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									Adherence to Antiretroviral
Therapy for Pediatric HIV Infection:
A Review with Recommendations
for Research and Clinical
Management



 Jane M. Simoni
 University of Washington

 NIMH/IAPAC International Conference
 on HIV Treatment Adherence
 Jersey City, New Jersey               March 8-10, 2006
Collaborators
  • Arianna Montgomery, CDC
  • Erin Martin, Children’s National Medical
    Center
  • Michelle New, Children’s National Medical
    Center
  • Penny Demas, Montefiore Medical Center
  • Sohail Rana, Howard University
Background
• Combination highly active antiretroviral therapy
  (HAART) can
   – 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
• Children
   – 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
   populations)
2. Summarize the empirical findings regarding
   estimates of adherence among pediatric
   patients
3. Review the findings on correlates of
   adherence
4. Describe empirically tested interventions to
   improve adherence
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.
RESULTS
1. Adherence Assessment
     Methodologies
• Range of methodologies for capturing antiretroviral
  medication adherence.
   – Direct methods:
      • biological assays of active drug, metabolite or other markers in
        bodily fluids
   – 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.
    Adherence Assessment
    Methodologies (cont)
• 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
  adherence rates.
• 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
  suboptimal
• 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
     desirability).
   – 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)


• Caregivers
  – 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
     mobility.
   – 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:
  Berrien 2004
• 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).
Gigliotti 2001
• Directly observed therapy (DOT)
  intervention.
  – To determine whether prolonged elevation
    of VL could be attributable to poor
    adherence.
  – Found that DOT administered for 4-8 days
    significantly lowered the viral loads of all 6
    children in their sample.
Roberts 2004
• Examined an intensive DOT program (6
  families who showed continued high VL loads
  despite viral sensitivity and caregiver
  assertions of regular medication
  administration.)
  – 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.
Lyon 2003
• 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
        “corroborated”.
      • None had a 1log reduction in VL to UD.
      • Four participants indicated improved immune functioning.
Rogers 2001
•   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
      Relapse.
    – e.g. Precontemplation material: addressed concerns about taking
      HAART.
    – e.g. Preparation program: practiced a regimen with surrogate pills for 1-2
      weeks.
• Primarily for treatment-naïve subjects, prepare for successful
  initiation.
• 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.
Shingadia 2000
• 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
     cases
   – 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
              administration.
    Ellis 2006
• Multisystemic therapy, an intensive, home-based family
  therapy
• 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.
• Results:
    –     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
        termination.
•    Results suggest that MST holds promise as an intervention
    for improving health outcomes among pediatric patients with
    HIV.
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
        services).
      • 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
  DC.
• Adolescent impact provides education, social support and skills
  training through an integrated series of one-on-one and group
  sessions.
   – 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.
Summary
1.   Researchers are using a range of strategies for measuring
     adherence, with patient self-report or caregiver reports the most
     frequently used
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
         1999).
   •     Different measures and study methodologies complicate the
         comparisons
3.   Correlates of adherence are reported rather haphazardly
   •     As variables related to the medication/regimen, patient, or
         caregiver
   •     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
Recommendations for
Assessing Adherence
1.   Need for definitive guidelines for selecting
     appropriate assessment methods
2.   Perhaps consider the use of multiple methods or
     triangulation.
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)
Recommendations for
Improving Adherence
1. Empirical studies provide:
  – Utility and efficacy of DOT, a 12-week educational
    program, gastrostomy tube insertion, and nursing
    home visits
  – However, findings were preliminary and N’s small
  – Adherence to the intervention itself was often
    problematic.
2. Other studies provide:
  – Strategies that rely on clinical practice wisdom and
    lack formal evaluation (Pontali et al 2005)
Recommendations for Future
Research
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).
Recommendations for
Future Research
3. Investigate adherence levels and
  potential correlates of adherence
  – Should incorporate prospective studies (HAART
    initiation)
  – 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
    non-U.S.-based sites)
Recommendations for
Future Research
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
Thank you

								
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