Publications by authors named "Pope Kosalaraksa"

97 Publications

Hexavalent vaccines in infants: a systematic literature review and meta-analysis of the solicited local and systemic adverse reactions of two hexavalent vaccines.

Expert Rev Vaccines 2021 Mar 24;20(3):319-330. Epub 2021 Mar 24.

GSK, Wavre, Belgium.

: The hexavalent vaccine DT3aP-HBV-IPV-Hib (, GSK) was first licensed in Europe in 2000. DT2aP-HBV-IPV-Hib (, Sanofi Pasteur), and DT5aP-HBV-IPV-Hib (, MCM Vaccine Company) were licensed in the EU in 2013 and 2016, respectively, based largely on studies demonstrating non-inferiority to DT3aP-HBV-IPV-Hib for immunogenicity and comparable reactogenicity profiles.: We conducted a systematic literature review looking for direct head-to-head trials comparing DT2aP-HBV-IPV-Hib and DT5aP-HBV-IPV-Hib with DT3aP-HBV-IPV-Hib. The incidence of solicited local and systemic reactions following primary series administration of DT3aP-HBV-IPV-Hib or DT2aP-HBV-IPV-Hib were meta-analyzed.: A total of 317 unique records were retrieved from the search; nine met the predefined inclusion criteria; seven reported studies comparing DT3aP-HBV-IPV-Hib and DT2aP-HBV-IPV-Hib. Six trials assessing outcomes of the primary vaccination series were identified. Odds ratios and 95% confidence intervals (OR; 95%CI) were computed for DT3aP-HBV-IPV-Hib, using DT2aP-HBV-IPV-Hib as reference, for redness (0.72; 0.63-0.83), pain (0.74; 0.62-0.89), swelling (0.86; 0.74-0.99) at injection site, fever (0.67; 0.54-0.83), persistent crying (0.72; 0.61-0.84), drowsiness (0.82; 0.71-0.94), irritability (0.82; 0.69-0.98), anorexia (0.83; 0.72-0.95), and vomiting (0.96; 0.83-1.11).: ORs of analyzed local and systemic solicited adverse reactions after primary vaccination with DT3aP-HBV-IPV-Hib appear to be slightly lower than with DT2aP-HBV-IPV-Hib.
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http://dx.doi.org/10.1080/14760584.2021.1892493DOI Listing
March 2021

Immunogenicity and safety profiles of a new MAV/06 strain varicella vaccine in healthy children: A multinational, multicenter, randomized, double-blinded, active-controlled phase III study.

Vaccine 2021 Mar 21;39(12):1758-1764. Epub 2021 Feb 21.

Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Immunization is the most effective preventive strategy against varicella. While the Oka strain is commonly used for varicella vaccination worldwide, Korea widely uses the MAV/06 strain. A new live attenuated MAV/06 strain varicella vaccine (MG1111), which uses the new cell line Medical Research Council-5 for better viral propagation, was developed. MG1111 was approved by Korean health authorities. Here, we report the results of phase III, randomized, double-blind, multicenter study conducted in Korea and Thailand, which compared the immunogenicity and safety profiles of MG1111 versus the control vaccine, Varivax. In total, 515 healthy children (12 month-12 years) were randomized 1:1 to receive either the MG1111 or control vaccine (MG1111: 258, Control: 257). The seroconversion rate (SCR) and geometric mean titer (GMT) were measured using the fluorescent antibody to membrane antigen (FAMA) test. The MG1111 group achieved a SCR of 97.9% (95% CI: 95.2-99.3) after vaccination. The lower limit of 95% CI for SCR difference (MG1111-Varivax) was -4.0%, which was higher than the specified non-inferiority margin of -10%. Further, the GMT of the MG1111 increased from 2.0 to 74.2 (95% CI: 65.0-84.8) and the lower limits of the 95% CI for post-vaccination GMT ratios (MG1111/Varivax) were 0.55 higher than the specified parameter of 0.5. Therefore, the MG1111 group was not statistically inferior to the control vaccine group in terms of SCR and GMT. Furthermore, the MG1111 and control vaccine groups were not significantly different in the percentage of participants showing adverse events-solicited, local, or systemic during 43-day period of observation and serious adverse events during 6 month of observation. The present results indicate that MG1111was not immunologically inferior to Varivax, and safety profiles of MG1111 are similar to those of Varivax.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.013DOI Listing
March 2021

HIV-related enacted stigma and increase frequency of depressive symptoms among Thai and Cambodian adolescents and young adults with perinatal HIV.

Int J STD AIDS 2021 Mar 18;32(3):246-256. Epub 2020 Dec 18.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Center, Bangkok, Thailand.

HIV-related enacted stigma and social problems may increase risk for depression and/or behavioral problems among adolescents and young adults with perinatal HIV(AYA-PHIV), yet few studies have explored stigma in AYA-PHIV residing in low-to-middle income regions, including Southeast Asia. We assessed HIV-related enacted stigma and social problems in AYA-PHIV who participated in the RESILIENCE study (clinicaltrials.gov identification: U19AI53741) in Thailand and Cambodia using specific questions during structured in-person interviews. Depression was measured by the Child Depression Inventory for children <15 years, or the Center for Epidemiologic Studies Depression Scales for youth ≥15 years); behavioral problems were measured by the Child Behavior Checklist (CBCL-caregiver report). Among 195 AYA-PHIV (median age 16.9 years), 25.6% reported a lifetime experience of enacted stigma, while 10.8% experienced social problems due to HIV infection. The frequency of depressive symptoms was nearly two-fold higher among AYA-PHIV with compared to those without HIV-related enacted stigma (34.7% vs. 16.0%, p = 0.005). Caregiver-reported behavioral problems were detected in 14.6% of all AYA-PHIV, with no differences between those with and without HIV-related enacted stigma. Low household income and caregiver mental health problems were independent risk factors for depressive symptoms; HIV-related enacted stigma was also associated with increased risk, warranting targeted services to support AYA-PHIV.
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http://dx.doi.org/10.1177/0956462420960602DOI Listing
March 2021

Efficacy of a dengue vaccine candidate (TAK-003) in healthy children and adolescents two years after vaccination.

J Infect Dis 2020 Dec 15. Epub 2020 Dec 15.

Takeda Pharmaceuticals International AG., Zurich, Switzerland.

Background: Takeda's dengue vaccine is under evaluation in an ongoing Phase 3 efficacy study; we present an update after 2 years.

Methods: 20,099 children (4-16 years old) were randomized to receive two doses of TAK-003 or placebo three months apart and are under long-term febrile surveillance to detect dengue by serotype-specific RT-PCR. (NCT02747927).

Results: Cumulative efficacy against dengue over ~27 months since first dose was 72.7% (95% CI: 67.1 - 77.3), which included efficacy of 67.0% (95% CI: 53.6 - 76.5) in dengue-naïve and 89.2% (82.4 - 93.3) against hospitalized dengue. In the second year after vaccination, a decline in efficacy was observed [56.2% (42.3 - 66.8)] with the largest decline in 4 - 5 year-old children [24.5% (-34.2 - 57.5)]; efficacy was 60.6% (43.8 - 72.4) in 6 - 11 year and 71.2% (41.0 - 85.9) in 12 - 16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to the efficacy differences in year by year analysis. No related serious adverse events occurred during the second year.

Conclusion: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.
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http://dx.doi.org/10.1093/infdis/jiaa761DOI Listing
December 2020

A prognostic study of patients with cervical cancer and HIV/AIDS in Bangkok, Thailand.

Gynecol Oncol Rep 2020 Nov 4;34:100669. Epub 2020 Nov 4.

Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Thailand.

Cervical cancer is one of the most common cancers of women. In Thailand, the incidence and death rate of cervical cancer are 18.1 and 5.7 per 100,000 women, respectively. Disease progresses faster in patients infected with human immunodeficiency virus (HIV) with acquired immune deficiency syndrome (AIDS). However, limited data are available for Thailand. Here we determined the prevalence of HIV/AIDS and identified factors affecting survival. We reviewed medical records of women infected with HIV with cervical cancer treated at Ramathibodi Hospital from 2007 through 2014. Demographic and clinical data were collected upon diagnosis. We used the Kaplan-Meier method and a Cox proportional hazards model to evaluate the association of overall survival (OS) with risk factors. The mean, median and range of ages at diagnosis of the 1,362 subjects were 53.9 years, 53.0 years and 20-94 years, respectively. The prevalence of HIV/AIDS in patients with cervical cancer was 2.3% and 5-year survival was 61.2%. Multivariable analysis revealed that favourable prognostic factors were a civil servant medical benefit plan and higher education. Advanced cervical cancer was a poor prognostic factor. Prognosis of women with stage III and IV cervical cancer was extremely poor (HR = 7.25 (95%CI: 4.39-11.98)) in stage III and HR = 20.57 (95%CI: 11.59-36.53) in stage IV). The 1-, 3-, and 5-year survival rates of patients with (74.2%, 67.6%, and 63.6%, respectively) or without (87.4%, 71.3% and 63.7%, respectively) HIV/AIDS were not significantly different.
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http://dx.doi.org/10.1016/j.gore.2020.100669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680700PMC
November 2020

The Effects of the Face Mask on the Skin Underneath: A Prospective Survey During the COVID-19 Pandemic.

J Prim Care Community Health 2020 Jan-Dec;11:2150132720966167

Khon Kaen University, Khon Kaen, Thailand.

Purpose: The study aimed to explore the prevalence and possible risk factors to prevent the face mask related adverse skin reactions during the ongoing COVID-19 after a recommendation of face mask wearing for public use in Thailand.

Results: The prevalence of face mask related adverse skin reactions was 454 cases (54.5%), of which acne was the most frequent (399; 39.9%), followed by rashes on the face (154; 18.4%), and itch symptoms (130; 15.6%). Wearing a surgical mask showed a higher risk of adverse skin reaction compared to a cloth mask, OR (95% CI) = 1.54 (1.16-2.06). A duration of face mask wearing of more than 4 hours/day and the reuse of face masks increased the risk of adverse skin reactions compared to changing the mask every day, adjusted OR(95% CI) = 1.96 (1.29-2.98), and 1.5 (1.11-2.02).

Conclusion: Suggestions were made for wearing a cloth mask in non-health care workers (HCW) to decrease the risk of face mask related adverse skin reactions. This suggestion could potentially help in decreasing the demand of surgical masks which should be reserved for the HCW population during the ongoing COVID-19 pandemic.
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http://dx.doi.org/10.1177/2150132720966167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786409PMC
October 2020

Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial.

Lancet 2020 05 17;395(10234):1423-1433. Epub 2020 Mar 17.

Takeda Vaccines, Boston, MA, USA.

Background: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years.

Methods: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927.

Findings: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo.

Interpretation: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance.

Funding: Takeda Vaccines.
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http://dx.doi.org/10.1016/S0140-6736(20)30414-1DOI Listing
May 2020

Implementation of an active case management network to identify HIV-positive infants and accelerate the initiation of antiretroviral therapy, Thailand 2015 to 2018.

J Int AIDS Soc 2020 02;23(2):e25450

Bureau of AIDS, TB and STIs, Ministry of Public Health, Nonthaburi, Thailand.

Introduction: Early initiation of antiretroviral therapy (ART) can reduce HIV-related morbidity and mortality in HIV-positive infants. We implemented an Active Case Management Network to promote early ART initiation Aiming for Cure (ACC) in August 2014. We describe ACC implementation, early infant diagnosis (EID) coverage and ART initiation during August 2014 to July 2018 compared with a national EID survey during October 2007 to September 2011 (pre-ACC).

Methods: Thailand's 2014 HIV Treatment Guidelines recommend that HIV-exposed infants have HIV polymerase chain reaction (PCR) testing at birth, one month and at two to four months. Testing is done at 14 national HIV PCR laboratories. When an HIV-positive infant (HIV PCR+) is identified, PCR laboratory staff send the result to the hospital staff responsible for the infant's care and to the national laboratory case manager (CM). As part of ACC, the national laboratory CM alerts a regional CM who contacts the hospital staff caring for the infant to offer technical support with ART initiation and ART adherence. CMs enter clinical, demographic and laboratory data into the national ACC database. We analysed the ACC data from August 2014 to July 2018 to assess the ACC's impact on EID coverage, ART initiation and time-to-ART initiation.

Results: The uptake of EID increased from 64% (pre-ACC) to >95% in 2018 (ACC). The number of HIV-positive infants born declined from 429 cases (pre-ACC) to 267 cases (ACC). Median age at the first-positive PCR declined from 75 days (pre-ACC) to 60 days (ACC); P < 0.001. Among 429 infants diagnosed before ACC was started, 241 (56%) received ART; during ACC, 235 (88%) of 267 HIV-positive infants received ART. The median age at ART initiation declined from 282 days before ACC to 83 days during ACC (P < 0.001) and the median time from blood collection to ART initiation declined from 168 days before ACC to 23 days during ACC (P < 0.001).

Conclusions: An innovative case management network (ACC) has been established in Thailand and results suggest that the network is promoting EID and early ART initiation. The ACC model, using case-managed PCR notification and follow-up, may speed ART initiation in other settings.
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http://dx.doi.org/10.1002/jia2.25450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046526PMC
February 2020

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

J Acquir Immune Defic Syndr 2020 03;83(3):260-266

SEARCH, Thailand The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

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.
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http://dx.doi.org/10.1097/QAI.0000000000002254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050817PMC
March 2020

Machine-learning classification of neurocognitive performance in children with perinatal HIV initiating de novo antiretroviral therapy.

AIDS 2020 04;34(5):737-748

HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center.

Objective: To develop a predictive model of neurocognitive trajectories in children with perinatal HIV (pHIV).

Design: Machine learning analysis of baseline and longitudinal predictors derived from clinical measures utilized in pediatric HIV.

Methods: Two hundred and eighty-five children (ages 2-14 years at baseline; Mage = 6.4 years) with pHIV in Southeast Asia underwent neurocognitive assessment at study enrollment and twice annually thereafter for an average of 5.4 years. Neurocognitive slopes were modeled to establish two subgroups [above (n = 145) and below average (n = 140) trajectories). Gradient-boosted multivariate regressions (GBM) with five-fold cross validation were conducted to examine baseline (pre-ART) and longitudinal predictive features derived from demographic, HIV disease, immune, mental health, and physical health indices (i.e. complete blood count [CBC]).

Results: The baseline GBM established a classifier of neurocognitive group designation with an average AUC of 79% built from HIV disease severity and immune markers. GBM analysis of longitudinal predictors with and without interactions improved the average AUC to 87 and 90%, respectively. Mental health problems and hematocrit levels also emerged as salient features in the longitudinal models, with novel interactions between mental health problems and both CD4 cell count and hematocrit levels. Average AUCs derived from each GBM model were higher than results obtained using logistic regression.

Conclusion: Our findings support the feasibility of machine learning to identify children with pHIV at risk for suboptimal neurocognitive development. Results also suggest that interactions between HIV disease and mental health problems are early antecedents to neurocognitive difficulties in later childhood among youth with pHIV.
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http://dx.doi.org/10.1097/QAD.0000000000002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072001PMC
April 2020

Nonalcoholic fatty liver disease and hepatic fibrosis among perinatally HIV-monoinfected Asian adolescents receiving antiretroviral therapy.

PLoS One 2019 19;14(12):e0226375. Epub 2019 Dec 19.

HIV-NAT, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

To assess and compare the prevalence of persistent hepatic abnormalities, including nonalcoholic fatty liver disease (NAFLD) and/or hepatic fibrosis, among perinatally HIV-monoinfected Asian adolescents with history of abnormal hepatic enzymes to those without, using noninvasive diagnostic tools. A multicenter cohort study was conducted in Thailand and Indonesia. Adolescents aged 10-25 years who were on antiretroviral treatment (ART), had virologic suppression (HIV RNA<400 copies/mL within the past 6 months), and had no history of chronic hepatitis B/C infection were enrolled. Participants were pre-classified into 2 subgroups (1:1 ratio) as participants with history of elevated versus normal aminotransferase enzymes. NAFLD was defined as hepatic steatosis (any severity) evaluated by liver ultrasonography. Significant hepatic fibrosis was defined as liver stiffness ≥7.4 kPa evaluated by transient elastography. Participants who met the criteria for protocol-defined NAFLD and/or hepatic fibrosis were re-assessed to evaluate disease progression (persistent versus transient hepatic abnormalities) at one year later. Of 120 participants, 62 (51.7%) were male, 7 (5.8%) had central obesity, and 19 (15.8%) had insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] >3.16). At enrollment, the median age and duration of ART (IQR) were 17.0 (14.6-19.2) years and 10.5 (7.1-12.0) years, respectively. Persistent hepatic abnormalities were identified in 5/60 participants listed in the group having history of elevated aminotransferases, corresponding to the prevalence of 8.3% (95% CI: 2.8-18.4%), whereas none (0/60) were among the group having history of normal hepatic enzymes. All 5 participants had persistent aminotransferase elevation (≥2 episodes within the past 12 months). Baseline alanine aminotransferase (ALT) >30 U/L (adjusted odds ratio [aOR]: 29.1; 95% CI: 1.7-511.8), and HOMA-IR >3.16 (aOR: 17.9; 95% CI: 1.1-289.7) were independently associated with persistent hepatic abnormalities. Among perinatally HIV-monoinfected Asian adolescents with history of elevated aminotransferase enzymes, persistent hepatic abnormalities are not uncommon. Screening for liver complications by noninvasive diagnostic tools might be considered in at risk individuals, including those with persistent ALT elevation and insulin resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922447PMC
March 2020

Quadrivalent Influenza Vaccine Prevents Illness and Reduces Healthcare Utilization Across Diverse Geographic Regions During Five Influenza Seasons: A Randomized Clinical Trial.

Pediatr Infect Dis J 2020 01;39(1):e1-e10

Institut Pediàtric Marès-Riera, Blanes, Spain.

Background: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6-35 months of age in a phase III, observer-blind trial.

Methods: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011-2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains.

Results: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1-5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1-5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America.

Conclusions: IIV4 prevented influenza in children 6-35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.
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http://dx.doi.org/10.1097/INF.0000000000002504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004464PMC
January 2020

Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents.

N Engl J Med 2019 11 6;381(21):2009-2019. Epub 2019 Nov 6.

From Takeda Vaccines, Singapore (S. Biswal); Centro de Atención e Investigación Médica, Bogota (H.R.), and Centro de Estudios en Infectología Pediatrica, Centro Médico Imbanaco and Department of Pediatrics, Universidad del Valle, Cali (P.L., E.L.-M.) - both in Colombia; the Department of Infectious Diseases at Hospital del Niño Dr. José Renán Esquivel, Sistema Nacional de Investigación at Secretaria Nacional de Ciencia y Tecnologia (SENACYT), Centro de Vacunación Internacional (Cevaxin), Panama City, Panama (X.S.-L., J.J.); the Research Institute for Tropical Medicine, Muntinlupa (C.B.-T.), and the University of the Philippines Manila, Ermita (L.B.) - both in the Philippines; Srinagarind Hospital, Khon Kaen University, Khon Kaen (P.K.), and the Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University (C.S.), and Phramongkutklao Hospital (V.W.), Bangkok - all in Thailand; Hospital Maternidad Nuestra Senora de Altagracia, Santo Domingo, Dominican Republic (L.R.); National Autonomous University of Nicaragua, Leon (F.E.); Center for Clinical Management of Dengue and Dengue Haemorrhagic Fever, Negombo General Hospital, Negombo, Sri Lanka (L.K.F.); Universidade Federal Do Espirito Santo, Hospital Universitário Cassiano Antônio de Moraes, Vitória (R.D.), Instituto de Medicina Tropical da Universidade Federal do Rio Grande do Norte, Natal (K.L.), and Universidade Federal de Mato Grosso do Sul, Campo Grande (R.V.C.) - all in Brazil; Takeda Pharmaceuticals International, Zurich, Switzerland (A.B., M.B., M.R., I.L., S. Bizjajeva); and Takeda Vaccines, Boston (D.W.).

Background: Dengue, a mosquito-borne viral disease, was designated a World Health Organization top 10 threat to global health in 2019.

Methods: We present primary efficacy data from part 1 of an ongoing phase 3 randomized trial of a tetravalent dengue vaccine candidate (TAK-003) in regions of Asia and Latin America in which the disease is endemic. Healthy children and adolescents 4 to 16 years of age were randomly assigned in a 2:1 ratio (stratified according to age category and region) to receive two doses of vaccine or placebo 3 months apart. Participants presenting with febrile illness were tested for virologically confirmed dengue by serotype-specific reverse-transcriptase polymerase chain reaction. The primary end point was overall vaccine efficacy in preventing virologically confirmed dengue caused by any dengue virus serotype.

Results: Of the 20,071 participants who were given at least one dose of vaccine or placebo (safety population), 19,021 (94.8%) received both injections and were included in the per-protocol analysis. The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group). In the per-protocol analyses, vaccine efficacy was 80.2% (95% CI, 73.3 to 85.3; 61 cases of virologically confirmed dengue in the vaccine group vs. 149 cases in the placebo group), with 95.4% efficacy against dengue leading to hospitalization (95% CI, 88.4 to 98.2; 5 hospitalizations in the vaccine group vs. 53 hospitalizations in the placebo group). Planned exploratory analyses involving the 27.7% of the per-protocol population that was seronegative at baseline showed vaccine efficacy of 74.9% (95% CI, 57.0 to 85.4; 20 cases of virologically confirmed dengue in the vaccine group vs. 39 cases in the placebo group). Efficacy trends varied according to serotype. The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1% and 3.8%, respectively).

Conclusions: TAK-003 was efficacious against symptomatic dengue in countries in which the disease is endemic. (Funded by Takeda Vaccines; TIDES ClinicalTrials.gov number, NCT02747927.).
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http://dx.doi.org/10.1056/NEJMoa1903869DOI Listing
November 2019

Trajectory Analysis of Cognitive Outcomes in Children With Perinatal HIV.

Pediatr Infect Dis J 2019 10;38(10):1038-1044

Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, Missouri.

Background: Children with perinatal HIV (pHIV) may display distinct long-term cognitive phenotypes. We used group-based trajectory modeling to identify clusters of children with pHIV after similar developmental trajectories and predictors of belonging to select cognitive trajectory groups.

Methods: Participants included children, 4-17 years of age, with pHIV in Thailand and Cambodia. Cognitive measures included translated versions of Intelligence Quotient tests, Color Trails Tests and Beery-Buktenica Developmental Test of Visual-Motor Integration conducted semiannually over 3-6 years. The best fit of trajectory groups was determined using maximum likelihood estimation. Multivariate logistic regression identified baseline factors associated with belonging to the lowest scoring trajectory group.

Results: Group-based trajectory analyses revealed a 3-cluster classification for each cognitive test, labeled as high, medium and low scoring groups. Most trajectory group scores remained stable across age. Verbal IQ declined in all 3 trajectory groups and the high scoring group for Children's Color Trails Test 1 and 2 showed an increase in scores across age. Children in the lowest scoring trajectory group were more likely to present at an older age and report lower household income.

Conclusions: Group-based trajectory modeling succinctly classifies cohort heterogeneity in cognitive outcomes in pHIV. Most trajectories remained stable across age suggesting that cognitive potential is likely determined at an early age with the exception of a small subgroup of children who displayed developmental gains in select cognitive domains and may represent those with better cognitive reserve. Poverty and longer duration of untreated HIV may predispose children with pHIV to suboptimal cognitive development.
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http://dx.doi.org/10.1097/INF.0000000000002427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776249PMC
October 2019

Emotional and behavioral resilience among children with perinatally acquired HIV in Thailand and Cambodia.

AIDS 2019 06;33 Suppl 1:S17-S27

HIV Center for Clinical and Behavioral Studies, New York State Psychiatric Institute, Columbia University, New York, New York, USA.

Objectives: Psychosocial challenges associated with perinatally acquired HIV (PHIV) infection are well known, yet many children infected with HIV since birth demonstrate positive outcomes, referred to as resilience. The purpose of this study was to evaluate emotional-behavioral development and identify salient predictors of resilience among long-term survivors of PHIV.

Design: Prospective investigation of children with PHIV compared with demographically similar perinatally HIV-exposed but uninfected (PHEU) and HIV-unexposed, uninfected (HUU) children, all from Thailand and Cambodia.

Methods: The Child Behavior Checklist (CBCL; parent version) was administered at baseline and annual follow-up visits (median follow-up of 3 years) to children age 6-14. Resilience was defined as consistent CBCL scores on the Internalizing, Externalizing or Total Problem T scales within normative ranges (T-scores <60) at every time point. Generalized estimating equations examined CBCL scores over time and logistic models examined demographic, socioeconomic, and cultural predictors of resilience.

Results: Participants included 448 children (236 PHIV, 98 PHEU, 114 HUU), with median (interquartile range) age at first evaluation of 7 (6-9) years. Children with PHIV exhibited similar rates of resilience as PHEU and HUU on the Externalizing and Total Problems scales. Resilience on the Internalizing scale was more likely in PHEU (71%) compared with PHIV (59%) or HUU (56%), P = 0.049. Factors associated with resilience in adjusted models included: HIV-exposed but uninfected status, higher household income, Cambodian nationality, female sex, and caregiver type.

Conclusion: Despite biopsychosocial risks, resilience is observed among PHIV and PHEU children. Further study is needed to understand mechanisms underlying associated factors and intervention priorities.
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http://dx.doi.org/10.1097/QAD.0000000000002182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799438PMC
June 2019

Increased Risk of Executive Function and Emotional Behavioral Problems Among Virologically Well-Controlled Perinatally HIV-Infected Adolescents in Thailand and Cambodia.

J Acquir Immune Defic Syndr 2019 11;82(3):297-304

HIV Center for Clinical and Behavioral Studies, New York State Psychiatric Institute, and Columbia University, New York, NY.

Background: Large numbers of perinatally HIV-infected (PHIV) children are aging into adolescence. We examined cognitive and behavioral outcomes in a longitudinal cohort of Asian youth.

Methods: We followed up 231 PHIV, 125 perinatally HIV-exposed, uninfected (HEU), and 138 HIV-unexposed, uninfected (HUU) adolescents (aged 10 years and older), matched by age/sex, in Thailand and Cambodia for 3 years. Executive function was assessed with Children's Color Trails Tests 1 and 2 (CCTT-1 and -2), the design fluency test, and the verbal fluency test. Working memory (Freedom from Distractibility Index) and processing speed index were assessed using WISC-III. Visual memory was assessed by design memory and design recognition subtests of the Wide Range Assessment of Memory and Learning (WRAML-2) and behavioral problems using the Child Behavior Checklist (CBCL). Generalized estimating equations examined adjusted odds ratios of cognitive impairment (Z-scores ≥2 SD below age-adjusted means of the HUU group) and CBCL T-scores in the borderline-clinical range (T-Scores ≥60) in PHIV and HEU versus HUU youth, adjusting for ethnicity, household income, and caregiver characteristics.

Results: The median age at enrollment was 13.8 years, with 58% women and 63% Thai participants. PHIV youth had >86% virological suppression and significantly higher impairment rates on CCTT-1 and -2 tests, design fluency test, verbal fluency tests, design memory, and CBCL internalizing and externalizing problems. Results were mostly similar between HEU and HUU groups, apart from higher impairment rates on CCTT-1 and internalizing problems in HEU.

Conclusion: Asian adolescents with PHIV remain at risk of cognitive and mental health problems despite HIV treatment. Selective risks are observed among HEU youth.
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http://dx.doi.org/10.1097/QAI.0000000000002132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814288PMC
November 2019

Clinical Presentation of Influenza in Children 6 to 35 Months of Age: Findings From a Randomized Clinical Trial of Inactivated Quadrivalent Influenza Vaccine.

Pediatr Infect Dis J 2019 08;38(8):866-872

Paediatric Institute Mares-Riera, Blanes, Spain.

Background: In an exploratory analysis of an inactivated quadrivalent influenza vaccine (IIV4) trial in children 6-35 months without risk factors for influenza, we evaluated clinical presentation of influenza illness and vaccine impact on health outcomes.

Methods: This phase III trial was conducted in 13 geographically diverse countries across 5 influenza seasons (2011-2014). Children were randomized 1:1 to IIV4 or control. Active surveillance was performed for influenza-like episodes (ILE); influenza was confirmed by reverse transcription polymerase chain reaction (RT-PCR). The total vaccinated cohort was evaluated (N = 12,018).

Results: 5702 children experienced ≥1 ILE; 356 (IIV4 group) and 693 (control group) children had RT-PCR-confirmed influenza. Prevalence of ILE was similar in RT-PCR-positive and RT-PCR-negative cases regardless of vaccination. Breakthrough influenza illness was attenuated in children vaccinated with IIV4; moderate-to-severe illness was 41% less likely to be reported in the IIV4 group than the control group [crude odds ratio: 0.59 (95% confidence intervals: 0.44-0.77)]. Furthermore, fever >39°C was 46% less frequent following vaccination with IIV4 than with control [crude odds ratio: 0.54 (95% confidence intervals: 0.39-0.75)] in children with breakthrough illness. Health outcome analysis showed that, each year, IIV4 would prevent 54 influenza cases per 1000 children and 19 children would need to be vaccinated to prevent 1 new influenza case.

Conclusions: In addition to preventing influenza in 50% of participants, IIV4 attenuated illness severity and disease burden in children who had a breakthrough influenza episode despite vaccination.
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http://dx.doi.org/10.1097/INF.0000000000002387DOI Listing
August 2019

Determinants of Viral Resuppression or Persistent Virologic Failure After Initial Failure With Second-Line Antiretroviral Treatment Among Asian Children and Adolescents With HIV.

J Pediatric Infect Dis Soc 2020 Apr;9(2):253-256

TREAT Asia/amfAR-Foundation for AIDS Research, Bangkok, Thailand.

Of 56 children with perinatally acquired human immunodeficiency virus (HIV) who had been prescribed second-line protease inhibitor-based antiretroviral therapy and had ≥1 previous episode of viral failure (HIV RNA, ≥1000 copies/mL), 46% had ≥1, 34% had ≥2, and 23% had ≥3 consecutive episodes of viral failure during the 2 years of follow-up. Two of these children experienced a major protease inhibitor mutation.
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http://dx.doi.org/10.1093/jpids/piz034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368343PMC
April 2020

CHAMP+ Thailand: Pilot Randomized Control Trial of a Family-Based Psychosocial Intervention for Perinatally HIV-Infected Early Adolescents.

AIDS Patient Care STDS 2019 05;33(5):227-236

1 HIV Center for Clinical and Behavioral Studies, New York State Psychiatric Institute and Columbia University, New York, New York.

Within Asia, HIV prevalence is highest in Thailand, including thousands of children and adolescents. Care for children born with HIV [perinatal transmission of HIV (PHIV)] will need to focus on adolescents for the foreseeable future. Thai PHIV adolescents experience significant mental health and psychosocial challenges, including treatment adherence. Yet, few, if any, comprehensive interventions for them exist. CHAMP+, an evidence-based intervention adapted for Thailand, was evaluated with a pilot randomized control trial at four HIV clinics. Eighty-eight dyads of 9- to 14-year-old PHIV young adolescents/caregivers were randomized to CHAMP+ or standard of care (SOC). Eleven cartoon-based sessions were delivered over 6 months. Participants completed baseline, 6-month (postintervention), and 9-month surveys, measuring youth outcomes (e.g., mental health and adherence), contextual factors (e.g., demographics and caregiver factors), and self- and social-regulation factors (e.g., HIV knowledge and youth-caregiver communication). Multi-level modeling to account for clustering within individuals was used to assess longitudinal changes within and between groups. All families randomized to CHAMP+ completed the intervention. Although the study was not statistically powered to detect differences in treatment effects, the CHAMP+ group significantly improved at 6 months in youth mental health and adherence, HIV knowledge, youth-caregiver communication, internalized stigma, and HIV-related social support, with most improvements sustained at 9 months and significantly better improvements than the SOC group on a number of outcomes. High levels of baseline viral suppression highlight the importance of reaching these young PHIV adolescents at a period of lower risk before adherence and other challenges emerge. Designed to be delivered with limited cost/resources, CHAMP+ Thailand holds scale-up potential.
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http://dx.doi.org/10.1089/apc.2019.0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531900PMC
May 2019

Mapping abnormal subcortical neurodevelopment in a cohort of Thai children with HIV.

Neuroimage Clin 2019 2;23:101810. Epub 2019 Apr 2.

Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA. Electronic address:

Alterations in subcortical brain structures have been reported in adults with HIV and, to a lesser extent, pediatric cohorts. The extent of longitudinal structural abnormalities in children with perinatal HIV infection (PaHIV) remains unclear. We modeled subcortical morphometry from whole brain structural magnetic resonance imaging (1.5 T) scans of 43 Thai children with PaHIV (baseline age = 11.09±2.36 years) and 50 HIV- children (11.26±2.80 years) using volumetric and surface-based shape analyses. The PaHIV sample were randomized to initiate combination antiretroviral treatment (cART) when CD4 counts were 15-24% (immediate: n = 22) or when CD4 < 15% (deferred: n = 21). Follow-up scans were acquired approximately 52 weeks after baseline. Volumetric and shape descriptors capturing local thickness and surface area dilation were defined for the bilateral accumbens, amygdala, putamen, pallidum, thalamus, caudate, and hippocampus. Regression models adjusting for clinical and demographic variables examined between and within group differences in morphometry associated with HIV. We assessed whether baseline CD4 count and cART status or timing associated with brain maturation within the PaHIV group. All models were adjusted for multiple comparisons using the false discovery rate. A pallidal subregion was significantly thinner in children with PaHIV. Regional thickness, surface area, and volume of the pallidum was associated with CD4 count in children with PaHIV. Longitudinal morphometry was not associated with HIV or cART status or timing, however, the trajectory of the left pallidum volume was positively associated with baseline CD4 count. Our findings corroborate reports in adult cohorts demonstrating a high predilection for HIV-mediated abnormalities in the basal ganglia, but suggest the effect of stable PaHIV infection on morphological aspects of brain development may be subtle.
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http://dx.doi.org/10.1016/j.nicl.2019.101810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482384PMC
April 2020

Prevention of vaccine-matched and mismatched influenza in children aged 6-35 months: a multinational randomised trial across five influenza seasons.

Lancet Child Adolesc Health 2018 05 5;2(5):338-349. Epub 2018 Mar 5.

Hospital of Antequera, Malaga, Spain.

Background: Despite the importance of vaccinating children younger than 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. We evaluated efficacy of an inactivated quadrivalent influenza vaccine (IIV4) in children aged 6-35 months.

Methods: In this phase 3, observer-blinded, multinational trial, healthy children from 13 countries in Europe, Central America, and Asia were recruited in five independent cohorts, each in a different influenza season. Participants were randomly assigned (1:1) to either IIV4 (15 μg haemagglutinin antigen per strain per 0·5 mL dose; a single dose on day 0 for vaccine-primed children, and two doses, on days 0 and 28, for vaccine-unprimed children) or to one or two doses of a non-influenza control vaccine. Primary endpoints were moderate-to-severe influenza or all influenza (irrespective of disease severity) confirmed by RT-PCR on nasal swabs. Cultured isolates were further characterised as antigenically matched or mismatched to vaccine strains. Efficacy was assessed in the per-protocol cohort and total vaccinated cohort (time-to-event analysis), and safety was assessed in the total vaccinated cohort.

Findings: Between Oct 1, 2011, and Dec 31, 2014, 12 018 children were recruited into the total vaccinated cohort (6006 children in the IIV4 group and 6012 children in the control group). 356 (6%) children in the IIV4 group and 693 (12%) children in the control group had at least one case of RT-PCR-confirmed influenza. Of these 1049 influenza strains, 138 (13%) were A/H1N1, 529 (50%) were A/H3N2, 69 (7%) were B/Victoria, and 316 (30%) were B/Yamagata. Overall, 539 (64%) of 848 antigenically characterised isolates were vaccine-mismatched (16 [15%] of 105 for A/H1N1; 368 [97%] of 378 for A/H3N2; 54 [86%] of 63 for B/Victoria; 101 [33%] of 302 for B/Yamagata). Vaccine efficacy was 63% (97·5% CI 52-72) against moderate-to-severe influenza and 50% (42-57) against all influenza in the per-protocol cohort, and 64% (53-73) against moderate-to-severe influenza and 50% (42-57) against all influenza in the total vaccinated cohort. There were no clinically meaningful safety differences between IIV4 and control.

Interpretation: IIV4 prevented influenza A and B in children aged 6-35 months despite high levels of vaccine mismatch. Vaccine efficacy was highest against moderate-to-severe disease, which is the most clinically important endpoint associated with greatest burden.

Funding: GlaxoSmithKline Biologicals SA.
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http://dx.doi.org/10.1016/S2352-4642(18)30062-2DOI Listing
May 2018

Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial.

Lancet Child Adolesc Health 2017 Sep 29;1(1):27-34. Epub 2017 Jun 29.

Gilead Sciences, Foster City, CA, USA. Electronic address:

Background: No once-daily single-tablet regimen is available for HIV-infected children under 12 years. The single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a once-daily, integrase strand transfer inhibitor-based regimen approved in the USA and European Union for individuals aged 12 years or older. In this study, we aimed to assess the pharmacokinetics, safety, and efficacy of this regimen in virologically suppressed, HIV-infected children.

Methods: In this single-arm, open-label trial, we enrolled virologically suppressed, HIV-infected children from five hospital clinics in Uganda, the USA, and Thailand. Eligible participants were aged 6-11 years, weighed 25 kg or more, had virological suppression (<50 copies of HIV-1 RNA per mL) on a stable regimen for at least 6 months, CD4 count of more than 100 cells per μL, and no history of resistance to elvitegravir, emtricitabine, tenofovir alafenamide, or tenofovir. All participants received the available fixed-dose oral formulation of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once per day. Primary outcomes were the pharmacokinetic parameters area under the curve (AUC) concentration at the end of the dosing interval (AUC) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUC) of tenofovir alafenamide, treatment-emergent serious adverse events, and all treatment-emergent adverse events. Results from baseline to week 24 are reported, unless specified otherwise. Primary and safety analyses included all enrolled participants who received one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01854775.

Findings: Between July 27 and Sept 28, 2015, we screened 26 children, of whom 23 were enrolled and initiated treatment. Median age was 10 years (IQR 8-11), median weight was 30·5 kg (IQR 27·5-33·0), and all participants had virological suppression. The mean AUC of elvitegravir was 33 814 ng × h/mL (coefficient of variation 58%), and the mean AUC of tenofovir alafenamide was 333 ng × h/mL (45%). Exposures to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were higher, but modestly so, than those previously reported in adults. All 23 participants tolerated the regimen well; there were no serious adverse events or adverse event-related discontinuations. All participants maintained virological suppression (HIV-1 RNA <50 copies per mL) at week 24. CD4 count decreased by a median of -130 cells per μL (range -472 to 266) with little change in CD4 cell percentage (-2·1%, range -8·4 to 5·9).

Interpretation: The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was efficacious and well tolerated in virologically suppressed, HIV-infected children. Although plasma exposure of all components was higher than has been reported in adults, there were no safety concerns and the overall bone and renal safety profile was favourable. These data support the use of this regimen in children at least 25 kg in weight.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-4642(17)30009-3DOI Listing
September 2017

Persistence of hepatitis B immune memory until 9-10 years of age following hepatitis B vaccination at birth and DTaP-IPV-HB-PRP∼T vaccination at 2, 4 and 6 months.

Hum Vaccin Immunother 2018 05 21;14(5):1257-1265. Epub 2018 Feb 21.

f Sanofi Pasteur , Lyon , France.

Objective: To evaluate the long-term persistence of anti-hepatitis B surface (HBs) antibodies and the response to a HB challenge re-vaccination in children who had received a primary series of DTaP-IPV-HB-PRP∼T (Hexaxim™) or DTaP-IPV-HB/PRP∼T (Infanrix hexa™).

Methods: Two cohorts of participants who had previously received HB vaccine at birth followed by either DTaP-IPV-HB-PRP∼T or DTaP-IPV-HB/PRP∼T co-administered with PCV7 at 2, 4, 6 months of age in a randomized, Phase III, observer-blind study in Thailand, were followed up for anti-HBs antibodies (geometric mean concentrations [GMCs] and seroprotection [SP] rate [% of participants with a titer ≥10 mIU/mL]) at 12-18 months of age and 9-10 years of age. A monovalent HB challenge re-vaccination was administered at 9-10 years of age and the anamnestic response was evaluated.

Results: Anti-HBs GMCs and SP rates in the DTaP-IPV-HB-PRP∼T and DTaP-IPV-HB/PRP∼T groups were high and similar post-primary vaccination series (2477 mIU/mL and 99.5% and 2442 mIU/mL and 99.5%, respectively) and declined to a similar extent in each group at 12-18 months (154.5 mIU/mL and 90.8% and 162.3 mIU/mL and 96.5%, respectively). Antibody levels further declined at 9-10 years of age (13.3 mIU/mL and 49.3% and 8.0 mIU/mL and 42.9%) and a strong anamnestic response occurred in each group post-HB challenge re-vaccination (92.8% and 98.7%, respectively).

Conclusion: The kinetics of long-term anti-HBs antibody persistence were similar following a primary series of DTaP-IPV-HB-PRP∼T or DTaP-IPV-HB/PRP∼T. The response to a subsequent HB challenge re-vaccination was strong and similar in each group, demonstrating persisting immune memory.
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http://dx.doi.org/10.1080/21645515.2018.1426418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989896PMC
May 2018

Cognition, Emotional Health, and Immunological Markers in Children With Long-Term Nonprogressive HIV.

J Acquir Immune Defic Syndr 2018 04;77(4):417-426

HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.

Background: HIV-infected children with long-term nonprogressive (LTNP) disease eventually convert to a progressive disease type, yet the extent to which these children experience the cognitive and emotional symptoms observed in typical progressive HIV (Progressors) is unknown.

Methods: Eighty-eight LTNPs, 53 Progressors, and 323 healthy controls completed annual assessments of cognitive and emotional health as part of a prospective study. The 2 HIV-infected groups and the healthy controls were matched on age and sex distribution at enrollment. Plasma HIV RNA, T-cell counts/percentages, activated monocytes, perivascular monocytes, and markers of macrophage activation (sCD163 and sCD14) were compared by progression subtype. Cognitive and emotional outcomes were compared using cross-sectional linear regression analysis and longitudinal sensitivity models.

Results: LTNPs exhibited the same cognitive phenotype and emotional dysregulation as Progressors, with worse outcomes in both groups compared with controls. In addition, cognitive and emotional symptoms were evident before children reached the minimum age for LTNP designation (8 years). Baseline plasma HIV RNA, sCD163, activated monocytes, and perivascular monocytes were lower in LTNPs versus Progressors, with no difference in T-cell counts/percentages or sCD14 levels. Most LTNPs converted to a progressive disease subtype during the study, with similar cognitive and emotion profiles between these subgroups.

Conclusions: Pediatric LTNPs experience cognitive and emotional difficulties that mirror symptoms of progressive disease. The abnormalities are present at young ages and persist independent of plasma T-cell counts. The findings highlight the neurodevelopmental risk of pediatric HIV, even in those with early innate disease control.
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http://dx.doi.org/10.1097/QAI.0000000000001619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825279PMC
April 2018

Structural Neuroimaging and Neuropsychologic Signatures in Children With Vertically Acquired HIV.

Pediatr Infect Dis J 2018 07;37(7):662-668

HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand.

Background: Children with vertically acquired HIV exhibit persistent cognitive impairments, yet the corresponding neuroimaging signature of vertical infection remains unclear.

Methods: Fifty healthy control children and 51 vertically infected children were included in the study. The HIV-infected group consisted of survivors who had not received antiretroviral therapy at birth. The HIV-infected group averaged 11.4 (2.5) years of age, with a median CD4 count of 683 cells/mm(3). Most (71%) of the HIV-infected children were on antiretroviral therapy for a median of 34 months (range: 33-42) with HIV RNA <40 copies/mL in 89% of the sample. The HIV-uninfected group averaged 10.6 (2.6) years of age. Magnetic resonance imaging was acquired to determine volumes of the caudate, putamen, thalamus, pallidum, hippocampus, nucleus accumbens, total white matter, total gray matter and cortical gray matter. Correlational analyses examined the degree of shared variance between brain volumes and both cognitive performances and laboratory markers of disease activity (T cells and plasma viral load).

Results: HIV-infected children exhibited larger volumes of the caudate, nucleus accumbens, total gray matter and cortical gray matter when compared with the controls. Volumetric differences were predominately evident in children under 12 years of age. HIV-infected children performed worse than controls on most neuropsychologic tests, though neither cognitive performances nor laboratory markers corresponded to brain volumes in the HIV-infected children.

Conclusions: Outcomes of the present study suggest abnormal brain maturation among HIV-infected pediatric survivors. Longitudinal studies of brain integrity and related resilience factors are needed to determine the impact of neuroimaging abnormalities on psychosocial function in pediatric HIV.
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http://dx.doi.org/10.1097/INF.0000000000001852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984109PMC
July 2018

Strategies to improve the uptake of effective contraception in perinatally HIV-infected adolescents.

J Virus Erad 2017 Jul 1;3(3):152-156. Epub 2017 Jul 1.

HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand.

Objective: To assess strategies to improve safe-sex practices in sexually active female adolescents living with HIV, through linking reproductive health (RH) care with HIV care.

Methods: A single arm, 48-week prospective study was conducted with 77 sexually active adolescents in five sites in Thailand. Guided RH education was carried out through video, brochures and individual counselling. Participants were offered free effective contraception (EC), in addition to a barrier method (dual contraception) versus barrier method only. Changes in EC use were assessed with McNemar's test; predicting factors with logistic regression.

Results: Median age was 19 years; 95% were perinatally infected; 30% had been pregnant. All but one showed RH-knowledge improvement after RH education. Individual counselling was most often rated the 'most helpful' educational method. At the screening visit 21% were using dual contraception; 53% a male condom only; 8% EC method only; and 18% were not using any contraceptive method. Dual-contraception use improved with time, reaching 74% at week 48. EC-use at the baseline visit was associated with having ever used EC prior to study entry (<0.0001), and the study site (<0.0001). Having ever used EC was associated with a history of pregnancy (=0.0085) and forced sex (=0.0386).

Conclusion: Offering continuous RH care, linked with HIV care, resulted in increased use of dual contraception. Healthcare providers played a significant role in the process. RH education should address the main predictors for EC use by adolescents, including past, personal experience.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518244PMC
July 2017

Treatment Outcomes of Third-line Antiretroviral Regimens in HIV-infected Thai Adolescents.

Pediatr Infect Dis J 2017 Oct;36(10):967-972

From the *The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; †Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ‡Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand; §Nakornping Hospital, Chiang Mai, Thailand; ¶Division of Infectious Diseases, Department of Pediatrics, Khon Kaen University, Khon Kaen, Thailand; ‖Prapokklao Hospital, Chantaburi, Thailand; **Surin Hospital, Surin, Thailand; ††Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; ‡‡The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia; §§Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands; ¶¶Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; and ‖‖The University of Amsterdam, Amsterdam, The Netherlands.

Background: Efficacy and safety data of third-line antiretroviral (ARV) regimens in adolescents are limited.

Methodology: This study enrolled HIV-infected Thais who were treated with third-line regimens consisting of darunavir/ritonavir (DRV/r), etravirine (ETR), tipranavir/ritonavir or raltegravir.

Results: Fifty-four adolescents 2-17 years of age were enrolled from 8 sites and followed for 48 weeks. Reasons for switch were second-line failure (n = 44) and toxicity to second-line regimens (n = 10). At switching to third-line ARV, the median age (interquartile range) was 14.3 (12.4-15.4) years. Genotypes at time of second-line failure (n = 44) were M184V (77%), ≥4 thymidine analogue mutations (25%), non-nucleoside reverse transcriptase inhibitor-resistant associated mutation (RAM) (80%), ETR-RAM score ≥4 (14%), any lopinavir-RAM (59%) and ≥1 major DRV-RAM (41%). The third-line regimens had a median of 4 (min-max, 4-6) drugs and included ETR/DRV/r (43%), DRV/r (33%), ETR (17%), tipranavir/ritonavir (2%) or raltegravir/DRV/r/ (4%). The median CD4 (interquartile range) increased from 16% (12-21) at third-line switch to 21% (18-25) and 410 (172-682) to 607 (428-742) cells/mm at 48 weeks (P < 0.001). HIV RNA declined from 3.9 (2.9-4.9) to 1.6 (1.6-3.0) log10 copies/mL (P < 0.001) and 33/50 (66%) had levels <50 copies/mL at 48 weeks. Seventeen (31%) had HIV-RNA ≥1000 copies/mL; about half due to poor adherence; genotyping in 13 of these adolescents revealed ETR-RAM score ≥4 in 2 (15%) and ≥1 major DRV-RAM in 7 (54%).

Conclusions: Third-line ARV therapy was well tolerated and resulted in virologic suppression in 70% of adolescents at 1 year. Poor adherence and limited ARV options are major problems in the long-term management of adolescents with HIV.
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http://dx.doi.org/10.1097/INF.0000000000001638DOI Listing
October 2017

Carbohydrate, lipid, bone and inflammatory markers in HIV-positive adolescents on antiretroviral therapy and hormonal contraception.

J Virus Erad 2017 Jan 1;3(1):56-60. Epub 2017 Jan 1.

HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand; SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Background: Little is known about the cumulative effect of HIV antiretroviral therapy (ART) and hormonal contraception (HC) on metabolism and inflammation in HIV-positive women.

Methods: We conducted a cross-sectional assessment of markers for carbohydrate, lipid, bone metabolism, inflammation and coagulation in HIV-positive adolescents on ART and HC (=37) versus on ART only (=51) in Thailand. The Wilcoxon rank-sum test was used to assess differences between groups.

Results: The median age was 19.5 years. Most adolescents (95%) were perinatally infected. All were on ART for a median of 9 years. HC used was progestin only (=21); combined oral contraceptive (COC) tablets (=6) for the whole study period or alternating between progestin only and COC (=10). Prevalence of any metabolic abnormalities was 99%. Four biomarkers were significantly higher with HC no HC: insulin (10.3 6.2 μU/mL, =0.002), insulin resistance (1.89 1.19 mass units, =0.005), 25-OH vitamin D (33.2 20.2 ng/mL, <0.0001) and C-terminal telopeptide (690 530 ng/L, =0.011). Triglycerides and D-dimer were significantly lower with HC (103 139 mg/dL, =0.014 and 140 155 ng/mL, =0.003, respectively). There was no relationship between the type of HC or ART and the above differences.

Conclusion: Perinatally infected HIV-positive adolescents on ART in this pilot study had a high prevalence of metabolic abnormalities. Bone turnover markers and insulin resistance were significantly higher with HC. Research on the cumulative effect of HIV, ART and HC on metabolism and inflammation in adolescents with HIV is important in order to devise strategies for preventing and mitigating long-term comorbidities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337422PMC
January 2017

HIV-infected children in the Asia-Pacific region with baseline severe anemia: antiretroviral therapy and outcomes.

Asian Biomed (Res Rev News) 2016 Jun;10(3):229-234

The Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia.

Background: Severe anemia is common among children infected with human immunodeficiency virus (HIV). The choice of antiretroviral (ART) regimen needs careful consideration. No information is available regarding the initial ART regimens used in the Asia-Pacific region and the rate of switch of ART regimens in HIV-infected children with severe anemia.

Objectives: To study the initial ART regimens and the rate of switch of ART regimens used during the first 36 months in HIV-infected children with severe anemia and to evaluate their clinical and laboratory outcomes.

Methods: We analyzed regional cohort data of 130 Asian children aged <18 years with baseline severe anemia (hemoglobin <7.5 g/dl) who started antiretroviral therapy (ART) between January 2003 and September 2013.

Results: At ART initiation, median age was 3.5 years old (interquartile range (IQR) 1.7 to 6.3) and median hemoglobin was 6.7 g/dL (IQR 5.9-7.1, range 3.0-7.4). Initial ART regimens included stavudine (85.4%), zidovudine (13.8%), and abacavir (0.8%). In 81 children with available hemoglobin data after 6 months of ART, 90% recovered from severe anemia with a median hemoglobin of 10.7 g/dL (IQR 9.6-11.7, range 4.4-13.5). Those starting AZT-based ART had a mortality rate of 10.8 (95% confidence interval (CI) 4.8-23.9) per 100 patient-years compared to 2.7 (95% CI 1.6-4.6) per 100 patient-years among those who started d4T-based ART.

Conclusions: With the phase-out of stavudine, age-appropriate non-zidovudine options are needed for younger Asian children with severe anemia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321077PMC
June 2016

Long-term Immunogenicity of a Single Dose of Japanese Encephalitis Chimeric Virus Vaccine in Toddlers and Booster Response 5 Years After Primary Immunization.

Pediatr Infect Dis J 2017 04;36(4):e108-e113

From the *Department of Pediatrics, Srinagarind Hospital, Khon Kaen, Thailand; †Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand; ‡Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; §Research Institute for Tropical Medicine, Muntinlupa City, Philippines; ¶Clinical Sciences Department, Sanofi Pasteur, Marcy l'Etoile, France; and ‖Clinical Sciences and Medical Affairs Asia Department, Sanofi Pasteur, Singapore.

Background: Japanese encephalitis (JE) is an important mosquito-borne viral disease that is endemic in Asia, Western Pacific countries and Northern Australia. Although there is no antiviral treatment, vaccination is effective in preventing this disease.

Methods: We followed a cohort of 596 children for 5 years after primary vaccination at 12-18 months of age with JE chimeric virus vaccine (JE-CV; IMOJEV) in a multicenter, phase III trial in Thailand and the Philippines to assess antibody persistence and safety. At the end of the 5 years, a subgroup of 85 participants, at 1 site in Thailand, was followed after administration of a JE-CV booster vaccination. JE antibody titers were measured annually after primary vaccination and 28 days after booster vaccination using a 50% plaque reduction neutralization test. Seroprotection was defined as a JE-CV neutralizing antibody titer ≥10 (1/dil). Kaplan-Meier survival analysis was used to estimate the proportion of participants maintaining protective JE-CV neutralizing antibody titers.

Results: At 1, 2, 3, 4 and 5 years after vaccination with JE-CV, 88.5%, 82.9%, 78.2%, 74.0% and 68.6% of the participants followed remained seroprotected. Geometric mean titers in the subgroup assessed after receipt of a booster dose increased from 61.2 (95% confidence interval: 43.8-85.7) pre-booster to 4951 (95% confidence interval: 3928-6241) 28 days post-booster, with all participants seroprotected. There were no safety concerns identified.

Conclusions: Protective immune responses persisted for at least 5 years after a JE-CV primary immunization in the majority of participants. JE-CV booster induced a robust immune response even after a 5-year interval.
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http://dx.doi.org/10.1097/INF.0000000000001494DOI Listing
April 2017