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. Author manuscript; available in PMC: 2021 Apr 1.
Published in final edited form as: AIDS Care. 2019 Oct 21;32(4):429–437. doi: 10.1080/09540121.2019.1680790

Behavioral problems in perinatally HIV-infected young children with early antiretroviral therapy and HIV-exposed uninfected young children: Prevalence and Associated Factors

Watsamon Jantarabenjakul a,b,c, Weerasak Chonchaiya a,d, Thanyawee Puthanakit a,b, Suvaporn Anugulruengkitt a,b, Tuangtip Theerawit b, Jesdapron Payapanon b, Jiratchaya Sophonphan e, Montida Veeravigrom a, Neda Jahanshad f, Paul M Thompson f, Jintanat Ananworanich g,h,i, Kathleen Malee j, Chitsanu Pancharoen a,b, DOET study
PMCID: PMC7259821  NIHMSID: NIHMS1572789  PMID: 31635484

Abstract

Although behavioral problems have been observed in children and adolescents with perinatally-acquired HIV infection (PHIV), behavioral information regarding younger PHIV children are scarce. This study aims to identify behavioral problems in PHIV and HIV-exposed uninfected (HEU) young children and to evaluate factors associated with such problems. A prospective study of PHIV and HEU young children was conducted. Behavioral problems were assessed with the Child Behavior Checklist (CBCL) at baseline and 12 months later among PHIV and PHEU children aged 18-60 months old. The Patient Health Questionnaire-9 and the Parenting Styles & Dimensions Questionnaire identified primary caregivers’ symptoms of depression and parenting styles, respectively, at both visits. Chi-squared analyses were used to compare prevalence of behavioral problems between groups of participants. Factors associated with behavioral problems were analyzed by logistic regression. From 2016 to 2017, 121 children (41 PHIV and 80 HEU) were assessed with no significant differences in prevalence of Total, Internalizing, Externalizing, and Syndrome scales problems between PHIV and HEU at both visits (p > 0.5). Primary caregivers’ depression and lower education in addition to authoritarian and permissive parenting styles were significantly related to presence of child behavioral problems. Family-centered care for families affected by HIV, including positive parenting promotion, mental health care, and education are warranted.

Keywords: perinatally HIV infected children, HIV exposed uninfected children, behavioral problems, depression, parenting style

Introduction

Behavioral problems among children and adolescents with perinatally-acquired HIV infection (PHIV) have been described prior to and during the antiretroviral therapy (ART) era. Among children with PHIV in middle-to-high resource settings, increased risk of impulsivity, hyperactivity, and attention deficits have been observed while anxiety, depression, and conduct problems are reported among PHIV adolescents (Chernoff et al., 2009; Mellins et al., 2003; Nozyce et al., 2006). Multiple etiologies of such behavioral problems have been proposed, including HIV effects on brain structure and neuronal development, in utero drug exposure, and social contextual factors, such as poverty, parenting styles, complex family dynamics, and life stressors (Elkington et al., 2011; Laughton, Cornell, Boivin, & Van Rie, 2013).

Recent investigations reveal the efficacy of early ART among young children with PHIV, including positive developmental outcomes (Laughton et al, 2012; Laughton et al, 2018). However, there is limited information on the effect of HIV infection on behavioral problems in young PHIV children with early ART initiation in developing countries, including Thailand. Thailand is an upper middle income country with free universal healthcare coverage that reached the World Health Organization’s targets for elimination of mother to child transmission of HIV in 2016 (less than 2%) (Thisyakorn U, 2017). Currently, the rate of newly diagnosed PHIV children in Thailand is 80-100 cases per year and HEU children is 4,000-5,000 cases per year, respectively. Since 2010, the Thai National Guideline recommends HIV DNA PCR for early infant diagnosis and immediate ART in those infected, regardless of symptoms and CD4+ T cell counts (Puthanakit et al., 2010). Through Thailand’s active case management network to promote early ART initiation aiming for cure, more than 80% of PHIV infants initiated ART before one year of age (Sirirungsi et al., 2016). We have documented better developmental outcomes in young children who initiated ART within 3 months of life (early ART) compared to a later treated group, as previously described in the South African studies (Laughton et al., 2012). In the current era of early HIV diagnosis and early ART initiation, understanding the presence of behavioral problems during early childhood and factors associated with such problems among PHIV children is essential to not only improve quality of life of young children with PHIV, but also to implement appropriate and timely intervention services and care. Therefore, this study aims to compare behavioral problems between young PHIV children with early ART treatment and HIV-exposed uninfected (HEU) children and to identify risk factors associated with such behavioral problems. Given relative similarities in environmental and psychosocial characteristics of children with perinatal HIV exposure and HIV infection in Thailand, we hypothesized that children with PHIV and HEU children would have similar emotional-behavioral functioning in the context of early ART for PHIV children.

Materials & Methods

Participants

This study was a sub-study of a prospective, observational study (the DOET study) of young children aged 12-56 months born to HIV-positive mothers in Thailand between 2016 and 2018. Children with PHIV were recruited from the country register database which identified PHIV children who were born during 2012 to 2016 and initiated ART within one year of age; their primary caregivers were invited to participate in this study. The PHEU group was recruited from the hospital where this investigation was conducted and was age-matched to those in the PHIV group. Neurodevelopmental functioning was evaluated with the Mullen Scales of Early Learning (MSEL) at enrollment and at a 12-month follow-up visit (Mullen EM., 1995). This sub-study of behavioral functioning included only children aged ≥ 18 months at enrollment due to age constraints of the Child Behavior Checklist (CBCL) at age 1.5–5 years. Inclusion criteria for PHIV children were: HIV infection with documented positive HIV DNA PCR and receipt of ART within the first year of life. Inclusion criteria for HEU children were: born to HIV-infected mothers, with no HIV infection documented by negative HIV DNA PCR at age > 4 months or anti-HIV negative at age > 12 months. HEU children were age-matched to PHIV children within a range of 6 months. Exclusion criteria were: prematurity (gestational age < 34 weeks), major congenital anomalies, genetic disorders, current neurologic diseases, or persistent or active AIDS defining opportunistic infection within 30 days prior to enrollment.

This sub-study was approved by the Research Ethnics Committee, Thailand. Written consent was obtained by mothers or legal guardians prior to children’s enrollment.

Procedures

Children’s and caregivers’ sociodemographic information was collected through parent/caregiver interview and data extraction from medical records. Included in the analyses were: children’s age, sex, birth weight, gestational age, MSEL early learning composite (ELC) score, an indication of child general cognitive ability, pregnancy history, primary caregiver identity, caregiver age and education, family income level, and biological markers of the child’s HIV disease (age of ART initiation, duration of ART, ART regimen, CD4+ T cell counts, and HIV-RNA). Primary caregiver was defined as the primary person who cared for the child. Caregiver identity in this current study included those who had a relationship with the child, such as biological mothers, biological fathers, grandparents and other relatives, as detailed in Table 1. Child behavioral outcomes were assessed by the Thai version of the Child Behavior Checklist (CBCL) for Ages 1.5-5 years (Achenbach TM. and Rescorla LA., 2000), completed by each participant’s primary caregiver at the enrollment and 12-month study visit. The CBCL has been widely used internationally to measure emotional and behavioral problems (Achenbach et al., 2008). Primary caregivers were asked to describe how much a particular behavior was characteristic of their child in the past 6 months, using a 3-point rating scale (“2” if the item was true, “1” if the item was somewhat true or “0” if the item was not true). Behavioral concerns were classified into subscales and broad groupings of Internalizing, Externalizing, and Total problems. Internalizing problems included emotional reactivity, anxiety, depression, somatic complaints without known medical causes, and withdrawal from social contact. Externalizing problems included aggressive, rule-breaking behaviors, and conflicts with other people. Total problems included internalizing behaviors, externalizing behaviors, sleep problems, and other individual problems, such as crying, fearfulness, accident-proneness, shyness, and loudness. Syndrome scale problems included emotionally reactive, anxious/depressed, somatic complaints, withdrawn, sleep problems, attention problems, and aggressive behavior. T-scores of ≥ 64 on Internalizing, Externalizing, and Total problems as well as T-score of ≥ 70 on each Syndrome scale problem were defined as clinically significant behavioral problems based on criteria documented in the CBCL manual (Achenbach TM. and Rescorla LA., 2000). The reference range T-score of Internalizing, Externalizing and Total score was 29-100, 28-100 and 28-100, respectively. The reference range T-score of Syndrome scale problems was 50-100 except attention problems was 50-80.

Table 1.

Demographic data and clinical characteristics of the perinatally HIV infected (PHIV) children, HIV-exposed uninfected (HEU) children, and their primary caregivers.

Variables Total
(n=121)		 PHIV
(n=41)		 HEU
(n=80)		 p
Children data
Age, months, median (IQR) 31 (25-44) 30 (25-37) 32 (25-45) 0.83
Female sex, n (%) 63 (52%) 20 (49%) 43 (54%) 0.61
Prematurity (GA 34-37 weeks), n (%) 20 (17%) 8 (20%) 12 (15%) 0.48
Birth weight < 2500 g, n (%) 26 (21%) 11 (27%) 15 (19%) 0.31
Cognitive score by MSEL early learning composite score, mean (SD)
 - Enrollment 86 (16.3) 81.4 (15.3) 88.3 (16.4) 0.03
 - 12-month visit 86 (15.3) 83.5 (14.7) 87.4 (15.5) 0.19
Mother data
No ART during pregnancy, n (%) 17 (14%) 13 (32%) 4 (5%) < 0.001
Substance use during pregnancy, n (%) 5 (4%) 4 (10%) 1 (1%) 0.045
Alcohol intake during pregnancy, n (%) 5 (4%) 4 (10%) 1 (1%) 0.045
Smoking during pregnancy, n (%) 4 (3%) 2 (5%) 2 (3%) 0.42
Primary caregiver data
Caregiver identity at enrollment, n (%) 0.30
 - Biological mothers 76 (63%) 22 (54%) 54 (68%)
 - Biological fathers 5 (4%) 3 (7%) 2 (2%)
 - Grandparents 34 (28%) 13 (32%) 21 (26%)
 - Other relatives 6 (5%) 3 (7%) 3 (4%)
Age, years, median (IQR) 38 (32-47) 37 (27-48) 38 (33-46) 0.81
Duration of education, years, median (IQR) 9 (6-12) 9 (6-12) 9 (6-13) 0.38
Depression score ≥ 9, n (%)
 - Enrollment 20 (17%) 4 (10%) 16 (20%) 0.15
 - 12-month visit 12 (10%) 6 (15%) 6 (8%) 0.19
Authoritative parenting style score, median (IQR)
 - Enrollment 3.8 (3.4-4.1) 3.7 (3.4-4.0) 4.0 (3.4-4.3) 0.03
 - 12-month visit 3.8 (3.1-4.1) 3.4 (2.7-3.9) 3.9 (3.3-4.2) 0.002
Authoritarian parenting style score, median (IQR)
 - Enrollment 1.9 (1.8-2.4) 2.0 (1.8-2.4) 1.9 (1.7-2.5) 0.59
 - 12-month visit 1.9 (1.6-2.3) 2.0 (1.6-2.4) 1.9 (1.6-2.2) 0.31
Permissive parenting style score, median (IQR)
 - Enrollment 2.6 (2.2-3.2) 2.6 (2.2-3.2) 2.6 (2.2-3.2) 0.85
 - 12-month visit 2.4 (2-2.8) 2.4 (2.0-3.1) 2.5 (2.0-2.8) 0.88
Socioeconomic status
Income per family 0.03
 - < 10,000 Baht/month 29 (24%) 15 (37%) 14 (17%)
 - 10,000 - 25,000 Baht/month 54 (45%) 18 (44%) 36 (45%)
 - > 25,000 Baht/month 38 (31%) 8 (19%) 30 (38%)
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GA, Gestational age; MSEL, Mullen Scale of Early Learning; ART, antiretroviral therapy.

Symptoms of depression among primary caregivers were assessed with the Thai version of the Patient Health Questionnaire-9 (PHQ-9); probable depression was characterized by a total score of ≥ 9 (Lotrakul, Sumrithe, & Saipanish, 2008). Parenting Styles & Dimensions Questionnaire-short version (PSDQ-short version) was used to determine primary caregivers’ parenting behaviors and styles; each primary caregiver rated on a 5-point Likert scale how often he or she exhibited certain behaviors towards the child (Robinson, Mandleco, Olsen, & Hart, 1995, 2001). For example, “I stated punishments to my child and do not actually do them.” There were 15, 12, and 5 items specific to each parenting style, including authoritative, authoritarian, and permissive parenting styles, respectively. To obtain an overall authoritative, authoritarian, and permissive parenting style score, an average of those items relevant to each parenting style was computed. Authoritative parents were defined as those who “direct the child’s activities, but in a rational, issue-oriented manner and evaluate both expressive and instrumental attributes, both autonomous self-will and disciplined conformity.” Authoritarian parents were defined as those who “shape, control, and evaluate the behavior and attitudes of the child in accordance with a set standard of conduct; they do not encourage verbal give and take, believing that the child should accept their word as right.” Permissive parents were defined as those who behave in a non-punitive, accepting, and affirmative manner toward the child’s impulses, desires, and actions; they avoid the exercise of control and do not encourage children to obey externally-defined standards (Baumrind, 1967, 1968).

Statistical analysis

Characteristics were reported as median and interquartile ranges (IQR) for continuous variables and percentages for categorical variables. The chi-squared test or the Fisher’s exact test were used to compare categorical variables; the Wilcoxon rank sum test was used to compare medians between two groups. Neurodevelopmental scores by MSEL and behavioral scores by CBCL were presented as mean (standard deviation). Independent two sample t-tests were used to compare mean scores between PHIV and HEU children. A Chi-squared test was used to compare proportion of abnormal CBCL scores between the two groups. Generalized estimating equations (GEE) for logistic regression were used to compare problematic CBCL behavioral functioning overtime and to determine factors associated with behavioral problems. Multivariate models were developed including covariates with p < 0.1 from univariate models. Covariates were children characteristics, including children’s age and sex; ELC scores; family characteristics, including primary caregiver’s age, education, income, and depression screening status; PHIV child health characteristics, including the child’s age at ART initiation, ART regimen, duration of ART, CD4+ T cell counts, and HIV-RNA. Moreover, parenting styles including authoritative, authoritarian, and permissive parenting were also included in the final multivariate models. Statistical significance was defined as p < 0.05. The STATA software, version 13.1 (Stata Corp., College Station, Texas, USA) was used for analysis.

Results

Participants

From 2016 to 2017, 121 children (41 PHIV and 80 PHEU) were enrolled and all of them had completed the 12-month study visit. Demographic and health characteristics of participants and their primary caregivers at enrollment are presented in Table 1. The median (IQR) age was 30 (25-37) months in PHIV and 32 (25-45) months in HEU; 52% were female. Only parent-child dyads (one child and one mother) were enrolled for each participant, with the exception of one set of twins and a pair of siblings in the PHEU group. ELC scores on the MSEL were significantly lower in PHIV children when compared to HEU at enrollment (p = 0.03), however, such differences were not detected at the 12-month-visit (p = 0.19). During pregnancy, 32% of PHIV mothers and 5% of HEU mothers did not use antiretroviral therapy (p < 0.001). In utero exposure to illicit substances and alcohol was significantly more likely among PHIV than HEU children (10% vs 1%, p = 0.045).

At time of first assessment, 63% of primary caregivers were biological mothers and 28% were grandparents. At 12-month visit, only 6 children had experienced a change of primary caregivers. Both groups of study participants were comparable with respect to primary caregiver’s age and education. Caregiver’s depression symptoms, assessed by the PHQ-9, were observed in 17% of caregivers at enrollment and in 10% at the 12-month visit; differences were not statistically significant. Authoritative parenting style by the PSDQ was more often reported among caregivers of HEU than PHIV children, p < 0.05. Families of PHIV children reported lower family income than families of HEU.

Among PHIV children, the median (IQR) age of ART initiation was 3.7 (2.3-5.3) months. All PHIV children were asymptomatic with the exception of one who had HIV encephalopathy. This child had severe global developmental delay and CBCL scores which were relatively similar to those without encephalopathy. Most PHIV (83%) children received a ritonavir boosted lopinavir-based regimen and the remainder received a nevirapine-based regimen. Median (IQR) CD4 counts were 1743 (1340-2471) cells/mm3 at enrollment and 1527 (1192-1824) cells/mm3 at the 12-month-visit. Rate of HIV-RNA < 200 copies/mL was 78% at enrollment and 80% at the 12-month visit.

Behavioral outcomes

Mean T-scores of Total, Externalizing, and Internalizing problems were not different between groups at both visits. The prevalence of clinically significant Total behavioral problems was 20% among PHIV and 30% among HEU children at enrollment (p = 0.22) and 29% among PHIV and 28% among HEU children at the 12-month visit (p = 0.87) (Table 2). HEU children tended to have higher rates of Total behavioral problems, Externalizing problems, Internalizing problems, and most Syndrome scales when compared to PHIV children, although differences were not statistically significant (Table 3). The most common problems among PHIV and HEU young children included somatic complaints, withdrawn behavior, and attention problems. The PHIV group had a higher rate of somatic complaints when compared to HEU children while the HEU group had higher rates of attention problems, aggressive behaviors, and sleep problems.

Table 2.

Comparison of Total behavioral problems, Externalizing, and Internalizing behaviors by Child Behavior Checklist (CBCL) between perinatally HIV infected (PHIV) and HIV-exposed uninfected (HEU) young children.

Variables At enrollment 12-month visit pb
PHIV
n=41		 HEU
n=80		 pa PHIV
n=41		 HEU
n=80		 pa
T-score, mean (SD)
Total problems 59.5 (7.5) 59.7 (9.8) 0.94 58.0 (7.9) 58.7 (10.6) 0.71 0.85
Externalizing 55.6 (7.5) 57.6 (9.8) 0.26 55.4 (7.2) 55.5 (10.1) 0.96 0.44
Internalizing 61.3 (7.3) 59.3 (9.6) 0.25 59.3 (7.6) 59.6 (9.6) 0.88 0.47
Clinical range (T-score ≥ 64), n (%)
Total problem 8 (20%) 24 (30%) 0.22 12 (29%) 22 (28%) 0.87 0.74
Externalizing 5 (12%) 15 (19%) 0.36 4 (10%) 14 (18%) 0.25 0.28
Internalizing 13 (32%) 31 (39%) 0.45 14 (34%) 30 (38%) 0.68 0.29
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The reference range T-score of Total, Externalizing and Internalizing score was 28-100, 28-100 and 29-100, respectively, pa for comparison of proportion of CBCL between 2 groups using chi-square test, pb using Generalized estimating equations (GEE) for logistic regression to compare abnormal CBCL overtime.

Table 3.

Prevalence of clinically significant behavioral problems by Child Behavior Checklist (CBCL) Syndrome scales in perinatally HIV infected (PHIV) and HIV-exposed uninfected (HEU) young children.

Syndrome scales n (%) At enrollment 12-month visit pb
PHIV
n=41		 HEU
n=80		 pa PHIV
n=41		 HEU
n=80		 pa
Emotionally-reactive problem 1 (2%) 4 (5%) 0.66 2 (5%) 9 (11%) 0.33 0.23
Anxious/depressed 2 (5%) 3 (4%) 0.77 0 (0%) 5 (6%) 0.16 0.49
Somatic complaints 11 (27%) 11 (14%) 0.08 9 (22%) 12 (15%) 0.36 0.08
Withdrawn 4 (10%) 11 (14%) 0.77 6 (15%) 12 (15%) 0.94 0.63
Sleep problems 1 (2%) 5 (6%) 0.66 0 (0%) 9 (11%) 0.03 0.06
Attention problems 1 (2%) 14 (18%) 0.09 5 (12%) 12 (15%) 0.66 0.18
Aggressive behaviors 1 (2%) 7 (9%) 0.26 2 (5%) 6 (8%) 0.71 0.29
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*

T-score of ≥ 70 on each Syndrome scale problem were defined as clinically significant behavioral problems based on criteria documented in the CBCL manual, pa for comparison of proportion of abnormal CBCL between 2 groups using chi-square test, pb using Generalized estimating equations (GEE) for logistic regression to compare abnormal CBCL overtime.

Among all children, factors associated with Total behavioral problems in the clinically significant range included primary caregiver’s depression (aOR 7.38, 95% CI 2.02 - 26.97, p = 0.003) and authoritarian parenting style (aOR 4.01, 95% CI 1.48 - 10.83, p = 0.006 (Table 4). In addition, primary caregiver’s depression was associated with Externalizing, Internalizing, somatic complaints, withdrawn behavior, attention problems, and aggressive behavior among study participants (Table 5). Authoritarian parenting style was associated with child Externalizing, Internalizing, and emotionally reactive behavioral problems while permissive parenting style was associated with withdrawal and aggressive behavioral problems (Table 5).

Table 4.

Factors associated with clinical range of Total Behavioral Problems by Child Behavior Checklist (CBCL) among perinatally HIV infected (PHIV) and HIV-exposed uninfected (HEU) young children.

Variables Univariate Multivariate
OR (95%CI) p aOR (95%CI) p
Male 2.18 (0.68-6.94) 0.19
Age ≤ 36 months 0.93 (0.36-2.38) 0.88
ELC score ≤ 70 3.78 (1.05-13.61) 0.04
Group
 HEU Ref
 PHIV 0.74 (0.22-2.48) 0.63
PHIV children
Age started ART > 3 months old 0.81 (0.26-2.51) 0.72
ART regimen: PIs vs NNRTI 5.29 (0.59-47.57) 0.14
Duration of ART > 24 months 1.3 (0.33-5.14) 0.71
CD4+ T cell < 2000 cells/mm3 0.62 (0.21-1.89) 0.41
HIV-RNA ≥ 200 copies/mL 0.28 (0.05-1.54) 0.14
Primary caregiver
Non-biological parent 1.11 (0.33-3.77) 0.87
Age, years 1.01 (0.96-1.06) 0.7
Duration of education < 12 years 3.89 (1.1-13.75) 0.04
Depression score ≥ 9 9.62 (2.53-36.5) 0.001 7.38 (2.02-26.97) 0.003
Income per family < 10,000 Baht/month 1.00 (0.27-3.71) 0.99
Parenting style
Authoritative 6.17 (1.14-33.43) 0.04
Authoritarian ≥ 2 4.75 (1.77-12.75) 0.002 4.01 (1.48-10.83) 0.006
Permissive ≥ 3 3.2 (1.27-8.07) 0.01
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GA; gestational age, ELC; Early learning composite score, ART; antiretroviral therapy, PIs; protease inhibitor, NNRTI; non-nucleotide reverse transcriptase inhibitor.

Table 5.

Factors associated with clinical range of Externalizing, Internalizing and Syndrome Scale Problems by Child Behavioral Checklist (CBCL) among perinatally HIV infected (PHIV) and HIV-exposed uninfected (HEU) young children.

Problems Variables aOR (95% CI) p
Externalizing Primary caregiver’s depression 5.71 (1.46-22.28) 0.01
Authoritarian score ≥ 2 7.58 (1.9-30.28) 0.004
Primary caregiver education < 12 years 5.64 (1.07-29.61) 0.04
Internalizing Primary caregiver’s depression 3.09 (1.11-8.63) 0.03
Authoritarian score ≥ 2 3.01 (1.38-6.59) 0.01
Emotionally-reactive problem Authoritarian score ≥ 2 19.94 (1.23-324) 0.04
Anxious/depress No report
Somatic complaints Primary caregiver’s depression 3.58 (1.07-11.97) 0.04
Withdrawn Primary caregiver’s depression 2.87 (1.17-7.05) 0.02
Permissive score ≥ 3 2.25 (1.03-4.9) 0.04
Attention problems Primary caregiver’s depression 10.93 (2.59-46.03) 0.001
Aggressive behaviors Primary caregiver’s depression 5.04 (1.14-22.22) 0.03
Permissive score ≥ 3 10.9 (2.15-55.17) 0.004
Sleep problems No report
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Discussion

Early studies of children with perinatally acquired HIV infection revealed increased risk of behavioral problems, although multiple non-HIV related factors were also implicated in behavioral difficulties in affected individuals (Elkington, et al., 2011; Havens, Whitaker, Feldman, & Ehrhardt, 1994; Louw, Ipser, Phillips, & Hoare, 2016; Malee et al., 2011; Mellins and Malee, 2013; Mellins, et al., 2003). Our investigation of preschool-aged children with HIV and early ART initiation revealed higher parent-reported behavioral problems, including Internalizing, Externalizing, and Total problems, among both PHIV and HEU children than previous studies (Louw, et al., 2016; Puthanakit et al., 2013; Sanmaneechai, Puthanakit, Louthrenoo, & Sirisanthana, 2005); however, no differences between the two groups, regardless of PHIV or HEU status, were observed. Primary caregivers’ characteristics, in particular symptoms of depression, lower education, authoritarian, and permissive parenting styles, rather than child HIV status, were significantly associated with the presence of behavioral difficulties in these pre-schoolers.

In prior studies of 284 PHIV and 155 HEU children affected by HIV in Thailand and Cambodia (PREDICT), PHIV children had significantly higher CBCL T-scores and borderline to clinical range CBCL Internalizing, Externalizing, and Total problems when compared with HEU children (Puthanakit, et al., 2013). Differences in behavioral outcomes between the current study of young children and the earlier PREDICT study may be related in part to the older age of most participants in the PREDICT study. As children age, particularly in the context of compromised parenting due to mental or physical health challenges, worrisome or problematic behavioral profiles may be more easily recognized or more often reported by caregivers, especially if child behaviors deviate from parental expectations. Additionally, children in the PREDICT study received ART relatively later than children in the current DOET cohort, mostly after age one, depending on CD4+ T cell counts or CDC category status. Treatment initiation at older ages allowed a longer period of untreated HIV infection and potential adverse effects on brain development, cognition, and behavior. However, the timing of ART, early (initiating ART at CD4+ T cell 15-24%) vs. late (initiating ART when CD4+ T cell <15% or a CDC category C event) initiation, was not associated with behavioral problems in the PREDICT study, as also observed in our current study (Puthanakit, et al., 2013). In other settings, higher rates of behavioral problems were observed among older HEU children and adolescents compared to those with PHIV (Malee, et al., 2011; Sanmaneechai, et al., 2005). Our current findings were consistent with studies that failed to find associations between HIV child health characteristics and behavioral problems (Bachanas et al., 2001; Betancourt et al., 2014; Chernoff, et al., 2009; Havens, et al., 1994; Louw, et al., 2016; Mellins, et al., 2003; Sanmaneechai, et al., 2005). Instead, behavioral problems in young children living with HIV in families in Thailand appeared to be highly associated with primary caregivers’ mental health, education, and parenting behaviors.

There is substantial evidence that the presence of caregiver mental health difficulties, such as depression, have significant impact on children’s behaviors and emotional development, regardless of child’s HIV status (Allen et al., 2014; Beck, 1999; Goodman et al., 2011; Louw, et al., 2016; Rochat, Houle, Stein, Pearson, & Bland, 2018). Symptoms of depression among primary caregivers might impact caregivers’ ability and motivation to engage in nurturing caregiving and play with their children, and might indirectly reduce opportunities for children’s development of social skills, executive function, peer relationships, and sense of agency (Yogman, Garner, Hutchinson, Hirsh-Pasek, & Golinkoff, 2018). Limited opportunities for positive parent-child interaction, including low attention to child emotional expression and low positive and high negative emotion in parenting, may have deleterious effects on children’s behaviors, especially in the presence of adversity and stress, which are not uncommon among women with HIV infection during pregnancy and thereafter (Allen, et al., 2014; Dix and Meunier, 2009).

Our results also highlighted the impact of parenting styles, especially authoritarian and permissive parenting on children’s behavioral functioning, regardless of the presence of symptoms of depression (Akhter, Hanif, Tariq, & Atta, 2011; Braza et al., 2013; Querido, Warner, & Eyberg, 2002; Sangawi, Adams, & Reissland, 2015). Authoritarian parenting, in which parents attempted to control the attitudes and behaviors of their children to an absolute standard, and permissive parenting style, in which parents provided few rules, with limited expectations for age-appropriate behaviors, were associated with child behavioral problems. In contrast, we did not identify associations between children’s cognitive functioning and behavioral problems (Malee, et al., 2011; Puthanakit, et al., 2013). Furthermore, behavioral difficulties were not related to HIV status, CD4+ T cell counts, and viral load among children with PHIV (Gadow et al., 2012; Jeremy et al., 2005; Laughton, et al., 2013; Nozyce, et al., 2006; Ruisenor-Escudero et al., 2015). Although in utero exposure to teratogenic substances, such as nicotine, alcohol, and others, have been associated with negative effects on cognition and behaviors, we did not observe such an association, likely related in part to low prevalence of these exposures in our cohort (Huizink and Mulder, 2006).

The results of this investigation may have important clinical implications for health management of HIV-exposed children and their families. ART uptake during pregnancy among women with HIV has increased dramatically during recent years, with notable prevention of mother-to-child HIV transmission. The ensuing increase in the number of HEU children coupled with the results of this and other studies highlight the importance of family-centered care for children and families affected by HIV. Careful attention to the mental health and parenting needs of mothers and other caregivers of children affected by HIV, particularly during the early childhood years, is needed to support both parental and child well-being and attachment. Such care, which may require psychiatric expertise for caregivers with persistent mental health needs, has potential for positive downstream effects on children’s behaviors, learning, and social-emotional functioning throughout childhood and adolescence. Parental empowerment education and guidance regarding parental responsivity could also be explored as mechanisms to support healthy child and parent development (Berkule et al., 2014; Cates et al., 2016).

Our study is not without limitations, including the absence of a healthy, non-HIV exposed comparison group with similar socioeconomic backgrounds as HIV-exposed children. However, in another healthy (HIV unexposed) cohort in our hospital, the rate of global developmental impairment by MSEL was 0.4-2.6% in children aged 1½ -4 years; behavioral problems assessed by the CBCL were reported among 1.5-19.6% at age 1½ year in that cohort (Tassanakijpanich N et al,. 2017; Chonchaiya W et al,. 2015). Most of these children were in families with middle to high socioeconomic status (a median (IQR) income of 60,000 (40,000-95,000) Baht/month) and most parents were college graduates, with at least a bachelor degree; while only 11% of participants had income > 50,000 Baht/month and only 14% of parents graduated with at least a bachelor degree in our current study. Furthermore, the rate of clinical range behavioral problems in this current study was relatively similar to HIV-unexposed children in a separate study conducted in another location in Thailand (Sanmaneechai, Puthanakit, Louthrenoo, & Sirisanthana, 2005). Although we expected comparable demographic data between those with PHIV and HEU, it was not the case in this study. Secondly, primary caregivers’ depression, parenting styles, and child behavioral profiles were obtained simultaneously at each time point. As such, causality and directionality of these factors could not be inferred. Although our sample size was relatively small, an important strength of this study was the consistent participation and full retention of children and caregivers in study activities at both time points and collection of thorough information regarding factors known or hypothesized to be associated with behavioral problems in young children.

Conclusion

To summarize, among young children affected by HIV in Thailand, including both PHIV and HEU children, caregivers’ depression, parenting styles, and lower education, were significantly associated with children’s behavioral difficulties during the preschool years. Family-centered care is warranted to address caregivers’ mental health needs, support appropriate parent-child interaction, and reduce multigenerational risk.

Acknowledgments

We are indebted to the participating families and children for their time and effort.

Funding sources: Funding for this project was made possible in part by a CIPHER grant from the International AIDS Society 2016, a grant from amfAR through the U.S. National Institutes of Health’s National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute of Mental Health, and the National Institute on Drug Abuse, as part of the International Epidemiology Databases to Evaluate AIDS (IeDEA; U01AI069907), and the 100th Chulalongkorn University Fund for Doctoral Scholarship. PT and NJ are also supported in part by U.S. National Institutes of Health grants (U54 EB020403 and P41 EB015922).

Conflict of Interest: JA has received honoraria for participating in advisory meetings for AbbVie, Roche, Gilead, Merck and ViiV Healthcare. The other authors declare that they have no conflicts of interest. PT and NJ have received partial research support from Biogen, Inc. (Boston, USA) on topics unrelated to the research in this manuscript. The other authors declare that they have no conflicts of interest.

Footnotes

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Publisher's Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Army or the Department of Defense or the National Institutes of Health.

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