Wicharn Luesomboon

Cognitive function and neurodevelopmental outcomes in HIV-infected Children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study.

Background: We previously reported similar AIDS-free survival at 3 years in children who were >1 year old initiating antiretroviral therapy (ART) and randomized to early versus deferred ART in the Pediatric Randomized to Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) study. We now report neurodevelopmental outcomes. Methods: Two hundred eighty-four HIV-infected Thai and Cambodian children aged 1–12 years with CD4 counts between 15% and 24% and no AIDS-defining illness were randomized to initiate ART at enrollment (“early,” n = 139) or when CD4 count became <15% or a Centers for Disease Control (CDC) category C event developed (“deferred,” n = 145). All underwent age-appropriate neurodevelopment testing including Beery Visual Motor Integration, Purdue Pegboard, Color Trails and Child Behavioral Checklist. Thai children (n = 170) also completed Wechsler Intelligence Scale (intelligence quotient) and Stanford Binet Memory test. We compared week 144 measures by randomized group and to HIV-uninfected children (n = 319). Results: At week 144, the median age was 9 years and 69 (48%) of the deferred arm children had initiated ART. The early arm had a higher CD4 (33% versus 24%, P < 0.001) and a greater percentage of children with viral suppression (91% versus 40%, P < 0.001). Neurodevelopmental scores did not differ by arm, and there were no differences in changes between arms across repeated assessments in time-varying multivariate models. HIV-infected children performed worse than uninfected children on intelligence quotient, Beery Visual Motor Integration, Binet memory and Child Behavioral Checklist. Conclusions: In HIV-infected children surviving beyond 1 year of age without ART, neurodevelopmental outcomes were similar with ART initiation at CD4 15%–24% versus <15%, but both groups performed worse than HIV-uninfected children. The window of opportunity for a positive effect of ART initiation on neurodevelopment may remain in infancy.

Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial

BACKGROUND The optimum time to start antiretroviral therapy for children diagnosed with HIV infection after 1 year of age is unknown. We assessed whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15% without affecting AIDS-free survival. METHODS In our multicentre, randomised, open-label trial at nine research sites in Thailand and Cambodia, we enrolled children aged 1-12 years who were infected with HIV and had CD4 percentages of 15-24%. Participants were randomly assigned (1:1) by a minimisation scheme to start antiretroviral therapy at study entry (early treatment group) or antiretroviral therapy to start when CD4 percentages declined to less than 15% (deferred treatment group). The primary endpoint was AIDS-free survival (based on US Centers for Disease Control and Prevention category C events) at week 144, assessed with the Kaplan-Meier analysis and the log-rank approach. This study is registered with ClinicalTrials.gov, number NCT00234091. FINDINGS Between March 28, 2006, and Sept 10, 2008, we enrolled 300 Thai and Cambodian children infected with HIV, with a median age of 6·4 years (IQR 3·9-8·4). 150 children were randomly allocated early antiretroviral therapy (one participant was excluded from analyses after withdrawing before week 0) and 150 children were randomly allocated deferred antiretroviral therapy. Median baseline CD4 percentage was 19% (16-22%). 69 children (46%) in the deferred treatment group started antiretroviral therapy during the study. AIDS-free survival at week 144 in the deferred treatment group was 98·7% (95% CI 94·7-99·7; 148 of 150 patients) compared with 97·9% (93·7-99·3; 146 of 149 patients) in the early treatment group (p=0·6). INTERPRETATION AIDS-free survival in both treatment groups was high. This low event rate meant that our study was underpowered to detect differences between treatment start times and thus additional follow-up of study participants or future studies are needed to answer this clinical question.

Neurodevelopmental outcomes in HIV-exposed-uninfected children versus those not exposed to HIV

Human immunodeficiency virus (HIV)-negative children born to HIV-infected mothers may exhibit differences in neurodevelopment (ND) compared to age- and gender-matched controls whose lives have not been affected by HIV. This could occur due to exposure to HIV and antiretroviral agents in utero and perinatally, or differences in the environment in which they grow up. This study assessed neurodevelopmental outcomes in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children enrolled as controls in a multicenter ND study from Thailand and Cambodia. One hundred sixty HEU and 167 HUU children completed a neurodevelopmental assessment using the Beery Visual Motor Integration (VMI) test, Color Trails, Perdue Pegboard, and Child Behavior Checklist (CBCL). Thai children (n = 202) also completed the Wechsler Intelligence Scale (IQ) and Stanford-Binet II memory tests. In analyses adjusted for caregiver education, parent as caregiver, household income, age, and ethnicity, statistically significant lower scores were seen on verbal IQ (VIQ), full-scale IQ (FSIQ), and Binet Bead Memory among HEU compared to HUU. The mean (95% CI) differences were −6.13 (−10.3 to −1.96), p = 0.004; −4.57 (−8.80 to −0.35), p = 0.03; and −3.72 (−6.57 to −0.88), p = 0.01 for VIQ, FSIQ, and Binet Bead Memory, respectively. We observed no significant differences in performance IQ, other Binet memory domains, Color Trail, Perdue Pegboard, Beery VMI, or CBCL test scores. We conclude that HEU children evidence reductions in some neurodevelopmental outcomes compared to HUU; however, these differences are small and it remains unclear to what extent they have immediate and long-term clinical significance.

Correlation of selenium and zinc levels to antiretroviral treatment outcomes in Thai HIV-infected children without severe HIV symptoms

Background/Objectives:Deficiencies in antioxidants contribute to immune dysregulation and viral replication. To evaluate the correlation of selenium (Se) and zinc (Zn) levels on the treatment outcomes in HIV-infected children.Subjects/Methods:HIV-infected Thai children 1–12 years old, CD4 15–24%, without severe HIV symptoms were included. Se and Zn levels were measured by graphite furnace atomic absorption spectrometry at baseline and 48 weeks. Deficiency cutoffs were Se <0.1 μmol/l and Zn <9.9 μmol/l. Serum ferritin and C-reactive protein (CRP) were measured every 24 weeks. No micronutrient supplement was prescribed.Results:In all, 141 children (38.3% male) with a median (interquartile range (IQR)) age of 7.3 (4.2–9.0) years were enrolled. Median baseline CD4% was 20%, HIV-RNA was 4.6 log10copies/ml. At baseline, median (IQR) Se and Zn levels were 0.9 (0.7–1.0) μmol/l and 5.9 (4.8–6.9) μmol/l, respectively. None had Se deficiency while all had Zn deficiency. Over 48 weeks, 97 initiated antiretroviral therapy (ART) and 81% achieved HIV-RNA <50 copies/ml with 11% median CD4 gain. The mean change of Se was 0.06 μmol/l (P=0.003) and Zn was 0.42 μmol/l (P=0.003), respectively. By multivariate analysis in children who received ART, predictors for greater increase of CD4% from baseline were lower baseline CD4% (P<0.01) and higher baseline Zn level (P=0.02). The predictors for greater decrease of HIV-RNA from baseline were higher baseline HIV-RNA and higher ferritin (both P<0.01). No association of CRP with the changes from baseline of CD4% or HIV-RNA was found.Conclusion:In HIV-infected Thai children without severe immune deficiency who commenced ART, no correlation between Se and ART treatment outcomes was found. Higher pre-ART Zn levels were associated with significant increases in CD4% at 48 weeks.

Impact of Antiretroviral Therapy on Quality of Life in HIV-Infected Southeast Asian Children in the PREDICT Study

Quality of life (QOL) is an important antiretroviral treatment (ART) outcome. We compared QOL among 299 Thai and Cambodian children ages 1-12 years-old, CD4 15-24% randomized to early (ART at week 0, N=149) versus deferred groups (ART when at CD4 <15%, N=150) and also compared with QOL data from age-matched healthy controls (N=275). Primary caregivers completed PACTG QOL questionnaires at week 0 and every 24 weeks until 144 weeks. Children were enrolled during March 2006 to September 2008. Mean (SD) age of children was 6.3 (2.8) years, 58% were female, 60% were Thai, %CDC N:A:B:C was 2:62:36:0%. During 144 weeks, all children in the early-group and 69 (46%) of deferred-group children started ART. There was no significant difference of QOL scores between treatment groups at baseline (all p>0.05) and at week 144 (all p>0.05). By multivariate analysis, the early-group had higher QOL score changes in five domains, including health perception (p=0.04), physical resilience (p=0.02), psychosocial well-being (p=0.04), social and role functioning (p<0.01), and symptoms (p=0.01) compared to the deferred group. QOL of HIV-infected children in both groups were lower than healthy control in all 7 domains at baseline (all p<0.05) and 5 of 7 domains at weeks 144 (p<0.01). In conclusion, no significant difference of QOL scores between treatment groups. Early ART commencement associated with greater increase of QOL scores over 144 weeks. QOL scores in HIV-infected children were lower than healthy controls.

Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age

BACKGROUND There are limited data on the immune profiles of HIV-positive children compared with healthy controls, and no such data for Asian children. OBJECTIVES To immunophenotype HIV-positive Asian children, including long-term nonprogressors (LTNPs), compared with age-matched healthy controls. METHODS We used flow cytometry to analyze 13 lymphocyte and monocyte subsets from 222 untreated, HIV-positive children with 15% to 24% CD4(+) T cells and no AIDS-related illnesses and 142 healthy children (controls). Data were compared among age categories. Profiles from LTNPs (n = 50), defined as children ≥8 years old with CD4(+) T-cell counts ≥350 cells/mm(3), were compared with data from age-matched non-LTNPs (n = 17) and controls (n = 53). RESULTS Compared with controls, HIV-positive children had lower values (cell count per mm(3) and percent distribution) for T(H) cells and higher values for cytotoxic T cells, with reductions in populations of naive T(H) and cytotoxic T cells, B cells, and natural killer (NK) cells. HIV-positive children had high values for activated T(H) and cytotoxic T cells. Compared with non-LTNPs, LTNPs had higher values of T(H) and cytotoxic T cells, naive and memory T-cell subsets, and B and NK cells. Surprisingly, counts of activated T(H) and cytotoxic T cells were also higher among LTNPs. LNTPs were more frequently male. CONCLUSION Untreated, HIV-infected Asian children have immune profiles that differ from those of controls, characterized by low values for T(H) cells, naive T cells, B cells, and NK cells but high values for cytotoxic, activated T(H), and cytotoxic T cells. The higher values for activated T cells observed in LTNPs require confirmation in longitudinal studies.

Prevalence of Human Leukocyte Antigen-B*5701 Among HIV-infected Children in Thailand and Cambodia: Implications for Abacavir Use

Human leukocyte antigen (HLA)-B*5701 allele is associated with abacavir hypersensitivity. Limited data among Asians showed lower rates of HLA-B*5701 compared with Caucasians. In 296 children with HIV in Thailand and Cambodia, the prevalence of HLA-B*5701 was 4.0% (95% confidence interval: 1.6–8.0%) among Thai and 3.4% (95% confidence interval: 0.9–8.5%) among Cambodian children. HLA-B*5701 carriage is not uncommon among Thai and Cambodian children; it is close to the prevalence found in European and higher than the prevalence found in East Asian and African studies.

Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial

BACKGROUND The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents. METHODS We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per μL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUCtau for elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUClast for tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults. INTERPRETATION The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children. FUNDING Gilead Sciences.

Poor quality of life among untreated Thai and Cambodian children without severe HIV symptoms

There are limited data on quality of life (QOL)1in untreated HIV-infected children who do not have severe HIV symptoms. Moreover, such data do not exist for Asian children. Poor QOL could be a factor in deciding if antiretroviral therapy (ART) should be initiated. Thai and Cambodian children (n=294), aged 1–11 years, naïve to ART, with mild to moderate HIV symptoms and CD4 15–24% were enrolled. Their caregivers completed the Pediatric AIDS Clinical Trials Group QOL questionnaire prior to ART commencement. Six QOL domains were assessed using transformed scores that ranged from 0 to 100. Higher QOL scores indicated better health. Mean age was 6.1 (SD 2.8) years, mean CD4 was 723 (SD 369) cells/mm3, 57% was female, and%CDC N:A:B was 2:63:35%. One-third knew their HIV diagnosis. Mean (SD) scores were 69.9 (17.6) for health perception, 64.5 (16.2) for physical resilience, 84.2 (15.6) for physical functioning, 77.9 (16.3) for psychosocial well-being, 74.7 (28.7) for social and role functioning, 90.0 (12.1) for health care utilization, and 87.4 (11.3) for symptoms domains. Children with CD4 counts above the 2008 World Health Organization (WHO) ART-initiation criteria (n=53) had higher scores in health perception and health care utilization than those with lower CD4 values. Younger children had poorer QOL than older children despite having similar mean CD4%. In conclusion, untreated Asian children without severe HIV symptoms had relatively low QOL scores compared to published reports in Western countries. Therapy initiation criteria by the WHO identified children with lower QOL scores to start ART; however, children who did not fit ART-initiation criteria and those who were younger also displayed poor QOL. QOL assessment should be considered in untreated children to inform decisions about when to initiate ART.

Comparison of adherence monitoring tools and correlation to virologic failure in a pediatric HIV clinical trial.

There is no consensus on a gold standard for monitoring adherence to antiretroviral therapy (ART). We compared different adherence monitoring tools in predicting virologic failure as part of a clinical trial. HIV-infected Thai and Cambodian children aged 1-12 years (N=207) were randomized to immediate-ART or deferred-ART until CD4% <15%. Virologic failure (VF) was defined as HIV-RNA >1000 copies/mL after ≥6 months of ART. Adherence monitoring tools were: (1) announced pill count, (2) PACTG adherence questionnaire (form completed by caregivers), and (3) child self-report (self-reporting from children or caregivers to direct questioning by investigators during the clinic visit) of any missed doses in the last 3 days and in the period since the last visit. The Kappa statistic was used to describe agreement between each tool. The median age at ART initiation was 7 years with median CD4% 17% and HIV-RNA 5.0 log(10)copies/mL and 92% received zidovudine/lamivudine/nevirapine. Over 144 weeks, 13% had VF. Mean adherence by announced pill count before VF in VF children was 92% compared to 98% in children without VF (p=0.03). Kappa statistics indicated slight to fair agreement between tools. In multivariate analysis adjusting for gender, treatment arm ethnicity and caregiver education, significant predictors of VF were poor adherence by announced pill count (OR 4.56; 95%CI 1.78-11.69), reporting any barrier to adherence in the PACTG adherence questionnaire (OR 7.08; 95%CI 2.42-20.73), and reporting a missed dose in the 24 weeks since the last HIV-RNA assessment (OR 8.64; 95%CI 1.96-38.04). In conclusion, we recommend the child self-report of any missed doses since last visit for use in HIV research and in routine care settings, because it is easy and quick to administer and a strong association with development of VF.