Chitsanu Pancharoen

Safety and Immunogenicity of a Single Administration of Live-attenuated Japanese Encephalitis Vaccine in Previously Primed 2- to 5-year-olds and Naive 12- to 24-month-olds: Multicenter Randomized Controlled Trial

Background: Safe and effective Japanese encephalitis (JE) vaccines are needed to protect populations living in or visiting endemic areas. A live-attenuated JE-chimeric virus vaccine (JE-CV) has been developed with a single-dose regimen. Methods: In an open-label, crossover study, 100 children aged 2 to 5 years with a history of 2-dose primary vaccination with mouse-brain derived inactivated JE vaccine according to the Thai Expanded Program for Immunization schedule, and 200 JE vaccination-naive 12- to 24-month-old toddlers were randomized 1:1 to receive JE-CV, containing ≥4 log10 plaque forming units, 1 month before or after hepatitis A control vaccine. Neutralizing antibody titers were assessed using PRNT50 (titers expressed in inverse of dilution) before and 28 days after JE-CV, and at months 7 and 12. Results: All 2- to 5-year-olds and 96% of 12- to 24-month-olds were seroprotected (titer ≥10) 28 days after JE-CV administration, and geometric mean titers (GMT) (95% confidence interval) in these age groups were 2634 (1928–3600) and 281 (219–362), respectively. One year later, seroprotection rates in the 2 age groups were 97% and 84% and GMTs were 454 and 62.3, respectively. Vaccine-induced antibodies neutralized a panel of wild-type JE isolates. There were no vaccine-related serious adverse events. Reactogenicity of JE-CV was comparable with that of the inactivated hepatitis A vaccine. Conclusions: A single administration of JE-CV has a good safety profile and elicits a protective immune response in both JE-naive toddlers and JE-primed young children.

Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children.

Objective: To assess the pharmacokinetics and 24-week efficacy and safety of dual boosted saquinavir/lopinavir/ritonavir combination in children. Design: Twenty reverse transcription inhibitor-pretreated children at 2 centers in Thailand were treated with saquinavir/lopinavir/ritonavir in an open label, single arm, 6-month prospective study. The dosage was 50 mg/kg twice daily (bid) for saquinavir and 230/57.5 mg/m2 bid for lopinavir/ritonavir. Ten children also received lamivudine. Methods: Samples were collected for a 12-hour pharmacokinetic profile in all children. Plasma concentrations of saquinavir, lopinavir and ritonavir were determined using a validated high performance liquid chromatography technique. Results: At baseline, the median age was 8.5 years, with human immunodeficiency virus (HIV) RNA 4.9 log10 copies/mL, CD4 count 129 cells/μL and CD4%, 6.5%. Median area under the concentration curve at 0–12 hours and Cmin were 39.4 mg/L·h and 1.4 mg/L for saquinavir and 118 mg/L·hr and 5.9 mg/L for lopinavir. After 24 weeks of treatment, HIV RNA was suppressed below 400 copies/mL for 16 of 20 (80%) children (intent-to-treat analysis) and below 50 copies/mL for 12 of 20 children (60%), and CD4% (count) rose by a median of 6% (216 cells/μL). Median changes of triglyceride and total cholesterol were 56 and 36.5 mg/dL, respectively (P = 0.01). Lopinavir Cmin <1 and saquinavir Cmin <0.28 mg/L correlated with HIV RNA >400 copies/mL, and lopinavir Cmax >15 mg/L correlated with rises in cholesterol (P < 0.05). Conclusion: Plasma drug concentrations of saquinavir, lopinavir and ritonavir were at the higher limits of expected ranges for adult treatment at approved dosages (1000/100 mg bid for saquinavir, 400/100 mg bid for lopinavir/ritonavir). The regimen was well-tolerated and had good efficacy at 24 weeks. This dual boosted protease inhibitor combination should be assessed in larger trials of reverse transcription inhibitor-experienced children.

Safety and Immunogenicity of Preexposure Rabies Vaccination in Children Infected with Human Immunodeficiency Virus Type 1

There has been an alarming increase in the number of HIV-infected children worldwide [1]. Dog bites are a serious publichealth problem in developing countries, and one-fourth of chil-dren in Thailand have experienced animal bites [2]. We con-ducted this study to evaluate the safety and immunogenicity ofrabies vaccine in children infected with HIV type 1 (HIV-1).HDCV (human diploid-cell rabies vaccine, lot 0544, antigencontent of 9.3 IU/mL; Institut Merieux, Lyon, France) wasgiven to 13 HIV-1–infected children (study group) and 9 healthychildren (control group) as 1 injection of 1 mL into deltoidmuscle on days 0, 7, and 28. All subjects were seen on days 0,7, 14, 21, 28, 60, 90, 180, and 360. Blood was drawn for de-termination of titers of rabies-neutralizing antibody by therapid fluorescent focus inhibition test [3] on days 0, 7, 14, 21,28, 60, 90, 180, and 360. The CD4

Failure of Pre- and Postexposure Rabies Vaccinations in a Child Infected with HIV

We report the case of a 6-y-old HIV-infected girl with severe immune deficiency who failed to respond to intramuscular pre-exposure rabies vaccination using human diploid cell rabies vaccine on days 0, 7 and 28. She also failed to respond to an intradermal postexposure rabies regimen using purified verocell rabies vaccine at 4 sites on days 0, 3 and 7 and at 2 sites on days 30 and 90 (double the usual regimen). Sequentially monitored rabies neutralizing antibody titers were below the WHO minimum acceptable level (> 0.15 IU/ml) in all specimens. Rabies prevention in HIV-infected persons with severe immune suppression requires further study.We report the case of a 6-y-old HIV-infected girl with severe immune deficiency who failed to respond to intramuscular pre-exposure rabies vaccination using human diploid cell rabies vaccine on days 0, 7 and 28. She also failed to respond to an intradermal postexposure rabies regimen using purified verocell rabies vaccine at 4 sites on days 0, 3 and 7 and at 2 sites on days 30 and 90 (double the usual regimen). Sequentially monitored rabies neutralizing antibody titers were below the WHO minimum acceptable level (> 0.15 IU/ml) in all specimens. Rabies prevention in HIV-infected persons with severe immune suppression requires further study.

Reduced-dose intradermal vaccination against hepatitis A with an aluminum-free vaccine is immunogenic and can lower costs.

A reduced dose (0.1 mL) of intradermal hepatitis A virus (HAV) vaccine could facilitate the control of hepatitis A in countries of endemicity. All study subjects receiving an aluminum-free HAV vaccine intradermally were seroprotected 28 days after vaccination (anti-HAV titer, > or =10 mIU/mL). Seroprotection rates decreased to 80.8% at 12 months but returned to 100%, with titers increasing 28-fold, after receipt of a booster vaccination.

Single-dose, live-attenuated Japanese encephalitis vaccine in children aged 12-18 months: randomized, controlled phase 3 immunogenicity and safety trial.

This trial in 1200 JE-vaccination naïve children (age 12–18 mo) in Thailand and the Philippines aimed to demonstrate consistency of three successive industrial scale manufacturing lots of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and consistency between industrial scale manufacturing lots and a fourth, development lot. Children received JE-CV from one of three successive industrial scale lots produced in Thailand (n = 899), or from a fourth development lot produced in the USA (n = 199), or hepatitis A control vaccine (n = 102). Antibodies were assessed by 50% plaque reduction neutralization test (PRNT50) at screening and Day 28. Seroconversion rates (titer of < 10 at baseline and ≥ 10 on Day 28, or a four-fold rise from a baseline titer of ≥ 10) were determined per group. Lot-to-lot consistency of seroconversion rate and GMT was demonstrated between the 3 industrial scale lots, and between these lots and the US lot. Seroconversion rate on pooled data 28 d after JE-CV vaccination (Thai lots) was 95.0% [95% confidence interval (CI); 93.3–96.3]. The safety profile of JE-CV was favorable and comparable with hepatitis A vaccine. There were no serious adverse events related to vaccination. This study demonstrated the consistency of three successive industrial scale JE-CV vaccine lots, as well as consistency with a development lot. The study also demonstrated that a single dose of JE-CV is well tolerated and elicits a high protective immune response, seroconverting 95% of JE-naïve Asian children aged 12–18 mo. ClinicalTrials.gov: NCT00735644

The immunogenicity and safety of live attenuated varicella-zoster virus vaccine in human immunodeficiency virus-infected children.

Background: The live attenuated varicella vaccine is recommended for HIV-infected children who are not severely immunosuppressed. This study aimed to assess the immunogenicity and safety of varicella vaccination among HIV-infected children who had severe immunosuppression before receiving antiretroviral therapy. Methods: Sixty HIV-infected children with no history of chickenpox or herpes zoster infection with CD4 T lymphocyte counts ≥15% or ≥200 cell/mm3 were enrolled. Two doses of varicella vaccine were administered at the time of enrollment and at 3 months. Varicella zoster virus (VZV) antibody was tested at baseline and 3 months after each dose by the enzyme-linked immunosorbent assay technique. An antibody titer >20 HU/mL was regarded as protective. Results: The median (interquartile range) of age, CD4 nadir, and current CD4 percentage were 11.2 (8.5–12.8) years, 9.5% (3–14), and 28% (22–32), respectively. Fifty-seven children (95%) received antiretroviral therapy for a median of 27 months. Among 34 children (57%) who were VZV seronegative at baseline, 11.8% (95% CI, 3.3%–27.5%) and 79.4% (95% CI, 62.1%–91.3%) were VZV seroconverted after first and second dose of vaccine, respectively. Children who had VZV seroconversion were more likely to have HIV RNA <1.7 copies/mL (92.6% vs. 71.4%, P = 0.18). Among 26 children who were seropositive at baseline, the geometric mean titers were increased from 56.7 to 107.9 and 134.6 unit/mL, respectively. Local and systemic reactions of grade 1 and 2 were reported in 13% and 4% of children, respectively. There was a trend toward better response among children with younger age, high CD4, and viral suppression. Conclusions: Administration of the 2 doses of varicella vaccine resulted in high seroconversion rates without serious adverse reactions. Varicella vaccination for HIV-infected children should be encouraged.

Rabies exposures in Thai children

OBJECTIVE To determine the epidemiology of potential rabies exposures in Thai children. METHODS The study was carried out at the Queen Saovabha Memorial Institute of the Thai Red Cross Society during I calendar year. All charts of victims aged 0 to 14 years with possible rabies exposures were retrospectively reviewed. RESULTS Subjects were 2622 children, with a male to female ratio of 1.6:1 and a mean age of 6.7 years (range, 2 months to 14 years). Most exposures (86.3%) were related to dogs. The most common site of exposure was the lower extremity. The majority of exposures occurred in or around the home and as the consequence of unprovoked attacks rather than provoked attacks. Antirabies vaccines were given in all cases: 68.4% using the Thai Red Cross intradermal route, and 31.6% using the intramuscular route. Rabies immunoglobulin (RIG) was prescribed in 57.5% of children; 35.2% received human RIG (HRIG), and 22.3% received purified equine RIG (ERIG). CONCLUSIONS This study confirms that rabies exposures, especially in children, are an important public health problem in Thailand. The reduced-dose, multiple-site intradermal rabies vaccine method and ERIG in place of HRIG reduce the cost of treatment.

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

Myocardial depression in dengue hemorrhagic fever: prevalence and clinical description.

Objectives: To determine the prevalence of myocardial depression and its effect on the clinical severity in patients with dengue hemorrhagic fever. Design: Clinical study. Setting: King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Patients: Ninety-one children (age 10.5 ± 2.9 yrs, male/female = 52/39) with serologically or polymerase chain reaction-proven dengue virus infection. Interventions: Left ventricular ejection fraction (EF) was measured. The proportions of patients with EF <50% were identified in patients with dengue fever (DF, n = 30), dengue hemorrhagic fever without shock (DHF, n = 36), and dengue shock syndrome (DSS, n = 25). Comparisons of clinical findings were made among DSS patients with depressed ventricular function (EF <50%), fair ventricular function (EF ≥50% and <60%), and good ventricular function (EF ≥60%). Serum troponin T was analyzed in nine patients. Measurements and Main Results: EF during toxic stage was significantly lower in patients with DSS than DHF, and lower in DHF than DF (p = .05) with rapid recovery within 24–48 hrs. EF <50% was found in 6.7%, 13.8%, and 36% of patients with DF, DHF, and DSS during the toxic stage, respectively (p = .01). DSS patients with poor ventricular function had significantly more tachycardia and hepatomegaly. While end-diastolic volumes were similarly reduced, patients with lower EF tended to have lower cardiac output, required more aggressive intravenous fluid resuscitation, developed larger pleural effusion, and had higher incidence of respiratory embarrassment. No patient had elevated troponin T level. Conclusions: Transient myocardial depression is not uncommon in patients with DSS. Cardiac dysfunction in children with DSS may contribute to the clinical severity and the degree of fluid overload in these patients.