Medication Adherence in Children and Adolescents with HIV
Infection: Associations with Behavioral Impairment
Kathleen Malee, Ph.D.,1Paige Williams, Ph.D.,2Grace Montepiedra, Ph.D.,2Marie McCabe, Ph.D.,3
Sharon Nichols, Ph.D.,4Patricia A. Sirois, Ph.D.,5Deborah Storm, Ph.D.,6John Farley, M.D.,7
Betsy Kammerer, Ph.D.,8and the PACTG 219C Team
The impact of behavioral functioning on medication adherence in children with perinatally acquired HIV in-
fection is not well-explored, but has important implications for intervention. This report addresses the rela-
tionship between behavioral functioning and child self-report or caregiver report of medication adherence
among children and adolescents enrolled in Pediatric AIDS Clinical Trials Group Protocol 219C (conducted
2000–2007). A total of 1134 participants, aged 3–17 years, received a behavioral evaluation and adherence
assessment. Complete adherence was defined as taking 100% of prescribed antiretroviral medications during
three days preceding the study visit. Multivariable logistic regression models were used to evaluate associations
between adherence and behavioral functioning, adjusting for potential confounders, including demographic,
psychosocial, and health factors. Children demonstrated higher than expected rates of behavioral impairment
(&7% expected with T>65) in the areas of conduct problems (14%, z¼7.0, p<0.001), learning problems (22%,
z¼12.2, p<0.001), somatic complaints (22%, z¼12.6, p<0.001), impulsivity-hyperactivity (20%, z¼11.1,
p<0.001), and hyperactivity (19%, z¼10.6, p<0.001). Children with behavioral impairment in one or more
areas had significantly increased odds of nonadherence [adjusted odds ratio (aOR)¼1.49, p¼0.04]. The odds of
nonadherence were significantly higher for those with conduct problems and general hyperactivity (aOR¼2.03,
p¼0.005 and aOR¼1.68, p¼0.02, respectively). Psychosocial and health factors, such as recent stressful life
events and higher HIV RNA levels, were also associated with nonadherence. Knowledge of behavioral, health,
and social influences affecting the child and family should guide the development of appropriate, evidence-
based interventions for medication adherence.
retroviral therapy (HAART), have resulted in improved
health and longer lives for children and adolescents with
perinatally acquired human immunodeficiency virus (HIV)
infection.1,2Adherence to ART/HAART regimens is difficult,
however, due to the demanding nature of ART and the
challenges faced by youth with HIV and their caregivers.
dvances in medical treatment, through combination
antiretroviral therapy (ART) and highly active anti-
Antiretroviral medications share characteristics that amplify
the inherent difficulties of medication adherence for children
and adolescents: poor palatability, heavy pill burden, dietary
restrictions, acute and long-term side effects, and restrictions
on daily schedules.3,4Additionally, children with HIV infec-
tion often face other life stressors that affect adherence, in-
cluding poverty, parental HIV disease, stigmatization, and
limited social support.5,6Poor adherence is dangerous in HIV
disease, potentially resulting in diminished treatment effi-
cacy, genotypically resistant viral mutations, vulnerability to
1Department of Child and Adolescent Psychiatry, Children’s Memorial Hospital, Chicago, Illinois.
2Center for Biostatistics in AIDS Research and the Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
3Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland.
4Department of Neurosciences, University of California, San Diego, California.
5Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana.
6Franc ¸ois-Xavier Bagnoud Center, School of Nursing, University of Medicine and Dentistry of New Jersey, Newark, New Jersey.
7Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland.
8Department of Psychiatry, Children’s Hospital Boston, Boston, Massachusetts.
AIDS PATIENT CARE and STDs
Volume 25, Number 3, 2011
ª Mary Ann Liebert, Inc.
risk of transmission of HIV to sexual partners.
Despite the importance of adherence in HIV disease, our
understanding of factors predictive of adherence in children
and adolescents remains incomplete. Multiple contextual
factors have been associated with adherence in children with
medications, and caregiver/family characteristics such as
education and problem-solving skills, familial relationship to
the child, and stress.7–10Youth characteristics, such as older
age, cognitive status, knowledge of HIV diagnosis, psycho-
logical adjustment, and coping skills have been implicated in
nonadherence, although findings remain inconsistent.11–16
Emotional and behavioral problems, including attention
problems and hyperactivity, and psychiatric disorders, such as
anxiety and attention deficit hyperactivity disorder (ADHD),
have been observed among children with perinatal HIV ex-
posure and HIV infection.17–21Nozyce and colleagues,18for
example, identified significant behavioral problems among
clinically and immunologically stable children with HIV in-
fection (HIVþ) compared to a general non-HIV–infected pop-
ulation. Mellins and colleagues19observed similar rates of
behavioral problems among children with HIV infection and a
comparison group of HIV-exposed but uninfected children
(HIV?), suggesting that problems may be related to shared
demographic and psychosocial characteristics of children’s
high-risk families rather than to HIV disease itself. In recent
investigations of the prevalence of psychiatric disorders, as
defined by the Diagnostic and Statistical Manual of Mental
Disorders-Fourth Edition (DSM-IV), higher than expected rates
of disorders were observed in both HIVþ and HIV-exposed or
affected youth,20,21although those with HIV infection had
significantly higher rates of ADHD than those without HIV.21
Emotional and behavioral problems, including depression,
conduct problems, and alcohol use have been associated with
nonadherence in older adolescents and adults with HIV infec-
tion.13,22–24Although there is evidence suggesting emotional
and behavioral problems are related to adherence in children
with other chronic illnesses,25the relationship between such
problems and adherence in children with HIV disease is not
well-described. Clarifying this relationship is critical since
emotional and behavioral problems in the context of chronic
illness may reduce the ability to take medications as directed
and affect a youth’s assumption of responsibility for this im-
portant health maintenance behavior.
The purpose of this investigation was to examine the be-
havioral functioning of youth with HIV and to evaluate the
relationship between behavioral functioning and medication
adherence. We hypothesized that behavioral problems would
occur at higher rates among children with HIV infection rel-
ative to the general population and behavioral problems
would be associated with increased risk for nonadherence.
We examined potential confounding factors, including de-
mographic characteristics, biological markers of health,
medication and adherence characteristics, and psychosocial
factors presumed to influence behavior and adherence.
Our analyses used data from the Pediatric AIDS Clinical
Trials Group (PACTG) Late Outcomes Protocol 219C, a pro-
spective cohort study designed to assess long-term effects of
HIV infection and in utero exposure to ART.26Children were
enrolled at over 80 sites in the United States and Puerto Rico.
Eligibility criteria for this investigation included: perinatally
acquired HIV, age 3–17 years, on ART during participation,
6 months of the protocol-required cognitive evaluation (see
Malee et al.11). The sites’ human subject research Institutional
Review Boards (IRBs) approved the protocol. Written in-
formed consent was obtained from children’s parents or legal
guardians or from older adolescents who could self-consent;
written assent was obtained from children in accordance with
PACTG 219C opened to accrual in 2000 and closed to
follow-up in 2007. As of April 2004, 2,384 children with
perinatally acquired HIV infection were enrolled; 2191 were
3–17 years old at some point during study follow-up. Of
these, 1682 (77%) had a cognitive test attempted and within
that group 1134 (67%) completed an adherence assessment
and behavioral evaluation. This sample (N¼1134) comprises
the study cohort.
sessed every 3 months with a validated 3-day self-report
measure, using a scripted interview with the person who self-
identified as responsible for medication administration, either
parent/caregiver or child/adolescent. The adherence mea-
sure was based on a version of the ACTG instrument modi-
fied for use in pediatric studies.27Respondents identified each
medication in the ART regimen and reported the number of
doses missed duringeachofthepreceding 3days. We defined
separate indicators of adherence for each drug class: nucleo-
side reverse transcriptase inhibitors (NRTIs), non-nucleoside
reverse transcriptase inhibitors (NNRTIs), and protease in-
hibitors (PIs). Earlier guidelines for ART use suggested 95%
adherence for therapeutic effect.28However, since each anti-
viral suppression and drug resistance and because recent
patterns of adherence rather than average adherence over
time may be important in determining the risk of viral re-
bound,29we defined complete adherence as taking all pre-
scribed ART medications (100%) during the 3 days preceding
the study visit. The interviewer recorded the following data:
medication burden (total number of expected doses over the
past 3 days), the need to prompt respondents for medication
names, and the types of aids utilized as reminders (e.g., pill-
boxes, buddy system).
Medication adherence was as-
(CPRS-48)30is a screening instrument used in 219C to evalu-
ate children’s behavioral functioning at ages 3, 6, 9, 12, and 15
years. It was administered to the parent/caregiver in English
or Spanish, depending upon the caregiver’s primary lan-
guage. Caregivers rated the child on 48 descriptors of
behavior, as observed during the previous month, using a
four-point Likert scale (not at all, just a little, pretty much,
very much) that yielded a standardized T score [mean
(M)?standard deviation (SD)¼50?10] in each of six be-
havioral domains: conduct problems, learning problems,
psychosomatic symptoms, impulsivity–hyperactivity, anxi-
ety, and general hyperactivity. The conduct problems index
The Conners’ Parent Rating Scale
192MALEE ET AL.
13. Williams P, Storm D, Montepiedra G, et al. Predictors of ad-
herence to antiretroviral medications in children and ado-
lescents with HIV infection. Pediatrics 2006;118:e1745–e1757.
14. Haberer J, Mellins C. Pediatric adherence to HIV antiretro-
viral therapy. Curr HIV/AIDS Rep 2009;6:194–200.
15. Merzel C, VanDevanter N, Irvine M. Adherence to anti-
retroviral therapy among older children and adolescents
with HIV: A qualitative study of psychosocial contexts.
AIDS Patient Care STDs 2008;22:977–987.
16. Michaud PA, Suris JC, Thomas R, Gnehm HE, Cheseaux JJ;
The Swiss HIV Mother & Child Cohort Study. Coping with
HIV infection. Swiss Med Wkly 2010;140:247–253.
17. Havens JF, Mellins CA. Psychiatric aspects of HIV/AIDS. In:
Rutter M, Bishop D, Pine D, Scott S, Stevenson JS, Taylor EA,
Thapar A, eds. Rutter’s Child and Adolescent Psychiatry,
5th ed. Oxford: Blackwell Publishing, 2008:945–955.
18. Nozyce M, Lee S, Wiznia A, et al. A behavioral and cogni-
tive profile of clinically stable HIV infected children. Pedia-
19. Mellins CA, Smith R, O’Driscoll P, et al. High rates of be-
havioral problems in perinatally HIV-infected children are
not linked to HIV disease. Pediatrics 2003;111:384–393.
20. Gadow KG, Chernoff M, Williams PL, et al. Co-occurring
psychiatric symptoms in children perinatally infected with
HIV and peer comparison sample. J Dev Behav Pediatr
21. Mellins CA, Brackis-Cott E, Leu C, et al. Rates and types of
psychiatric disorders in perinatally human immunodefi-
ciency virus-infected youth and seroreverters. J Child Psy-
chol Psychiatry 2009;50:1131–1138.
22. Catz SL, Kelly JA, Bogart LM, Benotsch EG, McAuliffe TL.
Patterns, correlates, and barriers to medication adherence
among persons prescribed new treatments for HIV disease.
Health Psychol 2000;19:124–133.
23. Murphy DA, Belzer M, Durako S, Sarr M, Wilson C, Muenz
L. Longitudinal antiretroviral adherence among adolescents
infected with human immunodeficiency virus. Arch Pediatr
Adolesc Med 2005;159:764–770.
24. Walkup J, Akincigil A, Bilder, S, Rosato NS, Crystal S.
Psychiatric diagnosis and antiretroviral adherence among
adolescent Medicaid beneficiaries diagnosed with human
immunodeficiency virus/acquired immunodeficiency syn-
drome. J Nerv Ment Dis 2009;197:354–361.
25. Rapoff MA. Adherence to Pediatric Medical Regimens. New
York: Kluwer Academic/Plenum, 1999.
26. Gortmaker SL, Hughes M, Cervia J, et al. Effect of combi-
nation therapy including protease inhibitors on mortality
among children and adolescents infected with HIV-1. N
Engl J Med 2001;345:1522–1528.
27. Van Dyke RB, Lee S, Johnson GM, et al. Reported adherence
as a determinant of response to highly active antiretroviral
therapy in children who have Human Immunodeficiency
Virus Infection. Pediatrics 2002;109:e61.
28. Paterson DL, Swindells S, Mohr J, et al. Adherence to pro-
tease inhibitor therapy and outcomes in patients with HIV
infection. Ann Intern Med 2000;133:21–30.
29. Bangberg DR. Preventing HIV antiretroviral resistance
through better monitoring of treatment adherence. J Infect
30. Conners CK. Conners Rating Scales: Technical Manual, Re-
vised. North Tonawanda, NY: MultiHealth Systems, 1989.
31. Center for Disease Control and Prevention. 1994 revised
classification system for human immunodeficiency virus
infection in children less than 13 years of age. MMWR Morb
Mortal Wkly Rep 1994;43:1–10.
32. Gortmaker SL, Lenderking WR, Clark C, Lee S, Fowler MG,
Oleske J. Development and use of a pediatric quality of life
questionnaire in AIDS clinical trials: Reliability and validity
of the General Health Assessment for Children (GHAC). In:
Drotar D, ed. Assessing Pediatric Health-Related Quality of
Life and Functional Status: Implications for Research, Prac-
tice and Policy. Mahwah, NJ: Lawrence Feldbaum Associ-
33. Lee GM, Gortmaker SL, McIntosh K, Hughes MD, Oleske
JM. Quality of life for children and adolescents: Impact of
HIV infectionand antiretroviral
34. Wallander JL, Varni JW. Effects of pediatric chronic physical
disorders on child and family adjustment. J Child Psychol
35. Van Rie A, Harrington PR, Dow A, Robertson K. Neurologic
and neurodevelopmental manifestations of pediatric HIV/
AIDS: A global perspective. Eur J Paediatr Neurol 2007;11:1–9.
36. Valcour VG, Shiramizu BT, Shikuma CM. HIV DNA in cir-
culating monocytes as a mechanism to dementia and other
HIV complications. J Leukoc Biol 2010;87:1–6.
37. Tashiro C. The meaning of race in healthcare and research-
part 2. Current controversies and emerging research. Pediatr
38. Wadsworth ME, Raviv T, Reinhard C, Wolff B, Santiago CD,
Einhorn L. Association between poverty and child func-
tioning: The role of children’s poverty-related stress. J Loss
39. Kishiyama MM, Boyce WT, Jimenez AM, Perry LM, Knight
RT. Socioeconomic disparities affect prefrontal function in
children. J Cogn Neurosci 2008;21:1106–1115.
40. Silver E, Heneghan A, Bauman L, Stein R. The relationship
of depressive symptoms to parenting competence and social
support in inner-city mothers of young children. Matern
Child Health J 2006;10:105–112.
41. Rutter M. Environmentally mediated risks for psychopa-
thology: Research strategies and findings. J Am Acad Child
Adolesc Psychiatry 2005;44:18.
Address correspondence to:
Kathleen Malee, Ph.D.
Children’s Memorial Hospital
2300 Children’s Plaza, Box 155
Chicago, IL 60614
200 MALEE ET AL.