Wanatpreeya Phongsamart

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.

Dengue virus infection in late pregnancy and transmission to the infants.

Background: Vertical dengue virus transmissions have been infrequently described. To date there are no published data on long-term outcome and antibody kinetics of infants who were infected in utero. This is the first report of vertical dengue transmission with 12 months follow-up evolution of antibody and the clinical outcome. Methods: Three mother-infant pairs were confirmed to have perinatally dengue infection by serology, viral isolation, or reverse transcription polymerase chain reaction (RT-PCR). The infants were followed clinically at 1, 2, 4, 6, 9, and 12 months. Sera were collected at 1, 6, and 12 months of age for serologic testing. Results: Three mothers developed symptomatic dengue infection 1 day, 12 days, and 5 weeks before delivery of their infants. The first infant developed presumed bacterial illness on day 6 of life. Dengue virus serotype 1 was detected by RT-PCR and viral isolation. The second infant developed fever, petechiae, and hepatomegaly 9 hours after birth. Dengue virus serotype 2 was detected by RT-PCR. The third infant was asymptomatic. All mothers and infants had uneventful recoveries. One year follow-up revealed normal growth and development in all infants. The pattern of antibody kinetics suggested primary infection in the first and second infants, and the transferred antibody without infection in the third infant. Conclusions: In endemic areas, dengue infection can cause an acute febrile illness in pregnant women and sepsis-like illness in neonates. Vertical infection did not result in long-term sequelae.

A population-based study of tuberculosis in children and adolescents in Ontario.

Background: There are few population-based data on presentation and treatment of tuberculosis (TB) in children and adolescents in Ontario. Methods: We analyzed data from 121 patients less than 17 years of age with TB disease reported to the Province of Ontario between 1999 and 2002. Physician provider data were obtained from the College of Physicians and Surgeons of Ontario. Results: Of the 121 patients, 84 (69.4%) patients were foreign born. The median time of residence in Canada before diagnosis was 2.7 years (range, 7 days–16 years). Diagnosis was made by symptoms in 78 (64.5%), by contact investigation in 25 (20.7%), and by immigration screening in 5 (4.1%) patients. Pulmonary TB occurred in 94 (77.7%) patients. When cases detected by contact tracing and screening were excluded, isolated extrapulmonary TB was present in 4 (23.5%), 6 (35.0%), and 19 (37.0%) of young children (0–4 years), older children (5–12 years), and adolescents (13–17 years), respectively. Eleven patients (9.1%) had drug-resistant strains. Eighty (66.1%) patients received directly observed therapy (DOT). Prescribed treatment was completed in 105 (86.8%) patients with a trend toward higher completion rates in those receiving DOT (P = 0.07). Of 57 physician providers, 50 (87.7%) had treated less than 1 pediatric TB patient/year during the study period. Conclusions: Extrapulmonary disease accounted for a high proportion of TB in older children and adolescents who presented with symptoms. One-third of patients did not receive DOT and most were cared for by physicians with limited experience in managing TB. Further studies are needed to determine whether these factors influence outcome in pediatric TB.

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.

Long-term outcomes of HIV-infected children in Thailand: the Thailand Pediatric HIV Observational Database

OBJECTIVE To describe the outcomes of antiretroviral therapy (ART) in a large cohort of HIV-infected children in Thailand. METHODS The data were obtained from four collaborative referral sites around the country. Data from 2008 to March 2011 were collected prospectively, and data before 2008 were collected retrospectively. RESULTS Of the 1139 children, 599 (52.6%) were female, and the duration of ART was a median 2.9 years (interquartile range (IQR) 3.3-5.5 years). At ART initiation, the median age was 7.1 years (IQR 3.4-10.0 years), CD4 percentage was 9.0% (IQR 3.0-17.0%), and 61.3% were in World Health Organization (WHO) stage 3 or 4. Seventy-four percent were initiated on an NNRTI-based regimen. The death and lost to follow-up rates were 1.3 (95% confidence interval (CI) 1.1-1.6) and 2.2 (95% CI 1.6-2.6)/100 patient-years of follow-up, respectively. At the last clinic visit of 919 children, the median CD4 percentage was 27.0% (IQR 23.0-32.0%) and 80.2% had HIV-RNA <40 copies/ml. WHO stage 1 or 2 at ART initiation was associated with having a viral load <40 copies/ml (p < 0.002), and baseline CD4 ≥15% and starting with a three-drug regimen were associated with achieving CD4 ≥25% (p<0.001). CONCLUSIONS Although most children initiated ART at low CD4 levels, the majority achieved immune reconstitution and long-term virological control. Earlier treatment may improve these outcomes.

Efficacy, safety and pharmacokinetics of tenofovir disoproxil fumarate in virologic-suppressed HIV-infected children using weight-band dosing.

Background: Tenofovir disoproxil fumarate (TDF) is approved for children but concerns remain about long-term renal and bone toxicity. We evaluated the efficacy, safety and pharmacokinetics of TDF in treatment-experienced children during 96 weeks. Methods: This was a prospective, open-label study in HIV-infected children 3–18 years of age (≥15 kg), with viral suppression on their first-line regimen without tenofovir. Children were given TDF/lamivudine/efavirenz once daily at entry; TDF was prescribed according to weight bands. Age-, gender- and CD4-matched controls receiving TDF-sparing regimens were concomitantly enrolled. Tenofovir pharmacokinetic assessment was performed at week 4. CD4 counts, HIV-1 RNA viral load and safety assessments were determined at baseline, 24, 48 and 96 weeks. Results: Eighty children were enrolled (40 per group); 35 (44%) were male. Median age was 12.2 (range 3.1–17.7) years. The median administered dose was 214 mg/m2. Tenofovir geometric mean AUC0–24 hours, Cmax and C24 hours were 2.66 [90% confidence interval (CI) 2.49–2.84] &mgr;g hours/mL, 0.26 (0.24–0.29) &mgr;g/mL and 0.057 (0.052–0.062) &mgr;g/mL, respectively. Estimated glomerular filtration rate did not significantly change overtime. The fractional excretion of calcium slightly increased but fractional excretion of phosphate was unchanged among children in TDF group. The bone mineral density Z score decreased in the first 24 weeks of TDF treatment and was stable afterward. The TDF group had lower cholesterol levels (P = 0.001). Thirty-nine of 40 children remained virologically suppressed. No serious adverse event related to tenofovir. Conclusion: TDF substitution in children and adolescents who were otherwise stable while receiving a first-line nonnucleoside reverse transcriptase inhibitor–based regimen achieved adequate exposure without clinically significant renal or bone adverse events over 96 weeks. While reassuring, these preliminary safety findings may not exclude delayed effects on renal function and bone density.

Immunogenicity and safety of monovalent influenza A (H1N1) 2009 in HIV-infected Thai children.

To evaluate the immunogenicity and safety of the monovalent pandemic influenza A (H1N1) 2009 (pH1N1) vaccine in HIV-infected Thai children, 2 doses, 28days apart, of non-adjuvant monovalent pH1N1 vaccine (Panenza(®) by Sanofi Pasteur, 15μg/dose) provided by the National Health Promotion Program of the Thai Ministry of Public Health were given to HIV-infected children. Immunogenicity was measured by hemagglutination inhibition test (HAI) using two antigens, pH1N1 (A/Thailand/104/09) and seasonal influenza A H1N1 (A/Brisbane/59/07-like), at baseline, and 28days after each dose. Serologic response was defined as four-fold rising of HAI titer or HAI titer ≥1:40 for those with baseline titer ≤1:10. Adverse events were recorded for 7days after each vaccination. Of the 119 HIV-infected children enrolled, 60 (50.4%) were female with a median (IQR) age of 10.4 (7.2-13.7)years. All but 2 (98.3%) children were receiving antiretroviral therapy. At baseline, the median CD4 cell count was 782 (570-1149)cells/mm(3), 91 (80.5%) children had HIV RNA level <40copies/ml. The baseline HAI titer ≥1:40 for pH1N1 and seasonal H1N1 were 45.4%, and 39.5%, respectively. At 28 days after doses 1 and 2, the serologic response rates for pH1N1 were 54.2% and 67.8% with the geometric mean titer of 109.9 and 141.8; and serologic response rate when tested with seasonal H1N1 were 2.5% and 3.5%, respectively. The presence of baseline HAI titer for pH1N1 or seasonal H1N1 was found to be associated with serologic response. The vaccine was well tolerated. The results suggested that monovalent pH1N1 vaccine was immunogenic and safe in well controlled HIV-infected children with low level of cross reacting antibody to seasonal H1N1.

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.

Lipodystrophy and reversal of facial lipoatrophy in perinatally HIV-infected children and adolescents after discontinuation of stavudine

Lipodystrophy (LD) was evaluated in 205 children receiving antiretroviral therapy by a single investigator: 51 (24.9%) had LD; 46 peripheral lipoatrophy, three central lipohypertrophy and two combined type. All cases of peripheral and combined LD also had facial lipoatrophy. Serial photographs were provided by the families to confirm the severity of facial lipoatrophy. Forty-six (95.8%) children with peripheral or combined LD, and 75 (48.7%) without LD were exposed to stavudine (d4T) for a median duration of 45.9 versus 26.4 months (P = 0.005). In multivariate analysis, exposure to d4T for more than three months was the only factor associated with peripheral or combined LD (P < 0.001). Noticeable improvement of facial lipoatrophy was found in 11/48 (22.9%) children after a mean duration of 45.6 months following d4T discontinuation, mostly occurring during early adolescence.

Echocardiography and carotid intima-media thickness among asymptomatic HIV-infected adolescents in Thailand.

Objectives:To evaluate the carotid intima–media thickness (cIMT) in perinatally HIV-infected adolescents and factors associated with cardiovascular abnormalities. Designs:A cross-sectional study was conducted in perinatally HIV-infected adolescents who had no known cardiovascular condition and healthy controls. Methods:Transthoracic echocardiogram and cIMT measurements were taken by pediatric cardiologists. Serum lipid profiles, high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide were measured. Results:Hundred HIV-infected and 50 healthy adolescents were enrolled. Echocardiograms revealed overall normal systolic function (median left-ventricular ejection fraction 66 vs. 66%; P = 0.825). The mean overall cIMTs of common carotid arteries and internal carotid arteries were not different between the groups (0.373 vs. 0.371; P = 0.744). Among the HIV-infected adolescents, those who had been receiving protease inhibitor-containing regimens had an increased cIMT (0.364 vs. 0.381 mm; P = 0.009). Hypertriglyceridemia was found in 52% of those who had received protease inhibitors for more than 6 months, but only in 21% of those who had never received protease inhibitors (odds ratio 4.0, 95% confidence interval 1.6–9.7, P = 0.002). Current HIV-RNA, CD4+, BMI, sex, cholesterol and low-density lipoprotein-cholesterol were not associated with increased cIMT. Serum high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide were not different between the groups and not associated with cardiac abnormalities. Conclusions:Perinatally HIV-infected adolescents had comparable myocardial function and similar cIMT measurements to healthy adolescents. However, hypertriglyceridemia and increased cIMT were found in HIV-infected adolescents receiving protease inhibitor-based regimens. Longer-term follow-up is needed to evaluate HIV-associated cardiovascular disease risk in this population.