D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.

A Three-Year Follow-Up of Bone Density Among Thai Adolescents With Perinatally Acquired HIV After Completion of Vitamin D and Calcium Supplementation.

PURPOSE: To determine changes in bone mineral density (BMD) and bone metabolism-related biomarkers among Thai adolescents with perinatally acquired HIV infection (PHIVA) at 3 years following completion of vitamin D and calcium (VitD/Cal) supplementation. METHODS: An observational follow-up study was conducted among PHIVA who received 48-week VitD/Cal supplementation (either high-dose [3,200 IU/1,200 mg daily] or standard-dose [400 IU/1,200 mg daily]). Lumbar spine BMD (LSBMD) was assessed by dual-energy x-ray absorptiometry. Serum 25-hydroxyvitamin D, intact parathyroid hormone, and bone turnover markers were measured. Changes in LSBMD z-scores and other bone parameters at 3 years after stopping VitD/Cal supplementation compared with baseline or week 48 of supplementation were assessed among participants previously receiving high-dose and standard-dose VitD/Cal supplementation. RESULTS: Of 114 enrolled PHIVA, 46% and 54% had previously received high-dose and standard-dose VitD/Cal supplementation, respectively. The median age was 20 years; 53% were male. At 3 years after completion of VitD/Cal supplementation, we observed a significant decline in 25-hydroxyvitamin D and increase in intact parathyroid hormone but no significant rebounds of C-terminal telopeptides of collagen type I and procollagen type I amino-terminal propeptides and no significant changes in LSBMD z-scores among PHIVA in both treatment groups, compared with the measurements at week 48 of supplementation. Notably, LSBMD z-scores at 3 years after stopping VitD/Cal supplements were not significantly altered from baseline evaluations in both PHIVA groups. DISCUSSION: Three years after completion of high-dose or standard-dose VitD/Cal supplementation, LSBMD z-scores of our Thai PHIVA were not significantly changed from baseline and week 48 of supplementation. VitD/Cal supplementation of PHIVA during periods of peak bone mass accrual may have sustained and long-term skeletal benefits.

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)]. Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Impact of Vitamin D and Calcium Supplementation on Bone Mineral Density and Bone Metabolism Among Thai Adolescents With Perinatally Acquired Human Immunodeficiency Virus (HIV) Infection: A Randomized Clinical Trial.

BACKGROUND: To evaluate the impact of vitamin D and calcium supplementation (VitD/Ca) on lumbar spine bone mineral density (LSBMD) and bone metabolism among Thai adolescents with perinatally acquired HIV (PHIVA). METHODS: A multicenter, randomized, active-control, open-labeled trial was conducted. PHIVA (aged 10-20 years) who were on stable cART were enrolled. Baseline LSBMD status was defined as low (z-score ≤ -2) and normal (> -2). Eligible PHIVA were randomly assigned to receive standard-dose (400 IU/1200 mg/day) or high-dose (400 IU/1200 mg/day plus ergocalciferol 20 000 IU/week) VitD/Ca supplementation for 48 weeks (ratio 1:1, stratified by baseline LSBMD). Study outcomes were changes in LSBMD, LSBMD z-scores, and bone metabolism-related biomarkers (25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone [iPTH], C-terminal telopeptide [CTX], procollagen type I amino-terminal propeptide [PINP]) from baseline to week 48. RESULTS: Among 200 enrolled PHIVA, median age was 16 (IQR:14-18) years; 61% were on NNRTI-based cART. Median 25(OH)D level was 25.5 (IQR: 20.8-33.0) ng/mL. After 48-week VitD/Ca supplementation, LSBMD significantly increased in both treatment groups (high-dose: median: +0.07 [IQR: +0.04 to +0.11] g/cm2; P < .001; standard-dose: +0.09 [+0.03 to +0.13] g/cm2; P < .001). Notably, the change in LSBMD z-scores was significantly greater in high-dose versus standard-dose groups (median: +0.4 [IQR: -0.1 to +0.9] vs +0.1 [-0.4 to +0.7]; P = .02). Levels of 25(OH)D increased, whereas iPTH, CTX, and PINP declined significantly in both groups (P < .05), but no between-group differences were demonstrated. CONCLUSIONS: Over 48-week VitD/Ca supplementation, significant increases in LSBMD, and significant decreases in bone metabolism-related markers were observed among our Thai PHIVA in both treatment groups. The improvement in LSBMD z-score was more enhanced with high-dose VitD/Ca supplementation than standard-dose. High-dose VitD/Ca supplementation might be considered to promote bone health in this population. CLINICAL TRIALS REGISTRATION: NCT02426840.

Behavioral impairment and cognition in Thai adolescents affected by HIV.

BACKGROUND: Cognitive and behavioral impairment are common in children living with perinatally acquired HIV (pHIV) and children exposed to HIV in utero but uninfected (HEU). METHODS: We sought to determine the prevalence of adverse behavioral symptomatology using a Thai-translated and validated version of the SNAP-IV questionnaire and assess cognitive function utilizing the Children's Color Trails Test, Delis-Kaplan Executive Function System, and the Wechsler Intelligence Scales, in our cohort of Thai adolescents (10-20 years old) with well-controlled pHIV compared to HEU and HIV-unexposed, uninfected youth. We then evaluated the interaction between HIV status, behavioral impairment, and executive function outcomes independent of demographic variables. RESULTS: After controlling for demographic factors of age and household income, adolescents with pHIV had higher inattentive symptomatology and poorer neuropsychological test scores compared to uninfected controls. Significant interactions were found between inattention and executive function across multiple neurocognitive tests. CONCLUSIONS: Behavioral impairment and poor executive functioning are present in adolescents with well-controlled pHIV compared to HIV-uninfected matched peers. The SNAP-IV questionnaire may be a useful tool to identify those with attentional impairment who may benefit from further cognitive testing in resource-limited settings.

Continuous Prophylactic Antiretrovirals/Antiretroviral Therapy Since Birth Reduces Seeding and Persistence of the Viral Reservoir in Children Vertically Infected With Human Immunodeficiency Virus.

BACKGROUND: Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. METHODS: We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. RESULTS: Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P < .020 and P < .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P < .01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during 3 years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARVs before starting ART and those who delayed ART initiation without receiving prior prophylaxis. CONCLUSIONS: Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir.

HIV-related enacted stigma and increase frequency of depressive symptoms among Thai and Cambodian adolescents and young adults with perinatal HIV.

HIV-related enacted stigma and social problems may increase risk for depression and/or behavioral problems among adolescents and young adults with perinatal HIV(AYA-PHIV), yet few studies have explored stigma in AYA-PHIV residing in low-to-middle income regions, including Southeast Asia. We assessed HIV-related enacted stigma and social problems in AYA-PHIV who participated in the RESILIENCE study (clinicaltrials.gov identification: U19AI53741) in Thailand and Cambodia using specific questions during structured in-person interviews. Depression was measured by the Child Depression Inventory for children <15 years, or the Center for Epidemiologic Studies Depression Scales for youth ≥15 years); behavioral problems were measured by the Child Behavior Checklist (CBCL-caregiver report). Among 195 AYA-PHIV (median age 16.9 years), 25.6% reported a lifetime experience of enacted stigma, while 10.8% experienced social problems due to HIV infection. The frequency of depressive symptoms was nearly two-fold higher among AYA-PHIV with compared to those without HIV-related enacted stigma (34.7% vs. 16.0%, p = 0.005). Caregiver-reported behavioral problems were detected in 14.6% of all AYA-PHIV, with no differences between those with and without HIV-related enacted stigma. Low household income and caregiver mental health problems were independent risk factors for depressive symptoms; HIV-related enacted stigma was also associated with increased risk, warranting targeted services to support AYA-PHIV.

Pattern and Frequency of Seroreactivity to Routinely Used Serologic Tests in Early-Treated Infants With HIV.

BACKGROUND: Previous studies have shown low frequencies of seroreactivity to HIV diagnostic assays for infected infants treated with antiretroviral therapy (ART) early in infection. METHODS: Fifty-eight HIV-infected infants treated with ART at a median age of 1.9 months (range: 0.2-5.4) for up to 4 years of life were assessed for seroreactivity to 4 routinely used HIV clinical immunoassays (IA): Second-generation (2ndG) IA and 2 rapid diagnostic tests (RDT), based on third-generation principles, measuring antibody only and a fourth-generation (4thG) antigen/antibody IA. HIV Western blot assay was also performed to assess HIV-specific antibodies. RESULTS: The 2ndG IA demonstrated the highest frequency of seroreactivity in children (69%) followed by the 4thG IA (40%) and the RDT (26%) after one year of ART. Infants initiating ART during ages 3-6 months (N = 15) showed a greater frequency (range: 53%-93%) and breadth (median and range: 3 [1-4]) of reactivity across the assays compared with those treated within 3 months (N = 43):16%-61% and breadth (1 [0-4]). The 4thG IA showed significantly reduced reactivity relative to the 2ndG IA at one (P = 0.016) and 3 (P = 0.004) years of ART. Western blot profiles following 3 years of ART showed the highest frequency of reactivity to HIV Gag p24 (76%) and lowest reactivity to Env gp120 and gp41, with only 24% of children confirmed positive by the assay. CONCLUSIONS: These results suggest that the use of 4thG IA and RDT test combination algorithms with limited HIV antigen breadth may not be adequate for diagnosis of HIV-infected children following early treatment.

Machine-learning classification of neurocognitive performance in children with perinatal HIV initiating de novo antiretroviral therapy.

OBJECTIVE: To develop a predictive model of neurocognitive trajectories in children with perinatal HIV (pHIV). DESIGN: Machine learning analysis of baseline and longitudinal predictors derived from clinical measures utilized in pediatric HIV. METHODS: Two hundred and eighty-five children (ages 2-14 years at baseline; Mage = 6.4 years) with pHIV in Southeast Asia underwent neurocognitive assessment at study enrollment and twice annually thereafter for an average of 5.4 years. Neurocognitive slopes were modeled to establish two subgroups [above (n = 145) and below average (n = 140) trajectories). Gradient-boosted multivariate regressions (GBM) with five-fold cross validation were conducted to examine baseline (pre-ART) and longitudinal predictive features derived from demographic, HIV disease, immune, mental health, and physical health indices (i.e. complete blood count [CBC]). RESULTS: The baseline GBM established a classifier of neurocognitive group designation with an average AUC of 79% built from HIV disease severity and immune markers. GBM analysis of longitudinal predictors with and without interactions improved the average AUC to 87 and 90%, respectively. Mental health problems and hematocrit levels also emerged as salient features in the longitudinal models, with novel interactions between mental health problems and both CD4 cell count and hematocrit levels. Average AUCs derived from each GBM model were higher than results obtained using logistic regression. CONCLUSION: Our findings support the feasibility of machine learning to identify children with pHIV at risk for suboptimal neurocognitive development. Results also suggest that interactions between HIV disease and mental health problems are early antecedents to neurocognitive difficulties in later childhood among youth with pHIV.

Trajectory Analysis of Cognitive Outcomes in Children With Perinatal HIV.

BACKGROUND: Children with perinatal HIV (pHIV) may display distinct long-term cognitive phenotypes. We used group-based trajectory modeling to identify clusters of children with pHIV after similar developmental trajectories and predictors of belonging to select cognitive trajectory groups. METHODS: Participants included children, 4-17 years of age, with pHIV in Thailand and Cambodia. Cognitive measures included translated versions of Intelligence Quotient tests, Color Trails Tests and Beery-Buktenica Developmental Test of Visual-Motor Integration conducted semiannually over 3-6 years. The best fit of trajectory groups was determined using maximum likelihood estimation. Multivariate logistic regression identified baseline factors associated with belonging to the lowest scoring trajectory group. RESULTS: Group-based trajectory analyses revealed a 3-cluster classification for each cognitive test, labeled as high, medium and low scoring groups. Most trajectory group scores remained stable across age. Verbal IQ declined in all 3 trajectory groups and the high scoring group for Children's Color Trails Test 1 and 2 showed an increase in scores across age. Children in the lowest scoring trajectory group were more likely to present at an older age and report lower household income. CONCLUSIONS: Group-based trajectory modeling succinctly classifies cohort heterogeneity in cognitive outcomes in pHIV. Most trajectories remained stable across age suggesting that cognitive potential is likely determined at an early age with the exception of a small subgroup of children who displayed developmental gains in select cognitive domains and may represent those with better cognitive reserve. Poverty and longer duration of untreated HIV may predispose children with pHIV to suboptimal cognitive development.

Incidence and risk factors of loss to follow-up among HIV-infected children in an antiretroviral treatment program.

INTRODUCTION: The success of antiretroviral treatment (ART) programs can be compromised by high rates of patient loss to follow-up (LTFU). We assessed the incidence and risk factors of LTFU in a large cohort of HIV-infected children receiving ART in Thailand. METHODS: All children participating in a multicenter cohort (NCT00433030) between 1999 and 2014 were included. The date of LTFU was 9 months after the last contact date. ART interruption was defined as ART discontinuation for more than 7 days followed by resumption of treatment. Baseline and time-dependent risk factors associated with LTFU were identified using Fine and Gray competing risk regression models with death or referral to another hospital as competing events. RESULTS: Of 873 children who were followed during a median of 8.6 years (interquartile range 4.5-10.6), 196 were LTFU, 73 died, and 195 referred. The cumulative incidence of LTFU was 2.9% at 1 year, 7.3% at 5 years and 22.2% at 10 years. Children aged 13 years and more had a 3-fold higher risk (95% confidence interval 2.06-4.78) of LTFU than those younger. Children who had interrupted ART within the previous year had a 2.5-fold higher risk (1.12-5.91) than those who had not. The risk of LTFU was lower in children stunted (height-for-age Z-scores <-2 SD) (0.42-0.96) or underweight (weight-for-age Z-scores <-2 SD) (0.24-0.97). CONCLUSION: Adolescence, ART interruption and absence of growth deficit were associated with LTFU. These may be warnings that should draw clinicians' attention and possibly trigger specific interventions. Children with no significant growth retardation may also be at risk of LTFU.

Impact of antiretroviral treatment on height evolution of HIV infected children.

BACKGROUND: Antiretroviral treatment (ART) has been shown to have a beneficial effect on the weight evolution but its effect on height remains unclear. We described patterns of height evolution and identified predictors of catch-up growth in HIV-infected children on ART. METHODS: To describe the height evolution from birth to adulthood, we developed a nonlinear mixed effect model using data from perinatally HIV-infected children who initiated ART from 1999 to 2013 in a prospective cohort study in Thailand. The main covariates of interest were: sex, ART regimen (dual nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based), baseline CD4 percentage, HIV-RNA load and CDC HIV Classification stage and occurrence of AIDS-defining events. RESULTS: A total 477 children (43% boys) contributed 18,596 height measurements over a median duration of 6.3 years on ART (interquartile range, 3.0 to 8.3). At ART initiation, median age was 6.2 years (1.8 to 9.6), 16% of children were underweight (weight-for-age z-score < - 2), 49% presented stunting (height-for-age z-score < - 2), and 7% wasting (weight-for-height z-score < - 2). The most frequent regimen at ART initiation was NNRTI-based (79%). A model with 4 components, birth length and 3 exponential functions of age accounting for the 3 growth phases was developed and show that the height-growth velocity was inversely associated with the age at ART initiation, the adult height was significantly lower in those who had experienced at least one AIDS-defining event while, as expected, the model found that adult height in females was lower than in males. Age at ART initiation, type of ART regimen, CDC stage, CD4 percentages, and HIV-RNA load were not associated with the final height. CONCLUSIONS: The younger the children at ART initiation, the greater the effect on height-growth velocity, supporting the World Health Organization's recommendation to start ART as early as possible. However, final adult height was not linked to the age at ART initiation.

Emotional and behavioral resilience among children with perinatally acquired HIV in Thailand and Cambodia.

OBJECTIVES: Psychosocial challenges associated with perinatally acquired HIV (PHIV) infection are well known, yet many children infected with HIV since birth demonstrate positive outcomes, referred to as resilience. The purpose of this study was to evaluate emotional-behavioral development and identify salient predictors of resilience among long-term survivors of PHIV. DESIGN: Prospective investigation of children with PHIV compared with demographically similar perinatally HIV-exposed but uninfected (PHEU) and HIV-unexposed, uninfected (HUU) children, all from Thailand and Cambodia. METHODS: The Child Behavior Checklist (CBCL; parent version) was administered at baseline and annual follow-up visits (median follow-up of 3 years) to children age 6-14. Resilience was defined as consistent CBCL scores on the Internalizing, Externalizing or Total Problem T scales within normative ranges (T-scores <60) at every time point. Generalized estimating equations examined CBCL scores over time and logistic models examined demographic, socioeconomic, and cultural predictors of resilience. RESULTS: Participants included 448 children (236 PHIV, 98 PHEU, 114 HUU), with median (interquartile range) age at first evaluation of 7 (6-9) years. Children with PHIV exhibited similar rates of resilience as PHEU and HUU on the Externalizing and Total Problems scales. Resilience on the Internalizing scale was more likely in PHEU (71%) compared with PHIV (59%) or HUU (56%), P = 0.049. Factors associated with resilience in adjusted models included: HIV-exposed but uninfected status, higher household income, Cambodian nationality, female sex, and caregiver type. CONCLUSION: Despite biopsychosocial risks, resilience is observed among PHIV and PHEU children. Further study is needed to understand mechanisms underlying associated factors and intervention priorities.

Increased Risk of Executive Function and Emotional Behavioral Problems Among Virologically Well-Controlled Perinatally HIV-Infected Adolescents in Thailand and Cambodia.

BACKGROUND: Large numbers of perinatally HIV-infected (PHIV) children are aging into adolescence. We examined cognitive and behavioral outcomes in a longitudinal cohort of Asian youth. METHODS: We followed up 231 PHIV, 125 perinatally HIV-exposed, uninfected (HEU), and 138 HIV-unexposed, uninfected (HUU) adolescents (aged 10 years and older), matched by age/sex, in Thailand and Cambodia for 3 years. Executive function was assessed with Children's Color Trails Tests 1 and 2 (CCTT-1 and -2), the design fluency test, and the verbal fluency test. Working memory (Freedom from Distractibility Index) and processing speed index were assessed using WISC-III. Visual memory was assessed by design memory and design recognition subtests of the Wide Range Assessment of Memory and Learning (WRAML-2) and behavioral problems using the Child Behavior Checklist (CBCL). Generalized estimating equations examined adjusted odds ratios of cognitive impairment (Z-scores ≥2 SD below age-adjusted means of the HUU group) and CBCL T-scores in the borderline-clinical range (T-Scores ≥60) in PHIV and HEU versus HUU youth, adjusting for ethnicity, household income, and caregiver characteristics. RESULTS: The median age at enrollment was 13.8 years, with 58% women and 63% Thai participants. PHIV youth had >86% virological suppression and significantly higher impairment rates on CCTT-1 and -2 tests, design fluency test, verbal fluency tests, design memory, and CBCL internalizing and externalizing problems. Results were mostly similar between HEU and HUU groups, apart from higher impairment rates on CCTT-1 and internalizing problems in HEU. CONCLUSION: Asian adolescents with PHIV remain at risk of cognitive and mental health problems despite HIV treatment. Selective risks are observed among HEU youth.

Risk of Liver Fibrosis in Hepatitis B Virus and HIV Coinfected Youths Receiving Tenofovir-Containing Antiretroviral Regimen.

BACKGROUND: Hepatitis B virus (HBV) and HIV coinfection is associated with risk of progression to chronic liver disease. We assessed liver stiffness in HBV-HIV coinfected youths. METHODS: A cross-sectional study in HBV-HIV coinfected youths aged 18 to 25 years who received a tenofovir (TDF)-containing antiretroviral therapy regimen for >96 weeks. Measurements included HBV DNA level, HBV serology profiles, and transient elastography (TE). The cutoff for TE results included ≥5.9 kPa for F2-moderate fibrosis, ≥7.4 kPa for F3-severe fibrosis, and ≥9.6 kPa for F4-cirrhosis. RESULTS: From March to December 2016, 15 HBV-HIV coinfected youths with a median duration on TDF-containing regimens of 3.3 years were enrolled. Five (33%) youths had significant liver fibrosis, 3 with F2-moderate, 1 with F3-advanced fibrosis, and 1 with F4-cirrhosis. Other 5 without liver fibrosis had hepatitis B surface e antigen (HBsAg) and hepatitis B surface e antigen (HBeAg) loss. Higher mean alanine transaminase (ALT) was observed among the group with F2-F4 when compared to those with F0. CONCLUSION: Liver fibrosis was evidenced in HBV-HIV coinfected youths in Thailand. Transient elastography might be considered for those who do not achieve HBsAg loss or have persistent ALT elevation while on treatment.

Cognition, Emotional Health, and Immunological Markers in Children With Long-Term Nonprogressive HIV.

BACKGROUND: HIV-infected children with long-term nonprogressive (LTNP) disease eventually convert to a progressive disease type, yet the extent to which these children experience the cognitive and emotional symptoms observed in typical progressive HIV (Progressors) is unknown. METHODS: Eighty-eight LTNPs, 53 Progressors, and 323 healthy controls completed annual assessments of cognitive and emotional health as part of a prospective study. The 2 HIV-infected groups and the healthy controls were matched on age and sex distribution at enrollment. Plasma HIV RNA, T-cell counts/percentages, activated monocytes, perivascular monocytes, and markers of macrophage activation (sCD163 and sCD14) were compared by progression subtype. Cognitive and emotional outcomes were compared using cross-sectional linear regression analysis and longitudinal sensitivity models. RESULTS: LTNPs exhibited the same cognitive phenotype and emotional dysregulation as Progressors, with worse outcomes in both groups compared with controls. In addition, cognitive and emotional symptoms were evident before children reached the minimum age for LTNP designation (8 years). Baseline plasma HIV RNA, sCD163, activated monocytes, and perivascular monocytes were lower in LTNPs versus Progressors, with no difference in T-cell counts/percentages or sCD14 levels. Most LTNPs converted to a progressive disease subtype during the study, with similar cognitive and emotion profiles between these subgroups. CONCLUSIONS: Pediatric LTNPs experience cognitive and emotional difficulties that mirror symptoms of progressive disease. The abnormalities are present at young ages and persist independent of plasma T-cell counts. The findings highlight the neurodevelopmental risk of pediatric HIV, even in those with early innate disease control.

Structural Neuroimaging and Neuropsychologic Signatures in Children With Vertically Acquired HIV.

BACKGROUND: Children with vertically acquired HIV exhibit persistent cognitive impairments, yet the corresponding neuroimaging signature of vertical infection remains unclear. METHODS: Fifty healthy control children and 51 vertically infected children were included in the study. The HIV-infected group consisted of survivors who had not received antiretroviral therapy at birth. The HIV-infected group averaged 11.4 (2.5) years of age, with a median CD4 count of 683 cells/mm(3). Most (71%) of the HIV-infected children were on antiretroviral therapy for a median of 34 months (range: 33-42) with HIV RNA <40 copies/mL in 89% of the sample. The HIV-uninfected group averaged 10.6 (2.6) years of age. Magnetic resonance imaging was acquired to determine volumes of the caudate, putamen, thalamus, pallidum, hippocampus, nucleus accumbens, total white matter, total gray matter and cortical gray matter. Correlational analyses examined the degree of shared variance between brain volumes and both cognitive performances and laboratory markers of disease activity (T cells and plasma viral load). RESULTS: HIV-infected children exhibited larger volumes of the caudate, nucleus accumbens, total gray matter and cortical gray matter when compared with the controls. Volumetric differences were predominately evident in children under 12 years of age. HIV-infected children performed worse than controls on most neuropsychologic tests, though neither cognitive performances nor laboratory markers corresponded to brain volumes in the HIV-infected children. CONCLUSIONS: Outcomes of the present study suggest abnormal brain maturation among HIV-infected pediatric survivors. Longitudinal studies of brain integrity and related resilience factors are needed to determine the impact of neuroimaging abnormalities on psychosocial function in pediatric HIV.

Brief Report: AIDS-Defining Events and Deaths in HIV-Infected Children and Adolescents on Antiretrovirals: A 14-Year Study in Thailand.

BACKGROUND: Data are scarce on the long-term clinical outcomes of perinatally HIV-infected children and adolescents receiving antiretroviral therapy (ART) in low/middle-income countries. We assessed the incidence of mortality before (early) and after (late) 6 months of ART and of the composite outcome of new/recurrent AIDS-defining event or death >6 months after ART start (late AIDS/death) and their associated factors. METHODS: Study population was perinatally HIV-infected children (≤18 years) initiating ART within the Program for HIV Prevention and Treatment observational cohort (NCT00433030). Factors associated with late AIDS/death were assessed using competing risk regression models accounting for lost to-follow-up and included baseline and time-updated variables. RESULTS: Among 619 children, "early" mortality incidence was 99 deaths per 1000 person-years of follow-up [95% confidence interval (CI): 69 to 142] and "late" mortality 6 per 1000 person-years of follow-up (95% CI: 4 to 9). Of the 553 children alive >6 months after ART initiation, median age at ART initiation was 6.4 years, CD4% 8.2%, and HIV-RNA load 5.1 log10 copies/mL. Thirty-eight (7%) children developed late AIDS/death after median time of 3.3 years: 24 died and 24 experienced new/recurrent AIDS-defining events (10 subsequently died). Factors independently associated with late AIDS/death were current age ≥13 years (adjusted subdistribution hazard ratio 4.9; 95% CI: 2.4 to 10.1), HIV-RNA load always ≥400 copies/mL (12.3; 95% CI: 4.0 to 37.6), BMI-z-score always <-2 SD (13.7; 95% CI: 3.4 to 55.7), and hemoglobin <8 g/dL at least once (4.6; 95% CI: 2.0 to 10.5). CONCLUSIONS: After the initial 6 months of ART, being an adolescent, persistent viremia, poor nutritional status, and severe anemia were associated with poor clinical outcomes. This supports the need for novel interventions that target children, particularly adolescents with poor growth and uncontrolled viremia.

Treatment Outcomes of Third-line Antiretroviral Regimens in HIV-infected Thai Adolescents.

BACKGROUND: Efficacy and safety data of third-line antiretroviral (ARV) regimens in adolescents are limited. METHODOLOGY: This study enrolled HIV-infected Thais who were treated with third-line regimens consisting of darunavir/ritonavir (DRV/r), etravirine (ETR), tipranavir/ritonavir or raltegravir. RESULTS: Fifty-four adolescents 2-17 years of age were enrolled from 8 sites and followed for 48 weeks. Reasons for switch were second-line failure (n = 44) and toxicity to second-line regimens (n = 10). At switching to third-line ARV, the median age (interquartile range) was 14.3 (12.4-15.4) years. Genotypes at time of second-line failure (n = 44) were M184V (77%), ≥4 thymidine analogue mutations (25%), non-nucleoside reverse transcriptase inhibitor-resistant associated mutation (RAM) (80%), ETR-RAM score ≥4 (14%), any lopinavir-RAM (59%) and ≥1 major DRV-RAM (41%). The third-line regimens had a median of 4 (min-max, 4-6) drugs and included ETR/DRV/r (43%), DRV/r (33%), ETR (17%), tipranavir/ritonavir (2%) or raltegravir/DRV/r/ (4%). The median CD4 (interquartile range) increased from 16% (12-21) at third-line switch to 21% (18-25) and 410 (172-682) to 607 (428-742) cells/mm at 48 weeks (P < 0.001). HIV RNA declined from 3.9 (2.9-4.9) to 1.6 (1.6-3.0) log10 copies/mL (P < 0.001) and 33/50 (66%) had levels <50 copies/mL at 48 weeks. Seventeen (31%) had HIV-RNA ≥1000 copies/mL; about half due to poor adherence; genotyping in 13 of these adolescents revealed ETR-RAM score ≥4 in 2 (15%) and ≥1 major DRV-RAM in 7 (54%). CONCLUSIONS: Third-line ARV therapy was well tolerated and resulted in virologic suppression in 70% of adolescents at 1 year. Poor adherence and limited ARV options are major problems in the long-term management of adolescents with HIV.

Incidence of Tuberculosis and Associated Mortality in a Cohort of Human Immunodeficiency Virus-Infected Children Initiating Antiretroviral Therapy.

BACKGROUND.: We assessed the incidence of tuberculosis, risk factors for tuberculosis, and the contribution of tuberculosis on mortality in a large cohort of human immunodeficiency virus (HIV)-infected children <15 years of age initiating first-line antiretroviral therapy (ART) between 1999 and 2012 in Thailand, one of the 22 high tuberculosis burden countries. METHODS.: A physician reviewed and classified tuberculosis cases. Incidence was the number of children with incident tuberculosis, defined as a first or recurrent tuberculosis diagnosis >30 days after ART initiation, divided by the total person-years of follow-up (PYFU). Risk factors for incident tuberculosis were identified using Fine and Gray's competing risks models, with death from other causes treated as a competing event, and risk factors for death were identified using Cox models. RESULTS.: At ART initiation, 670 children (55% female) had a median age of 6.4 years (interquartile range, 2.0-9.6), body mass index-for-age z-score -0.8 (-1.9 to 0.0), HIV ribonucleic acid viral load 5.1 log10 copies/mL (4.6-5.6), and CD4 9% (3-17). Median duration of follow-up was 7.7 years. Tuberculosis incidence was 7 per 1000 PYFU (95% confidence interval [CI], 5-11) and decreased with ART duration. Lower age-adjusted hemoglobin, hematocrit, and CD4 at ART initiation were associated with a higher risk of incident tuberculosis. Of the 30 incident tuberculosis cases, 9 died. Diagnosis of incident tuberculosis was associated with mortality (unadjusted hazard ratio = 10.2, 95% CI = 4.8-21.5, P < .001 and adjusted hazard ratio = 5.4, 95% CI = 2.5-11.7, P < .001). CONCLUSIONS.: Incident tuberculosis was strongly associated with mortality. CD4 counts or hemoglobin or hematocrit levels may prompt clinicians to consider a possible tuberculosis infection.