Economic Evaluation of Human Rotavirus Vaccine in Thailand.

INTRODUCTION: Rotavirus gastroenteritis is the leading cause of severe diarrhoea among young children < 5 years old. Previous cost-effectiveness analyses on rotavirus (RV) vaccination in Thailand have generated conflicting results. The aim of this current study is to evaluate the economic impact of introducing RV vaccination in Thailand, using updated Thai epidemiological and cost data. METHODS: Both cost-utility analysis (CUA) and budget impact analysis (BIA) of human rotavirus vaccine (HRV) under a universal mass vaccination (UMV) programme were conducted. A published static, deterministic, cross-sectional population model was adapted to assess costs and health outcomes associated with RV vaccination among Thai children < 5 years old during 1 year for CUA and over a 5-year period (2019-2023) for BIA. Data identified through literature review were incorporated into the model after consultation with local experts. Base case CUA was conducted from a societal perspective with quality-adjusted life year (QALY) discounted at 3% annually. Scenario analyses as well as one-way and probabilistic sensitivity analyses were conducted to assess the robustness of the base case CUA results. Costs were updated to 2017. RESULTS: At 99% coverage, HRV vaccination would substantially reduce RV-related disease burden. With an incremental cost-effectiveness ratio (ICER) of Thai baht (THB) 49,923/QALY gained, HRV vaccination versus no vaccination was cost-effective when assessed against a local threshold of THB 160,000/QALY gained. Scenario and sensitivity analyses confirmed the cost-effectiveness with all resultant ICERs falling below the willingness-to-pay threshold. HRV use in the UMV programme was estimated to result in a net expenditure of about THB 255-281 million to the Thai government in the 5th year of the programme, depending on vaccine uptake. CONCLUSION: HRV vaccination is estimated to be cost-effective in Thailand. The budget impact following inclusion of HRV into the UMV programme is expected to be partially offset by substantial reductions in RV-related disease costs. FUNDING: GlaxoSmithKline Biologicals SA GSK STUDY IDENTIFIER: HO-17-18213.

A Longitudinal Study of Behavioral Risk, Adherence, and Virologic Control in Adolescents Living With HIV in Asia.

BACKGROUND: Adolescents living with HIV (ALHIV) have poorer adherence and clinical outcomes than adults. We conducted a study to assess behavioral risks and antiretroviral therapy outcomes among ALHIV in Asia. METHODS: A prospective cohort study among ALHIV and matched HIV-uninfected controls aged 12-18 years was conducted at 9 sites in Malaysia, Thailand, and Vietnam from July 2013 to March 2017. Participants completed an audio computer-assisted self-interview at weeks 0, 48, 96, and 144. Virologic failure (VF) was defined as ≥1 viral load (VL) measurement >1000 copies/mL. Generalized estimating equations were used to identify predictors for VF. RESULTS: Of 250 ALHIV and 59 HIV-uninfected controls, 58% were Thai and 51% females. The median age was 14 years at enrollment; 93% of ALHIV were perinatally infected. At week 144, 66% of ALHIV were orphans vs. 28% of controls (P < 0.01); similar proportions of ALHIV and controls drank alcohol (58% vs. 65%), used inhalants (1% vs. 2%), had been sexually active (31% vs. 21%), and consistently used condoms (42% vs. 44%). Of the 73% of ALHIV with week 144 VL testing, median log VL was 1.60 (interquartile range 1.30-1.70) and 19% had VF. Over 70% of ALHIV had not disclosed their HIV status. Self-reported adherence ≥95% was 60% at week 144. Smoking cigarettes, >1 sexual partner, and living with nonparent relatives, a partner or alone, were associated with VF at any time. CONCLUSIONS: The subset of ALHIV with poorer adherence and VF require comprehensive interventions that address sexual risk, substance use, and HIV-status disclosure.

Effect of calcium and vitamin D supplementation on bone mineral accrual among HIV-infected Thai adolescents with low bone mineral density.

Background: The benefits of calcium and vitamin D supplementation for low bone mass remains controversial. This study assessed the changes in bone mineral density (BMD) during periods without and with calcium and vitamin D supplementation among HIV-infected adolescents with low BMD. Method: Perinatally HIV-infected Thai adolescents aged 12-20 years were enrolled into Phase 1 (pre-supplementation) to evaluate longitudinal change of BMD. We provided education about appropriate dietary intake and exercise. Lumbar spine (L2-L4) BMD and vitamin D status (25-hydroxyvitamin D [25(OH)D]) were assessed at baseline and at 12-24 month intervals. Participants with a BMD Z-score≤-2 were enrolled into Phase 2 (supplementation) that provided calcium 600 mg plus cholecalciferol 200 IU twice daily for 6 months. BMD and 25(OH)D were re-assessed at the end of study. Results: Ninety-four participants were enrolled into the Phase 1. Median age (IQR) was 14.3 (13.0-15.5) years, with 67% at Tanner stage 3-5, 89% with a plasma HIV-1 RNA<50 copies/mL. During Phase 1 and a 22.7-month follow-up, median L2-L4 BMD Z-scores remained unchanged (-1.06 vs -1.08, P=0.08), but 25(OH)D levels increased (24.7 vs 26.7 ng/mL, P=0.01). Twenty-six (28%) adolescents had low BMD and were enrolled into Phase 2, with 24 (92%) completing follow-up. The median L2-L4 BMD Z-scores (-2.59 vs -1.70; P<0.001) and calcium level (9.3 vs 9.5 mg/dL, P=0.04) significantly improved. There was an increase in BMD Z-scores during the 6-months post-supplementation as compared to the 21-month pre-supplementation period (0.65 vs -0.50, P=0.03). Conclusion: HIV-infected adolescents with low BMD had improved bone health after calcium and vitamin D supplementation. A randomised controlled trial is warranted to confirm the benefits of these supplements.

Adherence to antiretroviral therapy, stigma and behavioral risk factors in HIV-infected adolescents in Asia.

We studied behavioral risks among HIV-infected and uninfected adolescents using an audio computer-assisted self-interview. A prospective cohort study was initiated between 2013 and 2014 in Malaysia, Thailand, and Vietnam. HIV-infected adolescents were matched to uninfected adolescents (4:1) by sex and age group (12-14 and 15-18 years). We enrolled 250 HIV-infected (48% male; median age 14.5 years; 93% perinatally infected) and 59 uninfected (51% male; median age 14.1 years) adolescents. At enrollment, HIV-infected adolescents were on antiretroviral therapy (ART) for a median (IQR) of 7.5 (4.7-10.2) years, and 14% had HIV-RNA >1000 copies/mL; 19% reported adherence <80%. Eighty-four (34%) HIV-infected and 26 (44%) uninfected adolescents reported having ever smoked cigarettes or drunk alcohol (p = 0.13); 10% of HIV-infected and 17% of uninfected adolescents reported having initiated sexual activity; 6 of the HIV-infected adolescents had HIV-RNA >1000 copies/mL. Risk behaviors were common among adolescents, with few differences between those with and without HIV.

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.

Prevalence of Persistent Renal Dysfunction in Perinatally HIV-infected Thai Adolescents.

BACKGROUND: Persistent renal dysfunction (PRD) has been reported in up to 22% of perinatally HIV-infected adolescents (PHAs) in the United States and Europe. There are limited data available on PRD among PHAs in resource-limited settings regarding access to antiretroviral therapy (ART) at more advanced HIV stages. METHODS: We retrospectively described the prevalence of PRD and associated factors in a Thai PHA cohort. Inclusion criteria were current age ≥10 years old and at least 2 serum creatinine (Cr) measurements after ART initiation. Cr and urine examination were performed every 6-12 months. PRD was defined as having ≥2 measurements of low estimated glomerular filtration rate (eGFR); either <60 mL/min/1.73 m2 or elevated Cr for age and eGFR 60-89 mL/min/1.73 m2, or proteinuria (dipstick proteinuria ≥1+). Factors associated with PRD were analyzed using a multivariate logistic regression analysis. RESULTS: This study included 255 PHAs with median (interquartile range) age of 16.7 (14.5-18.8) and ART duration of 10.3 (7.1-12.4) years. Fifty-six percentage used boosted protease inhibitor (bPI)-based regimens, and 63% used tenofovir disoproxil fumarate (TDF). The overall PRD prevalence was 14.1% [95% confidence interval (CI): 10.1-19.0]; low eGFR 6.7%, proteinuria 3.5% and both 3.9%. Among 109 users of TDF with bPI, 22.9% had PRD and 2.8% discontinued/adjusted dosing of TDF because of nephrotoxicity. Factors associated with PRD were age 10-15 years old (adjusted odd ratio (aOR): 10.1, 95% CI: 4.1-25.2), male (aOR: 3.2, 95% CI: 1.4-7.7), CD4 nadir <150 cells/mm (aOR: 2.6, 95% CI: 1.1-6.1) and use of TDF with bPI (aOR: 9.6, 95% CI: 3.2-28.9). CONCLUSIONS: PRD is common among PHAs. Almost one-fifth of adolescents using TDF with bPI had PRD. These adolescents should be a priority group for renal monitoring.

Brief Report: Lopinavir Hair Concentrations Are the Strongest Predictor of Viremia in HIV-Infected Asian Children and Adolescents on Second-Line Antiretroviral Therapy.

BACKGROUND: Children/adolescents display suboptimal antiretroviral therapy (ART) adherence and outcomes versus adults. Hair ART concentrations are objective adherence measures that predict viremia in adults but longitudinal data on hair levels in pediatric populations is limited. We assessed the predictive utility of hair lopinavir (LPV) levels on viremia among youth on second-line ART. METHODS: We examined predictors of viremia (HIV-1 RNA >400 and >1000 copies/mL) at least 24 weeks after switch to LPV-based second-line ART in a cohort of HIV-infected Asian children followed between 2011 and 2014. Small hair samples, HIV-1 RNA, and self-reported adherence were collected biannually. Hair concentrations of LPV were measured through liquid chromatography/tandem mass spectrometry using validated methods. Time-to-first viremia was examined using discrete-time Cox models. RESULTS: Overall, 244 children met the inclusion criteria for the present analysis. Approximately half (55%) were boys and the median age 10 years [interquartile range (IQR) 7-13]; 40% were older than 11 years. At switch to second-line ART, median CD4 count was 300 (IQR 146-547) cells/mm and median HIV-RNA level was 5.0 (IQR 4.3-5.6) log10/mL. Median time of study follow-up was 48 weeks and a median of 3 (range 1-5) hair samples were collected from each participant. Adjusting for age, sex, country, self-reported adherence, CD4, and HIV-RNA, higher LPV hair concentrations were the strongest predictor of lower odds of viremia (HIV-RNA >400 copies/mL adjusted odds ratio = 0.41 per doubling in hair concentration, 95% confidence interval: 0.29 to 0.58, P < 0.001; HIV-RNA >1000 copies/mL, adjusted odds ratio = 0.54, 95% confidence interval: 0.45 to 0.65, P < 0.001). CONCLUSIONS: Hair concentrations predict viremia among children with HIV on second-line ART and could guide clinical decisions for this population.

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.

Therapeutic Drug Monitoring of Lopinavir in HIV-Infected Children on Second-Line Antiretroviral Therapy in Asia.

BACKGROUND: Failure rates of second-line boosted protease inhibitor antiretroviral therapy regimens in children rise over time. Therapeutic drug monitoring can contribute to assessments of adherence. The authors assessed the performance characteristics of the US DHHS-recommended lopinavir (LPV) concentration of 1.0 mg/L for predicting virologic failure (VF) and intermediate- to high-level LPV resistance in Asian children. METHODS: LPV concentration, HIV RNA level, and adherence data from study participants in Thailand, Vietnam, and Indonesia receiving second-line LPV-based ART and followed for ≥24 weeks were analyzed. RESULTS: A total of 223 children at a median age of 10.4 (interquartile range, 7.9-13.4) years were enrolled, and 61% of them were male. Their mean CD4 was 842 ± 438 cells per cubic millimeter, and the median LPV duration was 2.5 (interquartile range, 1.3-4.2) years. Five of 84 (6%) and 18 of 139 (13%) children had LPV trough and random concentrations <1.0 mg/L at study week 24. Using either of these trough or random LPV concentrations, a cutoff at 1.0 mg/L gave an area under the receiver operating characteristics curve of 0.69 in predicting VF with sensitivity of 44% (95% CI 23-66) and specificity of 94% (95% CI 89-97). Seven of 21 with VF and resistance results available had ≥1 major protease inhibitor mutation. Multivariate logistic regression found LPV concentrations <1.0 mg/L (odds ratio, 6.47; 95% CI 2.15-19.50, P = 0.001) and CD4 ≤20% (odds ratio, 2.83; 95% CI 1.01-7.89, P = 0.05) were independently associated with HIV RNA >1000 copies per milliliter. No factors predicted major LPV resistance mutations. CONCLUSIONS: The authors support that the DHHS target LPV concentration of <1.0 mg/L is predictive of VF, but not of the presence of major LPV mutations.

Treatment Outcomes and Resistance Patterns of Children and Adolescents on Second-Line Antiretroviral Therapy in Asia.

BACKGROUND: Data on pediatric treatment outcomes and drug resistance while on second-line antiretroviral therapy (ART) are needed to guide HIV care in resource-limited countries. METHODS: HIV-infected children <18 years who were switched or switching to second-line ART after first-line failure were enrolled from 8 sites in Indonesia, Thailand, and Vietnam. Genotyping was performed at virologic failure (VF; HIV-RNA >1000 copies/mL). Cox proportional hazards regression was used to evaluate factors predicting VF. RESULTS: Of 277 children, 41% were female. At second-line switch, age was 7.5 (5.3-10.3) years, CD4 count was 300 (146-562) cells per cubic millimeter, and percentage was 13 (7-20%); HIV-RNA was 5.0 (4.4-5.5) log10 copies per milliliter. Second-line regimens contained lamivudine (90%), tenofovir (43%), zidovudine or abacavir (30%), lopinavir (LPV/r; 91%), and atazanavir (ATV; 7%). After 3.3 (1.8-5.3) years on second-line ART, CD4 was 763 (556-1060) cells per cubic millimeter and 26% (20-31%). VF occurred in 73 (27%), with an incidence of 7.25 per 100 person-years (95% confidence interval [CI]: 5.77 to 9.12). Resistance mutations in 50 of 73 children with available genotyping at first VF included M184V (56%), ≥1 thymidine analogue mutation (TAM; 40%), ≥4 TAMs (10%), Q151M (4%), any major LPV mutation (8%), ≥6 LPV mutations (2%), and any major ATV mutation (4%). Associations with VF included age >11 years (hazard ratio [HR] 4.06; 95% CI: 2.15 to 7.66) and HIV-RNA >5.0 log10 copies per milliliter (HR 2.42; 95% CI: 1.27 to 4.59) at switch and were seen more commonly in children from Vietnam (HR 2.79; 95% CI: 1.55 to 5.02). CONCLUSIONS: One-fourth of children developed VF while on second-line ART. However, few developed major mutations to protease inhibitors.

Hypovitaminosis D and hyperparathyroidism: effects on bone turnover and bone mineral density among perinatally HIV-infected adolescents.

OBJECTIVES: The impact of hypovitaminosis D and secondary hyperparathyroidism on bone mineral density (BMD) in the setting of pediatric HIV infection remains unclear. This study aimed to determine the prevalence of hypovitaminosis D and hyperparathyroidism and their effects on bone turnover and BMD among HIV-infected adolescents in Southeast Asia. DESIGN: A multicenter, cross-sectional study evaluating bone health and vitamin D metabolism in HIV-infected adolescents in Thailand and Indonesia. METHODS: Perinatally HIV-infected adolescents aged 10-18 years on antiretroviral therapy with virologic suppression were enrolled. Serum 25-hydroxyvitamin D, intact parathyroid hormone, and bone turnover markers (C-terminal cross-linked telopeptide of type I collagen and procollagen type I amino-terminal propeptide) were assessed; serum 25-hydroxyvitamin D less than 20 ng/ml and intact parathyroid hormone more than 65 pg/ml were defined as hypovitaminosis D and hyperparathyroidism, respectively. Lumbar spine (L2-L4) BMD Z-score -2 or less was defined as low BMD. RESULTS: Of 394 adolescents, 57% were women. The median age [interquartile range (IQR)] was 15.0 (13.3-16.9) years. The prevalence of hypovitaminosis D, hyperparathyroidism, and both conditions were 21% [95% confidence interval (CI): 17-25%], 17% (95% CI: 13-20%), and 5% (95% CI: 3-7%), respectively. Adolescents with hypovitaminosis D and secondary hyperparathyroidism had the highest median bone resorption (C-terminal cross-linked telopeptide of type I collagen: 1610 vs. 1270 ng/l; P = 0.04) and bone formation (procollagen type I amino-terminal propeptide: 572 vs. 330 µg/l; P = 0.02) markers, and the greatest proportion of low BMD (42 vs. 15%; P = 0.01) compared with the rest of the cohort. CONCLUSION: Hypovitaminosis D complicated with secondary hyperparathyroidism was associated with increased bone turnover and bone loss. Early treatment of hypovitaminosis D before hyperparathyroidism occurs may be important to prevent bone mass deterioration.

Using Lopinavir Concentrations in Hair Samples to Assess Treatment Outcomes on Second-Line Regimens Among Asian Children.

We conducted a prospective monitoring study to determine whether antiretroviral (ARV) levels in hair of Asian children on second-line protease inhibitor-based ARV therapy (ART) are associated with virologic failure (VF), compared to plasma drug levels and self-reported adherence. HIV-infected Asian children on second-line ART regimens were enrolled into a longitudinal cohort. Traditional adherence measures, plasma, and hair samples were collected 24 weeks after study enrollment. Hair ARV levels were determined via liquid chromatography/tandem mass spectrometry. Among 149 children on lopinavir/ritonavir-based regimens, 47% were female; the median [interquartile range (IQR)] age was 10.3 (7.9-13.3) years. The median CD4% was 26% (IQR 21.7-32.1%) and the median CD4 cell count 754 (IQR 596-1,013) cells/mm(3). The median duration of lopinavir-based ART prior to week 24 of the study was 2.9 (IQR 1.6-4.2) years. Adherence was >95% in 91% (135/148) by visual analogue scale and 89% (129/145) by pill count. The median lopinavir hair concentrations were 5.43 (IQR 3.21-9.01) ng/mg in children with HIV RNA >1,000 copies/ml and 9.96 (IQR 6.51-12.31) ng/mg in children with HIV RNA <1,000 copies/ml (p = 0.003). Plasma trough and lopinavir hair concentrations were not statistically significantly correlated (Pearson's correlation coefficient 0.20; p = 0.13). Increasing lopinavir hair concentrations in quartiles were strongly associated with virologic success (odds ratios ≥4.0, overall p = 0.02), while self-reported adherence, pill count, and plasma lopinavir levels were not. Based on this first report of hair ARV concentrations and virologic outcomes in children, ARV hair concentrations, representing longer-term adherence, may be useful to identify children at risk for VF.

Brain Imaging and Neurodevelopment in HIV-uninfected Thai Children Born to HIV-infected Mothers.

BACKGROUND: Perinatal use of combination antiretroviral therapy dramatically reduces vertical (mother-to-child) transmission of HIV but has led to a growing population of children with perinatal HIV-exposure but uninfected (HEU). HIV can cause neurological injury among children born with infection, but the neuroanatomical and developmental effects in HEU children are poorly understood. METHODS: We used structural magnetic resonance imaging with diffusion tensor imaging to compare brain anatomy between 30 HEU and 33 age-matched HIV-unexposed and uninfected (HUU) children from Thailand. Maps of brain volume and microstructural anatomy were compared across groups; associations were tested between neuroimaging measures and concurrent neuropsychological test performance. RESULTS: Mean (standard deviation) age of children was 10.3 (2.8) years, and 58% were male. All were enrolled in school and lived with family members. Intelligence quotient (IQ) did not differ between groups. Caretaker education levels did not differ, but income was higher for HUU (P < 0.001). We did not detect group differences in brain volume or diffusion tensor imaging metrics, after controlling for sociodemographic factors. The mean (95% confidence interval) fractional anisotropy in the corpus callosum was 0.375 (0.368-0.381) in HEU compared with 0.370 (0.364-0.375) in HUU. Higher fractional anisotropy and lower mean diffusivity were each associated with higher IQ scores in analyses with both groups combined. CONCLUSIONS: No differences in neuroanatomical or brain integrity measures were detectable in HEU children compared with age-matched and sex-matched controls (HUU children). Expected associations between brain integrity measures and IQ scores were identified suggesting sufficient power to detect subtle associations that were present.

Pharmacokinetics of atazanavir/ritonavir among HIV-infected Thai children concomitantly taking tenofovir disoproxil fumarate.

BACKGROUND: Atazanavir/ritonavir (ATV/r) is a recommended once-daily protease inhibitor. Tenofovir disoproxil fumarate (TDF) can reduce ATV exposure. The authors studied ATV pharmacokinetic (PK) parameters among children who received atazanavir/ritonavir co-administered with TDF. METHODS: HIV-infected children aged 6-18 years with a body weight of 25-50 kg were eligible. Branded ATV 200 mg/capsule was taken with generic ritonavir 100 mg/tablet once daily plus TDF and lamivudine. A 24-hour PK study was performed at week 4 at t = 0 (pre-dose), 2, 4, 6, 8, 10, 12 and 24 hours. PK parameters were calculated using non-compartmental methods with WinNonlin software. Targeted ATV AUC 0-24 was 15 mg h/L and C trough was 0.15 mg/L. Comparisons of geometric means of ATV PK parameters between different weight bands were made using regression models. RESULTS: Eighteen HIV-infected children with a median (IQR) age of 13 (11-14) years were enrolled. Median (range) body weight and body surface area were 35 (25-42) kg and 1.21 (0.96-1.35) m2, respectively. Median (IQR) CD4 cell count was 735 (540-1233) cells/mm3. Median (range) of ATV was 164 (145-209) mg/m2. Geometric mean (SD) ATV AUC 0-24 was 35.05 (1.06) mg h/L, and ATV C trough was 0.31 (1.13) mg/L. No child had ATV AUC 0-24 or C trough below target levels. There were no significant differences in PK parameters among weight bands. CONCLUSION: Atazanavir/ritonavir 200/100 mg dosing provided adequate ATV AUC 0-24 when used with TDF in HIV-infected Thai children weighing between 25 and 50 kg.

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.

HIV disclosure and its effect on treatment outcomes in perinatal HIV-infected Thai children.

The World Health Organization guideline recommends informing children of their HIV status between the ages of 6-12 years. Primary caregivers of perinatal HIV-infected Thai children ≥6 years were interviewed in order to assess the HIV status disclosure rate. In addition, pill counts of antiretroviral therapy (ART) were performed every three months. CD4 and HIV-RNA were performed every six months. Of the 260 children/adolescents included, the median age of disclosure was 14.8 years. The disclosure rate among those from 6 to 12 years was 21% and for those greater than 12 years of age was 84%. When comparing children aged 6-12 years whose HIV status had been disclosed to them, to children whose HIV had yet to be disclosed, no difference was noted in median ART adherence by pill count, CD4 count, or proportion of HIV-RNA <50 copies/ml (p > 0.05). Factors associated with HIV disclosure were an age of ≥12 years (OR 17.8, 95% CI 8.86-35.79) and a current CD4 ≤ 30% (OR 2.09, 95% CI 1.20-3.62). In conclusion, although the majority of adolescents ≥12 years were aware of their HIV status only one-fifth of children aged 6-12 years were aware. Moreover, the child's/adolescent's disclosure status had no bearing on ART adherence by pill count or immunological and virological outcomes.

Impact of antiretroviral therapy on opportunistic infections of HIV-infected children in the therapeutic research, education and AIDS training asia pediatric HIV observational database.

BACKGROUND: There are limited data on opportunistic infections (OIs) and factors associated with their occurrence after highly active antiretroviral therapy (HAART) in Asian children. The use of HAART in Asia started much later than in developed countries and therefore reported findings may not be fully applicable to the pediatric HIV epidemic in Asia. METHODS: Retrospective and prospectively collected data from the Therapeutic Research, Education and AIDS Training Asia Pediatric HIV Observational Database cohort study from March 1993 to March 2009 were analyzed. OIs were defined according to World Health Organization clinical staging criteria and incidence rates calculated. Factors associated with the incidence of severe OIs were analyzed using random effects Poisson regression modeling. RESULTS: Of 2280 children in the cohort, 1752 were ever reported to have received antiretroviral therapy, of whom 1480 (84%) started on HAART. Before commencing any antiretroviral therapy, OIs occurred at a rate of 89.5 per 100 person-years. The incidence rate was 28.8 infections per 100 person-years during mono- or dual-therapy and 10.5 infections per 100 person-years during HAART. The most common OIs both before and after antiretroviral therapy initiation were recurrent upper respiratory tract infections, persistent oral candidiasis and pulmonary tuberculosis. The incidence rates of World Health Organization clinical stage 3 or 4 OIs after HAART were highest among children <18 months of age and those with low weight-for-age z scores, CD4 cell % <15%, and World Health Organization stage 3 at HAART initiation. CONCLUSIONS: Despite dramatic declines in their incidence, OIs remained important causes of morbidity after HAART initiation in this regional cohort of HIV-infected children in Asia.

Simplifying antiretroviral therapy to lopinavir/ritonavir monotherapy did not improve quality of life and therapy adherence in pretreated HIV-infected children.

We reported quality of life (QOL) and adherence in HIV-infected children after simplifying the antiretroviral regimen by switching to lopinavir/ritonavir monotherapy (mLPV/r). HIV-infected children with HIV-RNA <50 copies/ml while using second-line double boosted protease inhibitors were switched to mLPV/r. Primary caregivers completed PACTG QOL questionnaires at weeks 0, 48, 96, and 144. Adherence by pill count was performed at every visit. Thirty-eight pretreated HIV-infected Thai children were enrolled. The median (IQR) age was 11.5 (10.2-13.2) years and 53% were female. At enrollment, 34 used LPV/r+saquinavir and four used LPV/r+indinavir. The median (IQR) CD4% was 27 (23-30)%. At week 144, QOL scores were similar to baseline for all domains. A transient increase in the symptoms domain score was seen at week 96 (p=0.01), whereas the physical resilience domain score was decreased at weeks 48 and 96 (both p<0.05). Despite the mean number of pills decreasing from 7.9 pills/day before and 3.7 pills/day after mLPV/r (p<0.001), there were no differences over time in adherence rates by pill count and proportion of children with poor adherence (all p>0.05). Our study did not demonstrate improvement of QOL scores and adherence rates by pill count in pretreated HIV-infected children after simplification of the antiretroviral regimen to lopinavir/ritonavir monotherapy.

Prevalence, characteristics, management, and outcome of pulmonary tuberculosis in HIV-infected children in the TREAT Asia pediatric HIV Observational Database (TApHOD).

A multicenter, retrospective, observational study was conducted to determine prevalence, characteristics, management, and outcome of pulmonary tuberculosis (PTB) in Asian HIV-infected children in the TREAT Asia Pediatric HIV Observational Database (TApHOD). Data on PTB episodes diagnosed during the period between 12 months before antiretroviral therapy (ART) initiation and December 31, 2009 were extracted. A total of 2678 HIV-infected children were included in TApHOD over a 13-year period; 457 developed PTB, giving a period prevalence of 17.1% (range 5.7-33.0% per country). There were a total of 484 PTB episodes; 27 children had 2 episodes each. There were 21 deaths (4.3%). One third of episodes (n=175/484) occurred after ART initiation at a median of 14.1 months (interquartile range [IQR] 2.5-28.8 months). The median (IQR) CD4+ values were 9.0% (3.0-16.0%) and 183.5 (37.8-525.0) cells/mm(3) when PTB was diagnosed. Most episodes (n=424/436, 97.3%) had abnormal radiographic findings compatible with PTB, whereas half (n=267/484, 55.2%) presented with clinical characteristics of PTB. One third of those tested (n=42/122, 34.4%) had bacteriological evidence of PTB. Of the 156 episodes (32.2%) that were accompanied with extrapulmonary TB, pleuritis was the most common manifestation (81.4%). After treatment completion, most episodes (n=396/484, 81.9%) were recorded as having positive outcomes (cured, treatment completed and child well, and improvement). The prevalence of PTB among Asian HIV-infected children in our cohort was high. Children with persistent immunosuppression remain vulnerable to PTB even after ART initiation.