Wasana Prasitsuebsai

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.

Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV- infected children

BackgroundThere are limited data of immunologic and virologic failure in Asian HIV-infected children using non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART). We examined the incidence rate of immunologic failure (IF) and virologic failure (VF) and the accuracy of using IF to predict VF in Thai HIV-infected children using first-line NNRTI-based HAART.MethodsAntiretroviral (ART)-naïve HIV-infected children from 2 prospective cohorts treated with NNRTI-based HAART during 2001-2008 were included. CD4 counts were performed every 12 weeks and plasma HIV-RNA measured every 24 weeks. Immune recovery was defined as CD4%≥25%. IF was defined as persistent decline of ≥5% in CD4% in children with CD4%<15% at baseline or decrease in CD4 count ≥30% from baseline. VF was defined as HIV-RNA>1,000 copies/ml after at least 24 weeks of HAART. Clinical and laboratory parameter changes were assessed using a paired t-test, and a time to event approach was used to assess predictors of VF. Sensitivity and specificity of IF were calculated against VF.Results107 ART-naive HIV-infected children were included, 52% female, % CDC clinical classification N:A:B:C 4:44:30:22%. Baseline data were median (IQR) age 6.2 (4.2-8.9) years, CD4% 7 (3-15), HIV-RNA 5.0 (4.9-5.5) log10copies/ml. Nevirapine (NVP) and efavirenz (EFV)-based HAART were started in 70% and 30%, respectively.At 96 weeks, none had progressed to a CDC clinical classification of AIDS and one had died from pneumonia. Overall, significant improvement of weight for age z-score (p = 0.014), height for age z-score, hemoglobin, and CD4 were seen (all p < 0.001). The median (IQR) CD4% at 96 weeks was 25 (18-30)%. Eighty-nine percent of children had immune recovery (CD4%≥25%) and 75% of children had HIV-RNA <1.7log10copies/ml.Thirty five (32.7%) children experienced VF within 96 weeks. Of these, 24 (68.6%) and 31 (88.6%) children had VF in the first 24 and 48 weeks respectively.Only 1 (0.9%) child experienced IF within 96 weeks and the sensitivity (95%CI) of IF to VF was 4 (0.1-20.4)% and specificity was 100 (93.9-100)%.ConclusionImmunologic failure, as defined here, had low sensitivity compared to VF and should not be recommended to detect treatment failure. Plasma HIV-RNA should be performed twice, at weeks 24 and 48, to detect early treatment failure.Trial RegistrationClinicaltrials.gov identification numberNCT00476606

A Chewable Pediatric Fixed-dose Combination Tablet of Stavudine, Lamivudine, and Nevirapine: Pharmacokinetics and Safety Compared With the Individual Liquid Formulations in Human Immunodeficiency Virus-infected Children in Thailand

Background: Pediatric fixed-dose combinations (FDCs) are needed to facilitate antiretroviral therapy in children. We evaluated the relative bioavailability, safety, and therapeutic adequacy of a novel chewable pediatric FDC tablet of stavudine (7 mg), lamivudine (30 mg), and nevirapine (50 mg), referred to as GPO-VIR S7, and compared it with the individual original brand-name liquid formulations in human immunodeficiency virus-infected Thai children. Methods: The International Maternal Pediatric Adolescent AIDS Clinical Trials group (IMPAACT) P1056 study was a phase I/II, 2-arm, randomized, open-label, multidose pharmacokinetic cross-over study. Children ≥6 to ≤30 kg receiving nevirapine-based HAART for at least 4 weeks were randomized to receive GPO-VIR S7 chewable tablets or the equivalent liquid formulations. Children were stratified by weight and dosing was weight-based. Intensive 12-hour blood sampling was performed on day 28, and subjects then crossed-over to the alternate formulation at equal doses with identical 12-hour sampling on day 56. Pharmacokinetic indices were determined by noncompartmental analysis. Results: Thirty-four children completed the study. While taking Government Pharmaceutical Organization (GPO)-VIR S7 the geometric mean (90% CI) area under the curve was 1.54 &mgr;g·hr/mL (1.42–1.67) for stavudine, 6.39 (5.82–7.00) for lamivudine, and 74.06 (65.62–83.60) for nevirapine. Nevirapine drug exposure for GPO-VIR S7 was therapeutically adequate. Geometric mean area under the curve ratios (90% CI) of GPO-VIR S7/liquid formulation for stavudine, lamivudine, and nevirapine were 0.97 (0.92–1.02), 1.41 (1.30–1.53), and 1.08 (1.04–1.13), respectively. No serious drug-related toxicity was reported. Conclusions: The chewable FDC was safe and provided therapeutically adequate plasma drug exposures in human immunodeficiency virus-infected children. Substituting the FDC for liquid formulations can simplify antiretroviral therapy.

Efficacy and tolerability of nevirapine- versus efavirenz-containing regimens in HIV-infected Thai children.

BACKGROUND Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) has been the most affordable regimen for the HIV-infected in developing countries. There are limited data comparing nevirapine (NVP) to efavirenz (EFV) in HIV-infected children. This study aimed to assess the efficacy and tolerability of NVP-based regimens compared to EFV-based regimens in HIV-infected children in Thailand. METHODS The medical records of HIV-infected children who had received NNRTI-based regimens for more than 6 months at the Department of Pediatrics, Siriraj Hospital, Mahidol University, Thailand, were reviewed. RESULTS Of the 139 HIV-infected children studied, 70 were male, and the median age at treatment initiation was 6.08 years (range 0.32-14.56 years); the median duration of follow-up was 36 months (range 6-66 months). The median baseline CD4 cell count was 185cells/mm(3) (range 2-3482cells/mm(3)) and the median baseline CD4 percentage was 7.20% (range 0.11-36.57%). An NVP-based regimen was initiated in 61 (44%): 38 antiretroviral (ARV)-naïve and 23 ARV-experienced. An EFV-based regimen was initiated in 78 (56%): 34 ARV-naïve and 44 ARV-experienced. The CD4 cell count and percentage gains were not different between the NVP and EFV groups in both the ARV-naïve and the ARV-experienced. However, ARV-naïve children who received an EFV regimen had significantly lower baseline CD4 levels than those who received an NVP regimen. ARV-naïve children had a better CD4 response than the ARV-experienced. The survival rates of children in the NVP groups were not different from those in the EFV groups for both the ARV-naïve and the ARV-experienced. Treatment failure occurred in one ARV-naïve NVP case (2.6%), two ARV-naïve EFV cases (5.8%), and nine ARV-experienced NVP cases (39%) at 24 months of treatment, and 11 ARV-experienced EFV cases (25%) at 18 months of treatment. Seven (10%) children had adverse effects from treatment with NVP. The main side effects were rash and hepatitis; six had to switch to EFV. Four (5%) children had adverse effects from treatment with EFV; two had to switch to NVP. CONCLUSIONS Both NVP- and EFV-based HAART regimens were effective in children in Thailand for at least 3 years. HIV-infected Thai children generally tolerated NNRTI well.

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 childs/adolescents disclosure status had no bearing on ART adherence by pill count or immunological and virological outcomes.

High virologic response rate after second-line boosted protease inhibitor-based antiretroviral therapy regimens in children from a resource limited setting

BackgroundLimited data exist for the efficacy of second-line antiretroviral therapy among children in resource limited settings. We assessed the virologic response to protease inhibitor-based ART after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.MethodsA retrospective chart review was conducted at 8 Thai sites of children who switched to PI –based regimens due to failure of NNRTI –based regimens. Primary endpoints were HIV RNA < 400 copies/ml and CD4 change over 48 weeks.ResultsData from 241 children with median baseline values before starting PI-based regimens of 9.1 years for age, 10% for CD4%, and 4.8 log10 copies/ml for HIV RNA were included; 104 (41%) received a single ritonavir-boosted PI (sbPI) with 2 NRTIs and 137 (59%) received double-boosted PI (dbPI) with/without NRTIs based on physician discretion. SbPI children had higher baseline CD4 (17% vs. 6%, p < 0.001), lower HIV RNA (4.5 vs. 4.9 log10 copies/ml, p < 0.001), and less frequent high grade multi-NRTI resistance (12.4% vs 60.5%, p < 0.001) than the dbPI children. At week 48, 81% had HIV RNA < 400 copies/ml (sbPI 83.1% vs. dbPI 79.8%, p = 0.61) with a median CD4 rise of 9% (+7%vs. + 10%, p < 0.005). However, only 63% had HIV RNA < 50 copies/ml, with better viral suppression seen in sbPI (76.6% vs. 51.4%, p 0.002).ConclusionSecond-line PI therapy was effective for children failing first line NNRTI in a resource-limited setting. DbPI were used in patients with extensive drug resistance due to limited treatment options. Better access to antiretroviral drugs is needed.

Randomized study of intradermal compared to intramuscular hepatitis B vaccination in HIV-infected children without severe immunosuppression.

HIV infected individuals have poorer response to hepatitis B vaccine (HBV) compared to normal host. Intradermal administration (i.d.) facilitates the exposure of antigen to antigen-presenting cells compared to intramuscular administration (i.m.). HIV-infected children aged 1-18 years with CD4%≥15% or 200 cells/mm(3) who had negative HBs Ag, antiHBs, and antiHBc were randomized to receive 3-dose of HBV via i.d. (2 μg/dose) or i.m. (10 μg/dose) route at months 0, 2, and 6. AntiHBs titers were measured at months 2, 6 and 7 after first HBV. AntiHBs≥10 mIU/mL was considered protective and AntiHBs>100 mIU/mL was considered good response. Participants included 41 in i.d. and 39 in i.m. arms. 64% had completed 3-doses HBV during infancy. The mean (SD) of age, nadir CD4% and current CD4% were 12 (3.3) years, 10.6 (7.9)% and 28 (8.0)% respectively. 91% were on HAART and 84% had undetectable HIV-RNA. Proportion of children with protective antiHBs in i.d. vs. i.m. group were 19.5% vs. 25.6% at month 2, 56.1% vs. 76.9% at month 6, and 90.2% vs. 92.3% at month 7 (NS, all). The geometric mean (95% confidence interval) of antiHBs titer in i.d. vs. i.m. group were 112.5 (34.4-367.6) vs. 141.2 (49.4-404.1) mIU/mL at month 2 (p=0.74), 70.4 (39.8-124.4) vs. 132.1 (79.4-219.8) mIU/mL at month 6 (p=0.10), and 157.0 (103.0-239.3) vs. 458.9 (324.0-647.0) mIU/mL at month 7 (p<0.001). However, only 56.1% of the i.d. arm had good response to HBV compared to 82.1% in the i.m. arm (p=0.01). The predictors for being a good responder to HBV were i.m. administration [OR 4.0, 95%CI 1.4-11.8, p=0.012] and body weight <35 kg at baseline [OR 3.8, 95%CI 1.3-10.8, p=0.013]. No adverse events grade 3/4 occurred. In conclusion, HIV-infected children without severe immune suppression, both i.d. and i.m. routes of HBV resulted in similar rates of protective antibody titers. However, high antibody titers to HBV were more common with i.m.; therefore, i.m. administration is preferred.

Pediatric HIVQUAL-T: measuring and improving the quality of pediatric HIV care in Thailand, 2005-2007.

BACKGROUND As increasing numbers of children initiate antiretroviral treatment (ART), a systematic process is needed to measure and improve pediatric HIV care quality. METHODS Pediatric HIVQUAL-T, a model for performance measurement and quality improvement (QI), was adapted from the U.S. HIVQUAL model by incorporating Thai national guidelines as standards. In each of five pilot-site hospitals in Thailand in 2005-2007, clinical data abstracted from patient records were used to identify priority areas for QI. Improvement strategies were designed by clinic teams in different care system areas, and indicators were remeasured in 2006 and 2007. RESULTS At the five hospitals, 1119 HIV-infected children younger than 15 years of age received care in 2005, 1183 in 2006, and 1,341 in 2007--of whom 460, 435, and 418, respectively, were selected for chart abstraction. Of the eligible children, > or = 95% received clinical monitoring, annual CD4 count monitoring, ART, and adherence and growth assessments; 60%-90% received Pneumocystis jiroveci pneumonia (PCP) prophylaxis, tuberculosis (TB) screening, oral health assessments, and HIV disclosure. Indicators with a score < or = 40% in 2005 but with significant improvement (p < .05) in 2006-2007 following QI activities were Mycobacterium avium complex (MAC) prophylaxis, and cytomegalovirus (CMV) retinitis and immunization screenings. CONCLUSIONS Despite the promulgation of national guidelines, performance rates of some pediatric HIV indicators needed improvement. The pediatric HIVQUAL-T model facilitates use of hospital data for pediatric HIV care improvement and indicates that the U.S. HIVQUAL model is adaptable to developing countries.

Pediatric HIV Clinical Care Resources and Management Practices in Asia: A Regional Survey of the TREAT Asia Pediatric Network

Characterizing intraregional differences in current pediatric HIV care and treatment in Asia can guide the development of clinical practice guidelines and improve the understanding of local resource availability. The Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) Pediatric Program is a collaboration of clinics and referral hospitals studying pediatric HIV outcomes in the region. A Web-based survey to characterize clinical management practices and monitoring resources was developed and distributed to 20 sites in January 2008. Seventeen (85%) sites from 6 countries responded through April 2008; 14 (82%) were hospital-based and 16 (94%) were public facilities. Of 4050 HIV-infected children under care, 3606 (89%) were on antiretroviral treatment; 80% were on their first mono-, dual-, or triple-drug regimen and 74% were on nevirapine- or efavirenz-based regimens. Fifteen (88%) sites had consistent access to polymerase chain reaction (PCR) testing for infant diagnosis. All sites had access to CD4 testing, with 13 (76%) routinely monitoring patients every 3-6 months; 7 (41%) sites monitored viral load at 6- to 12-month intervals. Although there is some variation in clinical practices, high levels of treatment and monitoring resources were available at these sites. The availability of PCR for early infant diagnosis positions them to implement recent WHO recommendations to treat HIV-infected children younger than 1 year of age. This information will be used to develop future research and programs to support children with HIV in Asia.

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.