Pharmacokinetics of Generic Pediatric Dolutegravir Dispersible Tablet in Thai Young Children Living With HIV Weighing Below Twenty Kilograms.

INTRODUCTION: Dolutegravir (DTG) dispersible tablet (DTG-DT) is a pediatric-friendly formulation. We aimed to describe the pharmacokinetics and virologic responses of generic DTG-DT in children weighing <20 kg. METHODS: Children living with HIV-1 and <7 years of age weighing 6 to <20 kg were eligible. A generic 10-mg scored DTG-DT was administered to children using 3 weight bands (WB): WB1 (6 to <10 kg), WB2 (10 to <14 kg) and WB3 (14 to <20 kg), at doses of 20 mg (higher than World Health Organization recommendation of 15 mg), 20 mg and 25 mg, respectively. Steady-state intensive pharmacokinetics (PK) was performed in fasting condition with blood sampling at predose and 1, 2, 3, 4, 6 and 24 hours postdose. DTG PK parameters were estimated using a noncompartmental analysis, and DTG trough concentrations (C24) and 24-hour area under the concentration-time curve were calculated. Comparisons were made with ODYSSEY and IMPAACT 2019. And 90% effective concentration of 0.32 mg/L was used as a reference individual DTG C24 concentration. RESULTS: From August 2021 to March 2023, 29 Thai children with a median (interquartile range) age of 3.2 (1.5-4.8) years were enrolled; 8 in WB1, 9 in WB2 and 12 in WB3. All children were treatment experienced and 59% had HIV RNA <200 copies/mL. Overall geometric mean (coefficient of variation percentage) DTG C24 was 1.0 (46%) mg/L [WB1, 0.9 (53%); WB2, 0.9 (27%); WB3, 1.2 (51%)]. Geometric mean (coefficient of variation percentage) 24-hour area under the concentration-time curve was 83.2 (24%) mg h/L [WB1, 84.3 (31%); WB2, 76.9 (16%); WB3, 87.6 (25%)]. At weeks 24 and 48, 90% and 92% of participants had plasma HIV RNA <200 copies/mL. CONCLUSIONS: Generic DTG-DT provided adequate drug exposure in children weighing 6 to <20 kg. The exploratory dose of DTG 20 mg for children weighing 6 to <10 kg showed similar PK parameters to World Health Organization doses in the other WB.

Effective and safe transfer of maternal antibodies persisting two months postpartum following maternal immunization with different doses of recombinant pertussis-containing vaccines.

INTRODUCTION: Recombinant acellular pertussis (ap) vaccines containing genetically inactivated pertussis toxin (PTgen) and filamentous hemagglutinin (FHA) with or without tetanus (TT) and diphtheria (DT) vaccines (Td) were found safe and immunogenic in non-pregnant and pregnant women. We report here maternal antibody transfer and safety data in mothers and neonates. METHODS: This is the follow up of a phase 2 trial in 2019 among 400 pregnant women who randomly received one dose of recombinant pertussis-only vaccine containing 1 µg PTgen and 1 µg FHA (ap1gen), or Td combined with ap1gen (Tdap1gen), or with 2 µg PTgen and 5 µg FHA (Tdap2gen), or with 5 µg PTgen and 5 µg FHA (TdaP5gen, Boostagen®, BioNet, Thailand) or chemically-inactivated acellular pertussis comparator (Tdap8chem, Boostrix™, GSK, Belgium), either in the second or third trimester of gestation. IgG against PT, FHA, TT and DT were assessed by ELISA, PT-neutralizing antibodies (PTNA) by Chinese Hamster Ovary cell assay and safety outcomes at delivery in mothers and at birth. RESULTS: Anti-PT and anti-FHA geometric mean concentration (GMC) ratio between infants at birth and mothers at delivery was above 1 in all groups. PT GMC in infants at birth were ≥30 IU/mL in all groups with the highest titers in infants found in TdaP5gen group at birth (118.8 [95% CI 93.9-150.4]). At 2 months, PT GMC ratio to Tdap8chem (98.75% CI) was significantly higher for TdaP5gen (2.6 [1.7-4.0]) and comparable for other recombinant vaccines. No difference in PTNA titers at birth was observed between all groups nor between time of vaccination. Adverse events were comparable in all vaccine groups. CONCLUSIONS: BioNet licensed (TdaP5gen and Tdap2gen) and candidate vaccines (Tdap1gen and ap1gen) when given to pregnant women in the second or third trimester of gestation are safe and have induced passive pertussis immunity to infants.

Immunogenicity of BNT162b2 in children 6 months to under 5 years of age with previous SARS-CoV-2 infection, in the era of Omicron predominance.

Background: Children 6 months to < 5 years old are recommended to receive 3-dose regimen of BNT162b2. Children previously infected with Omicron variant of SARS-CoV-2 develop immunity from natural infection, therefore may require fewer doses of vaccine. Objective: To compare immunogenicity of 1- or 2-dose BNT162b2 in healthy children post COVID-19 with 3-dose BNT162b2 in COVID-naïve children. Methods: Children aged 6 months to < 5 years who developed COVID-19 during the Omicron-predominant period were enrolled; Group A 3-6 months(N = 40) and Group B > 6 months(N = 40) prior to vaccination. Participants in Group A and B received 2-dose BNT162b2 intramuscularly 1 month apart. COVID-naïve children were enrolled as a control group (N = 40) and received 3-dose BNT162b2 at month 0,1,3. Neutralizing antibody against Omicron variant(BA.2.75 and BA.4/5) was determined by pseudovirus assays(pVNT) as reported by neutralization dilution for 50%inhibition (ID50) at 28 days after the 1st and 2nd dose. Results: From October-November 2022, 120 children with a median age of 2.8 years (IQR 1.6-4.0) were enrolled. The median duration since COVID-19 to vaccination was 4.4 months(IQR 3.8-5.4) in Group A and 7.9 months(7.0-8.5) in Group B. In Group A, the geometric means(GMs) of pVNT-BA.2.75 ID50 were 553 (95%CI 338-906) and 753(516-1098) after 1 and 2 doses, respectively, and the GMs of pVNT-BA.4/5 ID50 were 1936(1402-2673) and 1885(1414-2512), respectively. In Group B, the GMs of pVNT-BA.2.75 ID50 were 1383(1100-1742) and 1419 (1104-1823), and the GMs of pVNT-BA.4/5 ID50 were 2627(2048-3367) and 2056(1546-2735), respectively. Meanwhile in COVID-naïve group, the GMs of pVNT-BA.2.75 and pVNT-BA.4/5 ID50 were 158(98-255) and 59(31-114) after the 3rd dose, respectively. The geometric mean ratio(GMR) of pVNT-BA.2.75 ID50 after 1 dose in Group A and B compared with after 3 doses in COVID-naïve group were 3.50 (1.93-6.34) and 8.74 (4.79-15.95), respectively. The GMR of pVNT-BA.2.75 ID50 after 1 dose in Group B compared with Group A was 2.50 (1.45-4.31). Conclusions: Children previously infected with SARS-CoV-2 Omicron variant, developed robust neutralizing antibody response against Omicron variant after single-dose BNT162b2. Children with an interval of > 6 months since COVID-19 infection developed higher neutralizing antibody response compared to those with a 3-to-6-month interval.

A phase 2 randomized controlled dose-ranging trial of recombinant pertussis booster vaccines containing genetically inactivated pertussis toxin in pregnant women.

INTRODUCTION: Despite a decrease in infections caused by Bordetella pertussis due to COVID-19 pandemic, booster vaccination of pregnant women is still recommended to protect newborns. Highly immunogenic vaccines containing genetically inactivated pertussis toxin (PTgen) and filamentous hemagglutinin (FHA) may generate comparable anti-PT antibody concentrations, even at lower doses, to chemically inactivated acellular pertussis vaccines (Tdapchem) shown effective for maternal immunization. METHODS: This phase 2 randomized, observer-blind, active-controlled non-inferiority trial was conducted in healthy Thai pregnant women randomly assigned to receive one dose of low-dose recombinant pertussis-only vaccine containing 1 µg PTgen and 1 µg FHA (ap1gen), or tetanus, reduced-dose diphtheria combined with ap1gen (Tdap1gen), or combined with 2 µg PTgen and 5 µg FHA (Tdap2gen), or with 5 µg PTgen and 5 µg FHA (TdaP5gen, Boostagen®) or comparator containing 8 µg of chemically inactivated pertussis toxoid, 8 µg FHA, and 2.5 µg pertactin (Boostrix™, Tdap8chem). Blood was collected at Day 0 and Day 28 post-vaccination. The non-inferiority of the study vaccines was assessed based on anti-PT IgG antibody levels on Day 28 pooled with results from a similarly structured previous trial in non-pregnant women. RESULTS: 400 healthy pregnant women received one dose of vaccine. Combined with data from 250 non-pregnant women, all study vaccines containing PTgen were non-inferior to comparator vaccine (Tdap8chem). Both ap1gen and TdaP5gen vaccines could be considered to have superior immunogenicity to Tdap8chem. Local and systemic solicited reactions were similar among all vaccine groups. CONCLUSIONS: Vaccine formulations containing PTgen were safe and immunogenic in pregnant women. The ap1gen vaccine, with the lowest cost and reactogenicity, may be suitable for use in pregnant women when diphtheria and tetanus toxoids are not needed. This study is registered in the Thai Clinical Trial Registry (www. CLINICALTRIALS: in.th), number TCTR20180725004.

Temporal trend of drug-resistant tuberculosis among Thai children during 2006-2021.

Background: The prevalence of drug-resistant tuberculosis (DR-TB) in adults has stabilized in the past decade. Our study aimed to describe the prevalence of DR-TB in Thai children between 2006 and 2021. Materials and methods: Children younger than 15 years old who had culture-confirmed Mycobacterium tuberculosis complex (MTB), positive PCR-MTB, or positive Xpert MTB/RIF were included in this cohort. Drug susceptibility testing (DST) was performed using phenotypic and/or genotypic methods. The prevalence of DR-TB was compared using the chi-square test. Results: Among 163 confirmed TB cases (44% as pulmonary TB, 27% as extrapulmonary TB, and 29% with both), the median age (IQR) was 12.2 (7.3-14.2) years. DST was performed in 139 cases (85%), revealing prevalences of all DR-TB, isoniazid-resistant TB (Hr-TB), and rifampicin monoresistant/multidrug-resistant TB (Rr/MDR-TB) of 21.6% (95% CI 14.7-28.4), 10.8% (95% CI 5.6-16.0%), and 2.9% (95% CI 0.1-5.7%), respectively. The DR-TB rates did not differ significantly between 2006-2013, 2014-2018, and 2019-2021 (p > 0.05). Two pre-extensively DR-TB (pre-XDR) cases with fluoroquinolone resistance were detected after 2014. Conclusion: The prevalence of DR-TB in Thai children was stable. However, one-tenth of DR-TB cases confirmed with DST were Hr-TB, which required adjustment of the treatment regimen. The pre-XDR cases should be closely monitored.

Immunogenicity to SARS-CoV-2 Omicron variant among school-aged children with 2-dose of inactivated SARS-CoV-2 vaccines followed by BNT162b2 booster.

Background: A primary series of 2-dose SARS-CoV-2 vaccines based on an ancestral strain generate inadequate neutralizing antibodies against the SARS-CoV-2 Omicron variant. This study aimed to describe the immune response from giving healthy school-aged children who previously received 2 inactivated vaccines an mRNA BNT162b2 booster. Methods: Healthy children aged 5-11 years who received 2 doses of CoronaVac or Covilo were enrolled and received 10 µg BNT162b2 intramuscularly. Neutralizing antibody against Omicron variant was measured at pre-booster and 14-21 days post-booster by surrogate virus neutralization test (sVNT, %inhibition) and pseudovirus neutralization test (pVNT, ID50). Antibody responses were compared with a parallel cohort of children who received 2 doses of BNT162b2 3 weeks apart. Results: From April to May 2022, 59 children with a mean age (SD) of 8.5 years (1.7) were enrolled: 20 CoronaVac and 39 Covilo recipients. The median interval from the primary series was 49 days (IQR 33-51). After booster, the geometric means (GMs) of sVNT and pVNT were 72.2 %inhibition (95 %CI 67.2-77.6) and 499 (95 %CI 399-624), respectively. The proportion of children with sVNT against Omicron strain ≥68 %inhibition increased from none to 70.2 %. The geometric mean ratio (GMR) of sVNT and pVNT compared with a parallel cohort were 4.3 and 12.2, respectively. The GMR of sVNT and pVNT between children who received booster dose at >6-week interval were 1.2 (95 %CI 1.1-1.3). and 1.8 (95 %CI 1.2-2.7) compared with 4-6 weeks interval. Conclusion: A regimen of 2-dose of inactivated vaccine followed by BNT162b2 booster dose elicited high neutralizing antibody against the Omicron variants in healthy school-aged children.

Pharmacokinetics of isoniazid and rifapentine in young pediatric patients with latent tuberculosis infection.

OBJECTIVES: This study investigated the steady-state pharmacokinetic profiles of 3-month weekly rifapentine plus isoniazid (3HP) in children with latent tuberculosisinfection (LTBI). We also assessed other factors, including tablet integrity, food, and pharmacogenetics. METHODS: During the 3HP treatment, blood and urine samples were collected in week 4. Isoniazid and rifapentine levels were measured using a high-performance liquid chromatography technique. The genetic variation of arylamine N-acetyltransferase 2 (NAT2) and arylacetamide deacetylase (AADAC) were assessed by the MassARRAY®. Safety and clinical outcomes at week 48 were monitored. RESULTS: A total of 12 children with LTBI (age 3.8 [range 2.1-4.9 years old]) completed the treatment (isoniazid and rifapentine dose 25.0 [range 21.7-26.8] and 25.7 [range 20.7-32.1] mg/kg, respectively). No serious adverse events or active TB occurred. Tablet integrity was associated with decreased area under the concentration-time curve (91 vs 73 mg.h/l, P= 0.026) and increased apparent oral clearance of isoniazid (0.27 vs 0.32 l/h/kg, P= 0.019) and decreased rifapentine's renal clearance (CLR, 0.005 vs 0.003 l/h, P= 0.014). Food was associated with increased CLR of isoniazid (3.45 vs 8.95 l/h, P= 0.006) but not rifapentine. Variability in NAT2 and AADAC did not affect the pharmacokinetics of both drugs. CONCLUSION: There is high variability in the pharmacokinetic profiles of isoniazid and rifapentine in young children with LTBI. The variability was partly influenced by tablet integrity and food, but not pharmacogenetics. Further study in a larger cohort is warranted to display the relationship of these factors to treatment outcomes.

Pharmacokinetics and Safety of WHO-Recommended Dosage and Higher Dosage of Levofloxacin for Tuberculosis Treatment in Children: a Pilot Study.

OBJECTIVES: To evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage. METHODS: Children aged 1-15 years with tuberculosis who received levofloxacin-based treatment for at least 7 days were enrolled. First, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day), then an additional five children received a dosage higher than the WHO-recommended dosage (20-30 mg/kg/day). Blood samples were collected at predose and postdose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was 100. RESULTS: The median (interquartile range) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years in the WHO dosage and higher-than-WHO dosage groups, respectively. The median (interquartile range) duration of antituberculosis treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO and higher-than-WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events. CONCLUSION: Levofloxacin at a higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children.

Diagnostic Accuracy of Loop-Mediated Isothermal Amplification (TB-LAMP) for Tuberculosis in Children.

BACKGROUND: Diagnosing tuberculosis (TB) in children is challenging due to its paucibacillary nature. Loop-mediated isothermal amplification (TB-LAMP) is a simple, rapid, and specific point-of-care molecular diagnostic test. However, evaluation of its performance remains limited in children. This study aimed to evaluate the diagnostic performance of Eiken TB-LAMP among children with presumed tuberculosis disease. METHODS: Pulmonary and extrapulmonary specimens were collected from children under 18 years with presumed TB. Each specimen was tested by using TB-LAMP, acid-fast bacilli (AFB) smear microscopy, and one of the two molecular assays (polymerase chain reaction [PCR] or Xpert MTB/RIF). Sensitivity and specificity were estimated compared to mycobacterial culture as reference standard. RESULTS: From January 2020 to January 2021, 75 participants with presumed TB were enrolled with median age of 7 years (IQR 2-12). Seventeen specimens from 16 (21.3%) children had bacteriologically confirmed TB: 10 pulmonary and 7 extrapulmonary specimens. Overall sensitivity and specificity of TB-LAMP was 76.5% (95% CI 50.1%-93.2%) and 100% (95% CI 94.3%-100%), respectively. It had significantly higher sensitivity than AFB (52.9%, 95% CI 27.8%-77.0%) and similar to other molecular assays; PCR 82.4% (95% CI 56.6%-96.2%), Xpert MTB/RIF 70.0% (95% CI 34.8%-93.3%). Sensitivity of TB-LAMP for pulmonary, lymph node tissue, and extrapulmonary fluid was 80% (95% CI 44.4%-97.5%), 100% (95% CI 39.8-100), and 33.3% (95% CI 0.8-90.6), respectively. TB-LAMP detected all smear-positive (N = 9) and 50% of smear-negative (N = 8) specimens. CONCLUSIONS: TB-LAMP had higher sensitivity than AFB microscopy and accuracy similar to other molecular assays in both pulmonary and extrapulmonary specimens. These findings support using TB-LAMP as a point-of-care test in children.

Efficacy of chlorhexidine patches on central line-associated bloodstream infections in children.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) are important hospital-acquired infections. Chlorhexidine-impregnated dressings (also known as chlorhexidine patches, CHG patches) are reported to decrease CLABSIs in adults. This study aims to determine the efficacy of CHG patches in reducing CLABSIs in children. METHODS: An open-label randomized controlled trial was conducted in children aged 2 months to 18 years, requiring a short-term catheter. Patients were randomized into two groups, allocated to receive CHG patches or standard transparent dressings. Care of the catheter was in accordance with Asia Pacific Society of Infection Control (APSIC) recommendations. Central-line-associated bloodstream infections were defined using National Healthcare Safety Network surveillance criteria. RESULTS: From April 2017 to April 2018, 192 children were enrolled. There were 108 CHG patch catheters and 101 standard dressing catheters, contributing to 3,113 catheter days. The median duration of catheter dwelling was 13 days, with an interquartile range (IQR) of 8-20 days. Half were placed at the jugular vein and 22% at the femoral vein. There were 23 CLABSI events. Incidence rates for CHG patches and standard dressings were 7.98 (95% confidence interval (CI), 4.25-13.65) and 6.74 (95% CI, 3.23-12.39) per 1,000 catheter days, respectively (incidence rate ratio 1.18; 95% CI, 0.52-2.70). The CLABSI pathogens were 15 Gram-negative bacteria, six Gram-positive bacteria, and two Candida organisms. Catheter colonization of CHG patches and standard dressings were 2.02 (95% CI, 0.42-5.91) and 3.07 (95% CI, 1.00-7.16) per 1,000 catheter days, respectively. Only local adverse effects occurred in 6.8% of the participants. CONCLUSIONS: In our setting, there was no difference in CLABSI rates when the chlorhexidine patch dressings were compared with the standard transparent dressings. Strengthening of CLABSI prevention bundles is mandatory.

Pattern and Frequency of Seroreactivity to Routinely Used Serologic Tests in Early-Treated Infants With HIV.

BACKGROUND: Previous studies have shown low frequencies of seroreactivity to HIV diagnostic assays for infected infants treated with antiretroviral therapy (ART) early in infection. METHODS: Fifty-eight HIV-infected infants treated with ART at a median age of 1.9 months (range: 0.2-5.4) for up to 4 years of life were assessed for seroreactivity to 4 routinely used HIV clinical immunoassays (IA): Second-generation (2ndG) IA and 2 rapid diagnostic tests (RDT), based on third-generation principles, measuring antibody only and a fourth-generation (4thG) antigen/antibody IA. HIV Western blot assay was also performed to assess HIV-specific antibodies. RESULTS: The 2ndG IA demonstrated the highest frequency of seroreactivity in children (69%) followed by the 4thG IA (40%) and the RDT (26%) after one year of ART. Infants initiating ART during ages 3-6 months (N = 15) showed a greater frequency (range: 53%-93%) and breadth (median and range: 3 [1-4]) of reactivity across the assays compared with those treated within 3 months (N = 43):16%-61% and breadth (1 [0-4]). The 4thG IA showed significantly reduced reactivity relative to the 2ndG IA at one (P = 0.016) and 3 (P = 0.004) years of ART. Western blot profiles following 3 years of ART showed the highest frequency of reactivity to HIV Gag p24 (76%) and lowest reactivity to Env gp120 and gp41, with only 24% of children confirmed positive by the assay. CONCLUSIONS: These results suggest that the use of 4thG IA and RDT test combination algorithms with limited HIV antigen breadth may not be adequate for diagnosis of HIV-infected children following early treatment.