Nirun Vanprapar

Apoptosis and Pathogenesis of Avian Influenza A (H5N1) Virus in Humans

Apoptosis may play a crucial role in the pathogenesis of pneumonia and lymphopenia caused by this virus in humans.

Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine

Objective:To evaluate the steady state pharmacokinetics of nevirapine (NVP) in HIV-infected children receiving a fixed-dose combination of stavudine, lamivudine and NVP. Methods:This cross-sectional study enrolled 34 children (18 girls) who had received GPO-VIR S30 (30 mg stavudine, 150 mg lamivudine and 200 mg NVP) for at least 8 weeks. Tablets were divided into quarter fractions (1/4, 1/2, 3/4 or 1 tablet) to attain the NVP dosages of 120–200 mg/m2 every 12 h. Plasma NVP levels were measured at predose, and at 2 and 6 h after drug administration. Results:The median age was 8.4 years (range, 3–15). Median CD4 lymphocyte count and percentage at study entry was 576 × 106 cells/l and 20.25%, respectively. The median pharmacokinetics parameters were area under the curve at 12 h, 78.4 h × μg/ml; minimum plasma drug concentration, 5.98 μg/ml; plasma half-life, 25.5 h; apparent oral clearance, 0.079 l/kg per h; and volume of distribution, 2.95 l/kg. Only one child had a minimum plasma drug concentration < 3.4 μg/ml (2.57 μg/ml). Of the 13 children who received GPO-VIR as their first-line regimen, 12 had plasma HIV-1 RNA < 400 copies/ml at 6–18 months, with a median CD4 lymphocyte increase of 216 and 433 × 106 cells/l at 6 and 12 months of treatment, respectively. Conclusions:The administration of GPO-VIR S30 fixed-dose combination tablets in fractions or as a whole tablet to children resulted in appropriate NVP exposure and satisfactory virological and immunological benefit. This finding confirms the effectiveness of using a fixed-dose combination as a ‘transitional option’ while waiting for a paediatric fixed-dose combination drug formulation.

Maternal herpes simplex virus type 2 coinfection increases the risk of perinatal HIV transmission : possibility to further decrease transmission?

Objectives:To evaluate the association between maternal herpes simplex virus type 2 seropositivity and genital herpes simplex virus type 2 shedding with perinatal HIV transmission. Study design:Evaluation of women who participated in a 1996–1997 perinatal HIV transmission prevention trial in Thailand. Methods:In this nonbreastfeeding population, women were randomized to zidovudine or placebo from 36 weeks gestation through delivery; maternal plasma and cervicovaginal HIV viral load and infant HIV status were determined for the original study. Stored maternal plasma and cervicovaginal samples were tested for herpes simplex virus type 2 antibodies by enzyme-linked immunoassay and for herpes simplex virus type 2 DNA by real-time PCR, respectively. Results:Among 307 HIV-positive women with available samples, 228 (74.3%) were herpes simplex virus type 2 seropositive and 24 (7.8%) were shedding herpes simplex virus type 2. Herpes simplex virus type 2 seropositivity was associated with overall perinatal HIV transmission [adjusted odds ratio, 2.6; 95% confidence interval, 1.0–6.7)], and herpes simplex virus type 2 shedding was associated with intrapartum transmission (adjusted odds ratio, 2.9; 95% confidence interval, 1.0–8.5) independent of plasma and cervicovaginal HIV viral load, and zidovudine treatment. Median plasma HIV viral load was higher among herpes simplex virus type 2 shedders (4.2 vs. 4.1 log10copies/ml; P = 0.05), and more shedders had quantifiable levels of HIV in cervicovaginal samples, compared with women not shedding herpes simplex virus type 2 (62.5 vs. 34.3%; P = 0.005). Conclusion:We found an increased risk of perinatal HIV transmission among herpes simplex virus type 2 seropositive women and an increased risk of intrapartum HIV transmission among women shedding herpes simplex virus type 2. These novel findings suggest that interventions to control herpes simplex virus type 2 infection could further reduce perinatal HIV transmission.

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.

HIV seroconversion during pregnancy and risk for mother-to-infant transmission

Summary: Pregnant women infected with HIV‐1 were enrolled in a prospective mother‐to‐infant transmission study from 1992 through 1994 in Bangkok. In participating hospitals, voluntary HIV testing was routinely offered at the beginning of antenatal care and again in the middle of the third trimester of pregnancy. Women who seroconverted to HIV during pregnancy were compared with women who had tested positive on their first antenatal test. Maternal HIV RNA levels were determined during pregnancy, at delivery, and postpartum using RNA polymerase chain reaction (PCR), and infection status in infants was determined by DNA PCR. No infants were breastfed, but prophylactic antiretroviral therapy was not yet used in Thailand to prevent transmission from mother to infant. Among enrolled women, 16 who seroconverted during pregnancy and 279 who were HIV‐1‐seropositive at their first antenatal test gave birth. Median plasma RNA levels at delivery were similar for the two groups (17,505 and 20,845 copies/ml, respectively; p = .8). Two (13.3%) of 15 infants born to women who seroconverted and 66 (24.8%) of 266 infants born to previously HIVseropositive women were infected with HIV (p = .5). There was no increased risk for mother‐to‐infant HIV transmission and no significant difference in viral load at delivery between HIV‐infected women who seroconverted to HIV during pregnancy and those who were HIV‐seropositive when first tested.

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.

Development of a diagnosis disclosure model for perinatally HIV-infected children in Thailand

While disclosure of HIV status to perinatally HIV-infected children has become an increasingly important clinical issue, specific disclosure guidelines are lacking. We developed a pediatric HIV diagnosis disclosure model to support caretakers. All HIV-infected children greater than 7-years-old at two participating hospitals in Bangkok, Thailand, and their caretakers, were offered disclosure according to the 4-step protocol: (1) screening; (2) readiness assessment; (3) disclosure; and (4) follow-up. Disclosure occurred after agreement of both providers and caretakers. Among 438 children who were screened, 398 (89%) were eligible. Readiness assessment was completed for 353 (91%) of eligible children and 216 (61%) were determined ready. Disclosure was done for 186 children. The mean age at eligibility screening was 10.5 years (range: 6.8–15.8 years); the mean age at disclosure was 11.7 years (range: 7.6–17.7 years). The mean duration between eligibility screening and disclosure was 15.2 months. There were no significant negative behavioral or emotional outcomes reported in children following disclosure. This HIV diagnosis disclosure model was feasible to implement and had no negative outcomes. As the time for preparation process was over 1 year for most cases, the disclosure process can be initiated as early as age 7 to allow enough time for disclosure to be completed by the age of adolescence.

Mother-to-child transmission of GB virus C in a cohort of women coinfected with GB virus C and HIV in Bangkok, Thailand.

BACKGROUND GB virus C (GBV-C) is an apathogenic virus that inhibits human immunodeficiency virus (HIV) replication in vitro. Mother-to-child transmission (MTCT) of GBV-C has been observed in multiple small studies. Our study examined the rate and correlates of MTCT of GBV-C in a large cohort of GBV-C-HIV-coinfected pregnant women in Thailand. METHODS Maternal delivery plasma specimens from 245 GBV-C-HIV-infected women and specimens from their infants at 4 or 6 months of age were tested for GBV-C RNA. Associations with MTCT of GBV-C were examined using logistic regression. RESULTS One hundred one (41%) of 245 infants acquired GBV-C infection. MTCT of GBV-C was independently associated with maternal antiretroviral therapy (adjusted odds ratio [AOR], 5.21 [95% confidence interval {CI}, 2.12-12.81]), infant HIV infection (AOR, 0.05 [95% CI, 0.01-0.26]), maternal GBV-C load (8.0 log(10) copies/mL: AOR, 86.77 [95% CI, 15.27-481.70]; 7.0-7.9 log(10) copies/mL: AOR, 45.62 [95% CI, 8.41-247.51]; 5.0-6.9 log(10) copies/mL: AOR, 9.07 [95% CI, 1.85-44.33]: reference, <5 log(10) viral copies/mL), and caesarean delivery (AOR, 0.26 [95% CI, 0.12-0.59]). CONCLUSIONS Associations with maternal GBV-C load and mode of delivery suggest transmission during pregnancy and delivery. Despite mode of delivery being a common risk factor for virus transmission, GBV-C and HIV were rarely cotransmitted. The mechanisms by which maternal receipt of antiretroviral therapy might increase MTCT of GBV-C are unknown.

Efficacy and plasma concentrations of indinavir when boosted with ritonavir in human immunodeficiency virus -- infected Thai children.

We evaluated 19 children using 220–300 mg/m2 of indinavir (IDV) boosted with 100 mg ritonavir (RTV) (n = 12) or full-dose RTV (n = 7). Geometric mean (GM) (90% confidence interval, CI) of IDV Ctrough in children who took IDV with 100 mg RTV (n = 12) was 0.17 (0.06–0.50) mg/L. For children who took IDV with full-dosage RTV, GM (90% CI) was 0.40 (0.10–1.61) mg/L. C2hours were less than 10 mg/L in all subjects. Eighteen children had good virologic response. This report demonstrates that smaller IDV dosages given with RTV provide efficacious plasma concentrations and can be safely used.

A comparative study of the serological response to Japanese encephalitis vaccine in HIV-infected and uninfected Thai children.

We report a prospective study of mouse brain derived inactivated Japanese encephalitis (JE) vaccine, given in 3-dose EPI program to human immune deficiency virus (HIV)-exposed Thai infants. 18 HIV-infected receiving antiretroviral therapy with median baseline CD4 of 33.1%, and 92 HIV-uninfected children were studied. All but one HIV-infected child seroconverted after the second dose. The geometric mean titers (GMTs) 3 months after the second and third doses in HIV-infected vs HIV-uninfected children were 247 vs 938 (p=0.022), and 2273 vs 24069 (p=0.009), respectively. Urticaria or angioedema found in 4% and 6% in HIV-infected and -uninfected children, respectively (p=1.0). The vaccine was safe and immunogenic but antibody response in HIV-infected children was not as high as in uninfected children.