Sirintip Sricharoenchai

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

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

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

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

A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial

BACKGROUND Increasing evidence shows that protection induced by acellular pertussis vaccines is short-lived, requiring repeated booster vaccination to control pertussis disease. We aimed to assess the safety and immunogenicity of a recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin and filamentous haemagglutinin, as either a monovalent vaccine (aP[PTgen/FHA]) or in combination with tetanus and reduced-dose diphtheria vaccines (TdaP[PTgen/FHA]), versus a licensed tetanus and reduced-dose diphtheria and acellular pertussis combination vaccine (Tdap). METHODS We did this phase 2/3, randomised controlled non-inferiority trial at two sites in Bangkok, Thailand. Healthy adolescents (aged 12-17 years) were randomly assigned (1:1:1), via a computer-generated randomisation list with block sizes of three, to receive one dose (0·5 mL) of aP(PTgen/FHA), TdaP(PTgen/FHA), or Tdap (comparator). Clinical research staff responsible for participant randomisation, vaccine preparation and administration, and accountability were aware of group allocation. However, allocation was concealed from all other site study staff, data management personnel, statisticians, laboratory staff, and study participants. The primary outcome was non-inferior immunogenicity of TdaP(PTgen/FHA) to Tdap based on seroconversion rates (a four-fold increase or more) for pertussis toxin and filamentous haemagglutinin IgG antibodies 28 days after vaccination, with a predefined 10% margin of equivalence. We did analysis by per protocol. This study is registered with the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS Between July 6 and Aug 20, 2015, we allocated 450 participants to receive one dose of TdaP(PTgen/FHA) (n=150), aP(PTgen/FHA) (n=150), or comparator Tdap (n=150). 28 days after vaccination, seroconversion rates for anti-pertussis toxin IgG were 96·6% (95% CI 93·8-99·5; n=144) in the TdaP(PTgen/FHA) group and 55·0% (47·1-63·0; n=82) in the comparator Tdap group (difference 41·6%, 95% CI 33·1-50·1; p<0·0001). Seroconversion rates for anti-filamentous haemagglutinin were 82·6% (95% CI 76·5-88·6; n=123) in the TdaP(PTgen/FHA) group and 54·4% (46·4-62·4; n=81) in the comparator group (difference 28·2%, 95% CI 18·1-38·2 p<0·0001). 28 days after vaccination, seroconversion rates in the aP(PTgen/FHA) group were 96·0% (95% CI 92·8-99·1; n=142) for anti-pertussis toxin IgG and 93·2% (89·2-97·3; n=138) for anti-filamentous haemagglutinin IgG. These findings support the non-inferior immunogenicity of TdaP(PTgen/FHA) over comparator Tdap. Reactogenicity and incidence of adverse events were similar between groups. INTERPRETATION The new TdaP(PTgen/FHA) vaccine is safe and induces higher pertussis responses 28 days after vaccination than does the available licensed Tdap booster vaccine. Results of our trial led to the licensure of new acellular pertussis vaccines containing genetically inactivated pertussis toxin in Thailand. The availability of recombinant monovalent pertussis vaccines that induce high antibody responses provides the medical community and consumers with the opportunity to vaccinate against pertussis when immunisation against diphtheria and tetanus is not required or not desired. Studies are underway to pave the way for licensure studies of this acellular pertussis vaccine in other countries. FUNDING BioNet-Asia.

Changing trends in serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae causing invasive diseases in Central Thailand, 2009-2012.

To describe the trends in serotype distribution and antimicrobial susceptibility of S. pneumoniae causing invasive pneumococcal diseases (IPD) we tested 238 pneumococci isolates from normally sterile sites between 2009 and 2012 and compared these findings with previous data collected within our network. Serotyping was performed for 15 serotypes contained in the 7-,10-, 13-, and experimental 15-valent pneumococcal conjugate vaccines (PCV). The most common serotypes found were 6B (13.9%), 19A (12.6%), 14 (8.0%), 18C (5.9%), and 6A (3.8%); and 39.9% were non-PCV15 serotypes. One of 81 patients with available data had breakthrough infection with vaccine serotype (19F). There was a significant increase of serotype 19A among children ≤5 years (5.6% in 2000–2009 vs 18.3% in 2009–2012, P = 0.003). The all-age serotype coverage was 36.4%, 41.5%, 59.3%, and 59.7% for PCV7, PCV10, PCV13, and PCV 15, respectively. The corresponding coverage in children ≤5 years were 46.4%, 48.8%, 73.2%, and 73.2% respectively. High susceptibilities to penicillin (89.7%), cefotaxime (95.7%), cefditoren (90.2% by Spanish breakpoints), ofloxacin (97.9%), and levofloxacin (100%), but low to cefdinir (50.0%), cefditoren (45.1% by US-FDA breakpoints), macrolides (<50%), clindamycin (67.7%), tetracycline (41.4%), and trimethoprim-sulfamethoxazole (32.4%) were observed. Serotype 19A was less susceptible to penicillin (80.0 vs 91.2%, P = 0.046), cefditoren (66.7 vs 95.5% by Spanish breakpoints, P = 0.004), and tetracycline (9.1 vs 45.5%, P = 0.024) than non-19A isolates. These data emphasize the need for continued surveillance to monitor changes in serotypes as well as antimicrobial susceptibilities in order to guide strategies for prevention and treatment.

Immunogenicity of a Live Attenuated Chimeric Japanese Encephalitis Vaccine as a Booster Dose After Primary Vaccination With Live Attenuated SA14-14-2 Vaccine: A Phase IV Study in Thai Children.

This single-group study investigated the immunogenicity and safety of a booster dose of the recently licensed live attenuated chimeric Japanese encephalitis vaccine in 50 healthy children (1–5 years old) who were primed with the live attenuated SA14-14-2 vaccine. A strong anamnestic response was induced 28 days postbooster: geometric mean titer, 9144 (95% confidence interval: 7365–11353); and seroprotection rate, 49 of 49 (100%) children.

Vitamin D status in perinatally HIV-infected Thai children receiving antiretroviral therapy.

Abstract Background: Low vitamin D level is associated with adverse health outcomes and compromises HIV treatment response. We assess vitamin D status in HIV-infected Thai children receiving combination antiretroviral therapy (cART). Methods: A cross-sectional study in perinatally HIV-infected children. Vitamin D deficiency and vitamin D insufficiency were defined as serum 25-hydroxyvitamin D (25-OHD) level <20, and 21–29 ng/mL, respectively. Results: Eighty participants were enrolled. Their median age was 12.2 years. The median CD4 lymphocyte count was 784 cell/mm3; 95% had HIV RNA <50 copies/mL. The median (interquartile range, IQR) 25-OHD level was 33.5 (26.2–39.8) ng/mL. Thirty-four (43%) participants had low vitamin D level; 26 (33%) and 8 (10%) had vitamin D insufficiency and deficiency, respectively. In multivariate analysis, only geographic location was significantly associated with low vitamin D level. Conclusions: Most of perinatally HIV-infected children receiving cART had low vitamin D level. Calcium and vitamin D supplement might be beneficial.

Antibody persistence after vaccination of adolescents with monovalent and combined acellular pertussis vaccines containing genetically inactivated pertussis toxin: a phase 2/3 randomised, controlled, non-inferiority trial

BACKGROUND The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. METHODS We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12-17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64-88) participants in the aP(PTgen/FHA) group and 41 (81%, 70-92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1-16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71-93 and 64%, 51-77, respectively) and TdaP(PTgen/FHA) group (75%, 63-87 and 56%, 42-70, respectively) than in the Tdap group (4%, 0-9, p<0·0001, and 28%, 16-41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. INTERPRETATION A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. FUNDING BioNet-Asia.

Risk Factors for Human Papillomavirus Infection and Abnormal Cervical Cytology Among Perinatally Human Immunodeficiency Virus-Infected and Uninfected Asian Youth

Background Infection with high-risk human papillomavirus (HR-HPV) may be higher in perinatally human immunodeficiency virus (HIV)-infected (PHIV) than HIV-uninfected (HU) adolescents because of long-standing immune deficiency. Methods PHIV and HU females aged 12-24 years in Thailand and Vietnam were matched by age group and lifetime sexual partners. At enrollment, blood, cervical, vaginal, anal, and oral samples were obtained for HPV-related testing. The Wilcoxon and Fisher exact tests were used for univariate and logistic regression for multivariate analyses. Results Ninety-three PHIV and 99 HU adolescents (median age 19 [18-20] years) were enrolled (June 2013-July 2015). Among PHIV, 94% were currently receiving antiretroviral therapy, median CD4 count was 593 (392-808) cells/mm3, and 62% had a viral load <40 copies/mL. Across anogenital compartments, PHIV had higher rates of any HPV detected (80% vs 60%; P = .003) and any HR-HPV (60% vs 43%, P = .02). Higher proportions of PHIV had abnormal Pap smears (eg, atypical squamous cells of unknown significance [ASC-US], 12% vs 14%; low-grade squamous intraepithelial neoplastic lesions, 19% vs 1%). After adjusting for ever being pregnant and asymptomatic sexually transmitted infections (STI) at enrollment, PHIV were more likely to have HR-HPV than HU (odds ratio, 2.02; 95% confidence interval, 1.09-3.77; P = .03). Conclusions Perinatal HIV infection was associated with a higher risk of HR-HPV and abnormal cervical cytology. Our results underscore the need for HPV vaccination for PHIV adolescents and for prevention and screening programs for HPV and other STIs.

Metabolic Disorders in HIV-Infected Adolescents Receiving Protease Inhibitors

Protease inhibitor (PI) may cause abnormal glucose metabolism, abnormal lipid metabolism, and metabolic syndrome in HIV-infected adults but less well studied in Asian adolescents. This cross-sectional study evaluated anthropometric factors, oral glucose tolerance test, and lipid profiles of perinatally HIV-infected Thai adolescents who had received PI-based antiretroviral therapy for at least 6 months. Eighty adolescents were enrolled [median (IQR) age 16.7 (14.6–18.0) years, 42 males]. Metabolic syndrome, prediabetes, and type 2 diabetes mellitus (T2DM) were found in 8 (10%), 17 (22.1%), and 3 (3.8%) adolescents, respectively. Dyslipidemia was found in 56 (70%) adolescents, with hypertriglyceridemia being the most common type. In multivariate analysis, presence of lipohypertrophy (OR: 25.7, 95% CI: 3.2–202.8; p = 0.002) and longer duration of PI use (OR: 1.04, 95% CI: 1.00–1.08; p = 0.023) were associated with metabolic syndrome. Obesity (OR: 7.71, 95% CI: 1.36–43.7; p = 0.021), presence of lipohypertrophy (OR: 62.9, 95% CI: 4.97–795.6; p = 0.001), and exposure to stavudine for ≥6 months (OR: 8.18, 95% CI: 1.37–48.7; p = 0.021) were associated with prediabetes/T2DM, while exposure to tenofovir for ≥6 months reduced the risk (OR: 0.17, 95% CI: 0.04–0.78; p = 0.022). Metabolic disorders were commonly found in adolescents receiving PI. Careful monitoring and early intervention to modify cardiovascular risk should be systematically implemented in this population particularly those with exposure to stavudine.