less autonomy, privacy, and
– Pugatch, 2002 (6 HIV+ teenagers aged 16-24 years)
• Unique factors: involvement and the present
orientation of youth.
– Trocme, 2002 (29 HIV-positive French adolescents)
• Unique factors: Nonadherence way to express autonomy
Adherence generally decreases as teenagers assume
responsibility for their medication (Battles et al., 2002).
Interventions and Strategies
to Improve ART Adherence:
Empirical Evidence of Efficacy
• Seven published studies that empirically
evaluated interventions to enhance
adherence among pediatric populations:
• Only RCT
• Home nursing visits (67 families) as a means
of increasing adherence.
– Designed to identify and resolve barriers to
medication adherence (e.g. pill swallowing
training, other barriers not reported).
– Treatment group:
• knowledge scores significantly improved (p < .02)
• self-reported adherence marginally improved (p=.07).
• Directly observed therapy (DOT)
– To determine whether prolonged elevation
of VL could be attributable to poor
– Found that DOT administered for 4-8 days
significantly lowered the viral loads of all 6
children in their sample.
• Examined an intensive DOT program (6
families who showed continued high VL loads
despite viral sensitivity and caregiver
assertions of regular medication
– Home health nurse and DOT. Supplemented by
intensive education and counseling during a 4-day
hospitalization and post-discharge.
– Four of the six families responded with improved
viral loads following the DOT hospitalization.
• 12-week educational program (23 HIV-positive youths,
aged 15-22 years, and 23 “treatment buddies”):
– 6 meetings with treatment buddy and 6 meetings with youths
only (2 hours and included a meal).
– Devices (watches, pill boxes, and calendars) were introduced.
– Three months post-intervention:
• 91% reported improved adherence, which case managers
• None had a 1log reduction in VL to UD.
• Four participants indicated improved immune functioning.
• Theory-driven intervention
• Based on Prochaska’s Stages of Change model.
• Intensive 8-week program with video- and audio-tape material
• Assessed stage of readiness to adhere with HAART.
– Precontemplation, Contemplation, Preparation, Action/Maintenance, and
– e.g. Precontemplation material: addressed concerns about taking
– e.g. Preparation program: practiced a regimen with surrogate pills for 1-2
• Primarily for treatment-naïve subjects, prepare for successful
• Evaluation was hampered by high attrition (only 18 of the 65 enrollees
completed the full program), attributed to difficulties in scheduling
program visits and the labor intensive intervention.
• Inserted a gastrostomy tube (GT) in 17 children on
HAART who were at least mildly symptomatic.
• In year post-procedure:
– Clinically significant improvement (>=2log VL reduction) in 10
– All 17 patients were noted to be “adherent” by care providers.
• Attributed to initiation of a new medication regimen at time of
procedure for all 10 who showed improvement
– Recommend that HAART regimen be changed after the
GT placement to minimize the impact of viral resistance
secondary to nonadherence.
• Parents reported:
– GT tubes were well tolerated
– Reductions in medication administration time
– Improvement in child behavior during medication
• Multisystemic therapy, an intensive, home-based family
• Conducted by retrospective chart review of 19 children
• 90% of children and families referred to the program
accepted the referral and 95% received a full dose of
treatment, suggesting high program feasibility.
– Caregiver general HIV knowledge improved significantly
– Caregiver-reported adherence did not change
– VL were found to significantly decrease; majority of children
maintained these improvements during the 3 months after treatment
• Results suggest that MST holds promise as an intervention
for improving health outcomes among pediatric patients with
2 Interventions in progress
1. Pediatric IMPACT
• Largest evaluation of a pediatric adherence intervention
and randomized controlled trial (on-going, CDC-funded)
– HIV+ children <13 and primary caregiver (New York City
and Washington, D.C).
– Intervention Includes:
• Adherence Coordinator, initial needs assessment, and
tailored modular interventions (including home-based
• Randomly assigned to either a “minimal” or “enhanced” arm.
• EIG: Six modules: HIV education, HIV diagnosis disclosure
education to children, behavior modification, medication
swallowing, medication management, and referrals to social
and mental health services.
2. Adolescent Impact
• CDC-funded RCT of an intervention to improve adherence to
care and treatment and reduce sexual transmission risk
behavior in youth ages 13-21 with HIV.
• The study is currently being conducted in five pediatric and
adolescent clinics in New York City, Baltimore, and Washington
• Adolescent impact provides education, social support and skills
training through an integrated series of one-on-one and group
– 7group sessions address health and developmental issues common to
youth with HIV
– 5 five one-on-one sessions are used to tailor prevention messages to the
unique health and risk profile of each teen.
– Teens receive organizational tools including a personal digital assistant
(PDA) with adherence software
– Optional home visit is also provided.
1. Researchers are using a range of strategies for measuring
adherence, with patient self-report or caregiver reports the most
2. Estimates of adherence across studies are low
• Nonadherence remains problematic
• Low levels of adherence are typical of pediatric populations
with other chronic illnesses (Dolezal et al. 2003; Rapoff book
• Different measures and study methodologies complicate the
3. Correlates of adherence are reported rather haphazardly
• As variables related to the medication/regimen, patient, or
• Overarching models for understanding correlates and
predictors of adherence are noticeably lacking
4. Literature on the development and formal evaluation of theory-
driven strategies for improving adherence remains sparse
1. Need for definitive guidelines for selecting
appropriate assessment methods
2. Perhaps consider the use of multiple methods or
3. Methods other than self-report may be too
unreliable, burdensome, or costly
4. Simple question (doses were missed in the last
week) may be sufficient (Wiener et al., 2004; Simoni,
J. M.(in press)
5. Getting valid self-reports of pediatric adherence may
depend on: honesty, respect, time to talk privately,
and ability to listen well. (Strug et al. 2003)
1. Empirical studies provide:
– Utility and efficacy of DOT, a 12-week educational
program, gastrostomy tube insertion, and nursing
– However, findings were preliminary and N’s small
– Adherence to the intervention itself was often
2. Other studies provide:
– Strategies that rely on clinical practice wisdom and
lack formal evaluation (Pontali et al 2005)
Recommendations for Future
1. Focus on evaluating the validity and
reliability of self-report adherence measures
2. Comparing self-report to more objective
measures or clinical indicators are needed to
identify the most cost-effective assessment
strategy (Wiener et al., 2004).
3. Investigate adherence levels and
potential correlates of adherence
– Should incorporate prospective studies (HAART
– Steele and Grauer advise systematically examining
factors that may predict adherence and developing
risk profiles to target potential non-adherers.
– Further examination of factors related to caregivers
– Development and evaluation of adherence models
that incorporate multiple domains of
influence.(multi-site studies and the incorporation of
4. Interventions to enhance adherence
– Need to be theory-based and empirically tested
– Need to go beyond cognitive intervention and
education and counseling (Pugatch, 2002) and will be
long-term (Brackis-Cott, 2003)
5. Need to expand work in international settings
and resource-constrained environments