Meta-analysis and cost-effectiveness analysis of intranasal corticosteroid treatment in allergic rhinitis with ocular symptoms.

BACKGROUND: Intranasal corticosteroid (INCS) has a beneficial effect on ocular symptoms in allergic rhinitis (AR). To our knowledge, the cost-effectiveness of available INCS for AR with ocular symptoms is yet to be demonstrated. OBJECTIVE: To evaluate the cost-effectiveness of INCSs including Budesonide (BANS), Mometasone furoate (MFNS), Triamcinolone (TANS), and Fluticasone furoate (FFNS) on ocular symptoms associated with AR in the Thai context. METHODS: The percentage of effectiveness in improving total ocular symptoms score (TOSS) was derived from the result of a meta-analysis that estimated the SMD of each INCS treatment compared to placebo as clinical input parameters. A cost-effectiveness analysis based on a decision-tree model to assess one-year costs and outcomes from a Thai societal perspective. The outcomes were to compare incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analyses (PSA) were also conducted to capture parameter uncertainties. RESULTS: 13 eligible RCTs with a total of 3,722 patients with SAR were included in the analysis. The percentage of effectiveness of FFNS, MFNS, TANS, and BANS was 59.89%, 45.60%, 24.89%, and 16.00%, respectively. The ICER of FFNS, MFNS, and TANS is THB-6,539.92, 4,593.83, and 1,401.24 compared to BANS. CECA result showed the probability of using FFNS is considered cost-effective in 87.50% of cases from zero value followed by MFNS (0.80%), TANS (5.40%), and BANS (6.30%). With a threshold greater than THB20,000, FFNS is considered a cost-effective strategy. CONCLUSIONS: FFNS is a cost-effective option compared to alternative INCSs in Thailand for treating AR with ocular symptoms.

Pharmacogenetics-based population pharmacokinetic analysis for dose optimization of ritonavir-boosted atazanavir in Thai adult HIV-infected patients.

BACKGROUND: This population pharmacokinetic-pharmacogenetic study aimed to investigate the optimal dose of RTV-boosted ATV (ATV/RTV) for Thai adult HIV-infected patients. METHODS: A total of 1460 concentrations of ATV and RTV from 544 patients receiving an ATV/RTV-based regimen were analyzed. The CYP3A5 6986 A > G, ABCB1 3435 C > T, ABCB1 2677 G > T, SLCO1B1 521 T > C, and NR1I2 63396 C > T were genotyped. A population pharmacokinetic model was performed using a nonlinear mixed-effect model (NONMEM®). Monte Carlo simulations were conducted to compare the percentages of patients achieving the therapeutic range of ATV through concentrations (Ctrough). RESULTS: The apparent oral clearance of ATV (CL/FATV) without RTV was 7.69 L/h with interindividual variability (IIV) of 28.7%. Patients with CYP3A5 6986 GG had a 7.1% lower CL/FATV than those with AA or AG genotype. The CL/FATV decreased by 10.8% for females compared with males. Simulation results showed higher percentages (~70%) of patient receiving doses of 200/100 or 200/50 mg achieved the target ATV Ctrough, while more patients (~40%) receiving a standard dose (300/100 mg) had ATV Ctrough above this target. CONCLUSIONS: Both CYP3A5 6986 A > G and female decreased CL/FATV in Thai HIV-infected patients. Simulations supported that the reduced dose of ATV/RTV was sufficient to achieve the target concentration for Thai population.

Direct healthcare cost comparison of Fluticasone propionate/Salmeterol vs Budesonide/Formoterol Maintenance And Reliever Therapy for moderate/severe asthma: Results from Thailand.

BACKGROUND: Inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) for moderate/severe asthma i.e. regular Fluticasone propionate/Salmeterol (FP/Salm) with as-needed short acting beta-2 agonist (SABA) or ICS/Formoterol Maintenance And Reliever Therapy (MART) are the recommended options. OBJECTIVE: To compare healthcare cost between regular FP/Salm with as-needed SABA vs MART in Thailand. METHODS: Direct healthcare cost data from 3 published randomized trials in asthma patients aged ≥12 years comparing regular twice-daily FP/Salm with as-needed SABA vs Budesonide/Formoterol (BUD/Form) MART in moderate/severe asthma were considered: AHEAD (NCT00242775/17 countries/2309 patients), COMPASS (AstraZeneca study SD-0390735/16 countries/3335 patients), and COSMOS (AstraZeneca study SD-039-0691/16 countries/2143 patients). Total direct treatment cost comparison/patient/year was calculated as a combination from 1) medication costs plus 2) healthcare utilization costs i.e. cost for health care visit, emergency room visit, and hospitalization. Unit costs referred from National drug information and Health Intervention and Technology Assessment (HITAP), Ministry of Public Health. RESULTS: Annual medication costs of FP/Salm + SABA were lower than MART in all studies with average cost as 182.01 vs 347.21 USD. Average annual healthcare utilization costs were 17.51 vs 13.01 USD in FP/Salm + SABA and MART, respectively. In overall, total direct treatment costs/patient/year with FP/Salm was 199.53 vs 360.22 USD of MART. Percent saving of total direct treatment costs by FP/Salm + SABA was 45% lower than with MART. CONCLUSIONS: In moderate/severe asthma patients, total direct treatment costs with regular twice-daily FP/Salm with as-needed SABA were lower than with BUD/Form MART primarily due to lower medication costs. Healthcare cost should be considered for asthma care in Thailand.

Impact of Vitamin D and Calcium Supplementation on Bone Mineral Density and Bone Metabolism Among Thai Adolescents With Perinatally Acquired Human Immunodeficiency Virus (HIV) Infection: A Randomized Clinical Trial.

BACKGROUND: To evaluate the impact of vitamin D and calcium supplementation (VitD/Ca) on lumbar spine bone mineral density (LSBMD) and bone metabolism among Thai adolescents with perinatally acquired HIV (PHIVA). METHODS: A multicenter, randomized, active-control, open-labeled trial was conducted. PHIVA (aged 10-20 years) who were on stable cART were enrolled. Baseline LSBMD status was defined as low (z-score ≤ -2) and normal (> -2). Eligible PHIVA were randomly assigned to receive standard-dose (400 IU/1200 mg/day) or high-dose (400 IU/1200 mg/day plus ergocalciferol 20 000 IU/week) VitD/Ca supplementation for 48 weeks (ratio 1:1, stratified by baseline LSBMD). Study outcomes were changes in LSBMD, LSBMD z-scores, and bone metabolism-related biomarkers (25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone [iPTH], C-terminal telopeptide [CTX], procollagen type I amino-terminal propeptide [PINP]) from baseline to week 48. RESULTS: Among 200 enrolled PHIVA, median age was 16 (IQR:14-18) years; 61% were on NNRTI-based cART. Median 25(OH)D level was 25.5 (IQR: 20.8-33.0) ng/mL. After 48-week VitD/Ca supplementation, LSBMD significantly increased in both treatment groups (high-dose: median: +0.07 [IQR: +0.04 to +0.11] g/cm2; P < .001; standard-dose: +0.09 [+0.03 to +0.13] g/cm2; P < .001). Notably, the change in LSBMD z-scores was significantly greater in high-dose versus standard-dose groups (median: +0.4 [IQR: -0.1 to +0.9] vs +0.1 [-0.4 to +0.7]; P = .02). Levels of 25(OH)D increased, whereas iPTH, CTX, and PINP declined significantly in both groups (P < .05), but no between-group differences were demonstrated. CONCLUSIONS: Over 48-week VitD/Ca supplementation, significant increases in LSBMD, and significant decreases in bone metabolism-related markers were observed among our Thai PHIVA in both treatment groups. The improvement in LSBMD z-score was more enhanced with high-dose VitD/Ca supplementation than standard-dose. High-dose VitD/Ca supplementation might be considered to promote bone health in this population. CLINICAL TRIALS REGISTRATION: NCT02426840.

Impact of low-level viraemia on virological failure among Asian children with perinatally acquired HIV on first-line combination antiretroviral treatment: a multicentre, retrospective cohort study.

INTRODUCTION: The clinical relevance of low-level viraemia (LLV) and virological outcomes among children living with HIV (CLHIV) remains controversial. This study aimed to determine the impact of LLV on virological failure (VF) among Asian CLHIV on first-line combination antiretroviral therapy (cART). METHODS: CLHIV aged <18 years, who were on first-line cART for ≥12 months, and had virological suppression (two consecutive plasma viral load [pVL] <50 copies/mL) were included. Those who started treatment with mono/dual antiretroviral therapy, had a history of treatment interruption >14 days, or received treatment and care at sites with a pVL lower limit of detection >50 copies/mL were excluded. LLV was defined as a pVL 50 to 1000 copies/mL, and VF as a single pVL >1000 copies/mL. Baseline was the time of the second pVL < 50 copies/mL. Cox proportional hazards models were performed to assess the association between LLV and VF. RESULTS: From January 2008 to September 2016, 508 CLHIV (55% female) were eligible for the study. At baseline, the median age was 9.6 (IQR: 7.0 to 12.3) years, cART duration was 1.4 (IQR: 1.3 to 1.8) years, 97% of CLHIV were on non-nucleoside reverse transcriptase inhibitor-based regimens, and the median CD4 was 25% (IQR: 20% to 30%). Over a median follow-up time of 6.0 (IQR: 3.1 to 8.9) years from baseline, 86 CLHIV (17%) had ever experienced LLV, of whom 32 (37%) had multiple LLV episodes. Female sex, living in Malaysia (compared to Cambodia), having family members other than biological parents/grandparents as a primary caregiver, and baseline CD4 < 25% increased risk of LLV. Overall, 115 children (23%) developed VF, corresponding to a rate of 4.0 (95%CI: 3.4 to 4.9) per 100 person-years of follow-up (PYFU). VF was greater among children who had ever experienced LLV compared with those who maintained virological suppression throughout the study period (8.9 vs. 3.3 per 100 PYFU; p < 0.001). In multivariable analyses, ever experiencing LLV was associated with increased risk of subsequent VF (adjusted hazard ratio: 3.01; 95%CI: 1.97 to 4.60). CONCLUSIONS: LLV increased the risk of subsequent VF among Asian CLHIV who had previously been suppressed on first-line cART. Adherence interventions and additional targeted pVL monitoring may be warranted among children with LLV to facilitate early detection of VF.

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

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.

A survey of management practices in coexistent allergic rhinitis and asthma (Asia-pacific Survey of Physicians on Asthma and allergic Rhinitis): results from Thailand.

BACKGROUND: Underdiagnosis and undertreatment of allergic rhinitis (AR) in patients with asthma can worsen treatment outcomes. There is limited evidence of clinical practices for management of coexistent AR-asthma in Thailand. METHODS: A multicountry, cross-sectional study (Asia-pacific Survey of Physicians on Asthma and allergic Rhinitis) to evaluate physician perceptions and management practices related to AR-asthma overlap in 6 Asian countries was conducted. For Thailand specifically, AR-asthma linkage questionnaires were developed and translated to Thailaland. General physicians (GPs) or pediatricians, randomly selected from hospitals in urban cities, routinely treating >10 asthma patients/month were interviewed. Here we present the results for Thailand. RESULTS: Two hundred physicians (100 GPs and 100 pediatricians), of whom 70% worked in government hospitals, were interviewed. In their experience, 50% of asthma patients had AR and 28% of AR patients had asthma. Among diagnosed asthma patients, 65% of physicians routinely asked for any AR symptoms at every visit. Among diagnosed AR patients, 63% of physicians routinely asked for any asthma symptoms at every visit. In patients with coexisting AR-asthma, 91% of physicians treated both diseases simultaneously, while 6% of physicians treated asthma as a chronic disease but managed AR symptomatically. The most preferred treatment options for patients with AR-asthma were inhaled corticosteroids with intranasal steroids (46% in GPs, 71% in pediatricians). CONCLUSION: The physicians interviewed in Thailand are aware about coexistent asthma-AR. There is a need to increase the awareness further for coexistent AR-asthma and to educate nonspecialist physicians in the proper management of AR-asthma patients.

Impact of the frequency of plasma viral load monitoring on treatment outcomes among children with perinatally acquired HIV.

INTRODUCTION: Recommendations on the optimal frequency of plasma viral load (pVL) monitoring in children living with HIV (CLWH) who are stable on combination antiretroviral therapy (cART) are inconsistent. This study aimed to determine the impact of annual versus semi-annual pVL monitoring on treatment outcomes in Asian CLWH. METHODS: Data on children with perinatally acquired HIV aged <18 years on first-line, non-nucleoside reverse transcriptase inhibitor-based cART with viral suppression (two consecutive pVL <400 copies/mL over a six-month period) were included from a regional cohort study; those exposed to prior mono- or dual antiretroviral treatment were excluded. Frequency of pVL monitoring was determined at the site-level based on the median rate of pVL measurement: annual 0.75 to 1.5, and semi-annual >1.5 tests/patient/year. Treatment failure was defined as virologic failure (two consecutive pVL >1000 copies/mL), change of antiretroviral drug class, or death. Baseline was the date of the second consecutive pVL <400 copies/mL. Competing risk regression models were used to identify predictors of treatment failure. RESULTS: During January 2008 to March 2015, there were 1220 eligible children from 10 sites that performed at least annual pVL monitoring, 1042 (85%) and 178 (15%) were from sites performing annual (n = 6) and semi-annual pVL monitoring (n = 4) respectively. Pre-cART, 675 children (55%) had World Health Organization clinical stage 3 or 4, the median nadir CD4 percentage was 9%, and the median pVL was 5.2 log10 copies/mL. At baseline, the median age was 9.2 years, 64% were on nevirapine-based regimens, the median cART duration was 1.6 years, and the median CD4 percentage was 26%. Over the follow-up period, 258 (25%) CLWH with annual and 40 (23%) with semi-annual pVL monitoring developed treatment failure, corresponding to incidence rates of 5.4 (95% CI: 4.8 to 6.1) and 4.3 (95% CI: 3.1 to 5.8) per 100 patient-years of follow-up respectively (p = 0.27). In multivariable analyses, the frequency of pVL monitoring was not associated with treatment failure (adjusted hazard ratio: 1.12; 95% CI: 0.80 to 1.59). CONCLUSIONS: Annual compared to semi-annual pVL monitoring was not associated with an increased risk of treatment failure in our cohort of virally suppressed children with perinatally acquired HIV on first-line NNRTI-based cART.

Validation of a self-report adherence measurement tool among a multinational cohort of children living with HIV in Kenya, South Africa and Thailand.

INTRODUCTION: There are few data on adherence and low-cost measurement tools for children living with HIV. We collected prospective data on adherence to antiretroviral therapy (ART) among a multinational cohort of children to evaluate an adherence questionnaire. METHODS: We enrolled 319 children ages 0 to 16 years on ART in Kenya (n = 110), South Africa (n = 109) or Thailand (n = 100). Children were followed up for six months of adherence monitoring between March 2015 and August 2016 using Medication Event Monitoring Systems (MEMS® ) with at least one viral load measure. At month 3 and 6, children or their caregivers were administered a 10-item adherence questionnaire. Repeated measures analyses were used to compare responses on questionnaire items to external adherence criteria: MEMS® dichotomized adherence (≥90% of doses taken vs. <90%), 48-hour MEMS® treatment interruptions and viral suppression (<1000 copies/mL). Items associated with outcomes (p < 0.10) were coefficient-weighted to calculate a total adherence score, which was tested in multivariate regression against MEMS® and viral suppression outcomes. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. RESULTS: Mean child age was 11 years and 54% were female. Children from Thailand (median age 14 years) were significantly older compared to Kenya (10 years) and South Africa (10 years). Prevalence of viral suppression was 97% in Thailand, 81% in South Africa and 69% in Kenya, while the prevalence of MEMS® adherence ≥90% was 57% in Thailand, 58% in South Africa and 40% in Kenya. Across sites, child-reported adherence using the questionnaire was significantly associated with dichotomized MEMS® adherence (OR 1.8, 95% CI 1.4 to 2.4), 48-hour treatment interruptions (OR 0.41, 95% CI 0.3 to 0.6), and viral suppression (OR 3.4, 95% CI 1.7 to 6.7). We did find, however, that different cut-points for the adherence score may be context-specific. For example, MEMS® non-adherent children in Kenya had a lower adherence score (0.98) compared to South Africa (1.77) or Thailand (1.58). CONCLUSIONS: We found suboptimal adherence to ART was common by multiple measures in this multi-country cohort of children. The short-form questionnaire demonstrated reasonable validity to screen for non-adherence in these diverse settings.

Influence of CYP3A5 and SLCO1B1 polymorphisms on atazanavir/r concentrations in Thai HIV-infected patients.

Aim: To evaluate the influence of genetic polymorphisms on plasma trough concentrations of atazanavir (ATV) and ritonavir (RTV). Patients & methods: The concentration-to-dose ratios were compared between different genotype groups of CYP3A5, ABCB1, SLCO1B1 and NR1I2 in 490 patients. Multiple regression analysis was used to examine the association between genetic and clinical factors and log-transformed concentration-to-dose ratio of ATV and RTV. Results: Higher concentrations of ATV and RTV were significantly associated with CYP3A5 6986 GG and SLCO1B1 521 TC or CC. Female patients had significantly higher ATV plasma concentration than male patients. Conclusion: Genetic polymorphisms and gender are factors affecting the variability of ATV and RTV concentrations in the Thai population. Thus, genetic testing is worth considering when atazanavir + low dose ritonavir is prescribed.

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

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.

Early and Late Virologic Failure After Virologic Suppression in HIV-Infected Asian Children and Adolescents.

BACKGROUND: Virologic failure is a major threat to maintaining effective combination antiretroviral therapy, especially for children in need of lifelong treatment. With efforts to expand access to HIV viral load testing, our understanding of pediatric virologic failure is evolving. SETTING: An Asian cohort in 16 pediatric HIV services across 6 countries. METHODS: From 2005 to 2014, patients younger than 20 years who achieved virologic suppression and had subsequent viral load testing were included. Early virologic failure was defined as a HIV RNA ≥1000 copies per milliliter within 12 months of virologic suppression, and late virologic as a HIV RNA ≥1000 copies per milliliter after 12 months following virologic suppression. Characteristics at combination antiretroviral therapy initiation and virologic suppression were described, and a competing risk time-to-event analysis was used to determine cumulative incidence of virologic failure and factors at virologic suppression associated with early and late virologic failure. RESULTS: Of 1105 included in the analysis, 182 (17.9%) experienced virologic failure. The median age at virologic suppression was 6.9 years, and the median time to virologic failure was 24.6 months after virologic suppression. The incidence rate for a first virologic failure event was 3.3 per 100 person-years. Factors at virologic suppression associated with late virologic failure included older age, mostly rural clinic setting, tuberculosis, protease inhibitor-based regimens, and early virologic failure. No risk factors were identified for early virologic failure. CONCLUSIONS: Around 1 in 5 experienced virologic failure in our cohort after achieving virologic suppression. Targeted interventions to manage complex treatment scenarios, including adolescents, tuberculosis coinfection, and those with poor virologic control are required.

A Qualitative Exploration of Psychosocial Challenges of Perinatally HIV-Infected Adolescents and Families in Bangkok, Thailand.

Thailand has the highest HIV prevalence in Asia, with 9,600 HIV+ adolescents and thousands additional younger HIV+ children (World Bank, 2015; UNICEF, 2015). Studies from other settings suggest perinatally HIV-infected (PHIV+) adolescents are at high risk for mental health problems and engagement in risk behaviors that threaten individual and public health. Yet, few studies exist in Thailand, and few evidence-based psychosocial interventions have been developed for and studied in this population, despite great need. The current study qualitatively explored psychosocial issues among Thai PHIV+ adolescents to inform development or adaptation of interventions. Thai and US-based researchers and clinicians conducted two focus group discussions with PHIV+ adolescents aged 12-16 and their adult caregivers, and six in-depth key informant interviews with health/social work providers at a large clinic for PHIV+ youth in Bangkok, Thailand. Data were analyzed thematically using framework analysis. Multiple challenges for PHIV+ youth and caregivers were identified. Adherence to antiretroviral treatment was a significant challenge attributed to lack of adult support, side effects, feeling too well to take medicines, and avoiding acknowledging sickness. Poor child-caregiver communication and conflict was a key concern, explained in part by cultural expectation of obedience and generation gaps. Concerns about societal stigma and discrimination emerged strongly and influenced delay or avoidance of disclosing HIV status to children and others. Respondents identified positive approaches to addressing these issues and highlighted the need for interventions to improve child-caregiver communication and generate peer and community support for PHIV+ youth. Thai PHIV+ adolescents and families experience significant psychosocial challenges, similar to those seen in other contexts. Cultural adaptation of an existing evidence-based clinic-based family group intervention is recommended to rapidly address these needs.

Seroprevalence of Hepatitis B Among HIV-infected Children and Adolescents Receiving Antiretroviral Therapy in the TREAT Asia Pediatric HIV Observational Database.

BACKGROUND: Hepatitis B (HBV)-HIV coinfection is associated with liver inflammation, which can progress to liver fibrosis/cirrhosis and hepatocellular carcinoma. We determined HBV seroprevalence in children and adolescents participating in the TREAT Asia Pediatric HIV Observational Database. METHODS: A multisite cross-sectional study was conducted in HIV-infected patients currently <25 years old receiving antiretroviral treatment (ART) who had HBV surface antigen (HBsAg), or HBV surface antibody (anti-HBs) or HBV core antibody (anti-HBc) tested during 2012-2013. HBV coinfection was defined as having either a positive HBsAg test or being anti-HBc positive and anti-HBs negative, reflective of past HBV infection. HBV seroprotection was defined as having a positive anti-HBs test. RESULTS: A total of 3380 patients from 6 countries (Vietnam, Thailand, Cambodia, Malaysia, Indonesia and India) were included. The current median (interquartile range) age was 11.2 (7.8-15.1) years. Of the 2755 patients (81.5%) with HBsAg testing, 130 (4.7%) were positive. Of 1558 (46%) with anti-HBc testing, 77 (4.9%) were positive. Thirteen of 1037 patients with all 3 tests were anti-HBc positive and HBsAg and anti-HBs negative. One child was positive for anti-HBc and negative for anti-HBs but did not have HBsAg tested. The prevalence of HBV coinfection was 144/2759 (5.2%) (95% confidence interval: 4.4-6.1). Of 1093 patients (32%) with anti-HBs testing, 257 (23.5%; confidence interval: 21.0-26.0) had positive tests representing HBV seroprotection. CONCLUSIONS: The estimated prevalence of HBV coinfection in this cohort of Asian HIV-infected children and adolescents on ART was 5.2%. The majority of children and adolescents tested in this cohort (76.5%) did not have protective HBV antibody. The finding supports HBV screening of HIV-infected children and adolescents to guide revaccination, the use of ART with anti-HBV activity and future monitoring.

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial.

BACKGROUND: Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS: BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS: Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/µL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS: Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION: EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016.

Effect of calcium and vitamin D supplementation on bone mineral accrual among HIV-infected Thai adolescents with low bone mineral density.

Background: The benefits of calcium and vitamin D supplementation for low bone mass remains controversial. This study assessed the changes in bone mineral density (BMD) during periods without and with calcium and vitamin D supplementation among HIV-infected adolescents with low BMD. Method: Perinatally HIV-infected Thai adolescents aged 12-20 years were enrolled into Phase 1 (pre-supplementation) to evaluate longitudinal change of BMD. We provided education about appropriate dietary intake and exercise. Lumbar spine (L2-L4) BMD and vitamin D status (25-hydroxyvitamin D [25(OH)D]) were assessed at baseline and at 12-24 month intervals. Participants with a BMD Z-score≤-2 were enrolled into Phase 2 (supplementation) that provided calcium 600 mg plus cholecalciferol 200 IU twice daily for 6 months. BMD and 25(OH)D were re-assessed at the end of study. Results: Ninety-four participants were enrolled into the Phase 1. Median age (IQR) was 14.3 (13.0-15.5) years, with 67% at Tanner stage 3-5, 89% with a plasma HIV-1 RNA<50 copies/mL. During Phase 1 and a 22.7-month follow-up, median L2-L4 BMD Z-scores remained unchanged (-1.06 vs -1.08, P=0.08), but 25(OH)D levels increased (24.7 vs 26.7 ng/mL, P=0.01). Twenty-six (28%) adolescents had low BMD and were enrolled into Phase 2, with 24 (92%) completing follow-up. The median L2-L4 BMD Z-scores (-2.59 vs -1.70; P<0.001) and calcium level (9.3 vs 9.5 mg/dL, P=0.04) significantly improved. There was an increase in BMD Z-scores during the 6-months post-supplementation as compared to the 21-month pre-supplementation period (0.65 vs -0.50, P=0.03). Conclusion: HIV-infected adolescents with low BMD had improved bone health after calcium and vitamin D supplementation. A randomised controlled trial is warranted to confirm the benefits of these supplements.

Pharmacokinetics of rilpivirine and 24-week outcomes after switching from efavirenz in virologically suppressed HIV-1-infected adolescents.

BACKGROUND: Rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor drug, could be a favourable drug for maintenance therapy in HIV-infected adolescents because it has few long-term side effects. However, data among adolescents switching from efavirenz (EFV) to RPV are limited. This study investigated the pharmacokinetics (PK), safety and efficacy of RPV in virologically suppressed HIV-1-infected adolescents after switching from EFV. METHODS: Adolescents aged 12-18 years on EFV-based antiretroviral therapy (ART) were switched from EFV to RPV (25 mg, once daily). Intensive 24-h blood samplings at 0 (pre-dose), 1, 2, 4, 5, 6, 9, 12 and 24 h were performed 4 weeks after switching. PK parameters were calculated using a non-compartmental method and compared with published data from the PAINT and pooled ECHO/THRIVE substudies. HIV RNA level was measured at weeks 12 and 24. Biochemical profiles were measured at baseline and week 24. RESULTS: From January to June 2016, 20 adolescents (12 male) were enrolled. Median (IQR) age was 16 (15-17) years and weight was 49 (42-59) kg. Mean (sd) AUC24 h, C24 h and Cmax of RPV were 2,041 (745) ng•h/ml, 69 (29) ng/ml and 143 (65) ng/ml, respectively. Median (IQR) Tmax was 5 (2-9) h. Four adolescents had C24 h <40 ng/ml. All PK parameters were comparable with published data. All adolescents remained virologically suppressed at week 24. Significant decreases in fasting total cholesterol, triglyceride and low-density lipoprotein were observed (P-value <0.05). CONCLUSIONS: Virologically suppressed HIV-infected adolescents had adequate RPV exposure and remained virologically suppressed after switching from EFV. RPV can be used as long-term maintenance ART in HIV-infected adolescents.

Prevalence of Persistent Renal Dysfunction in Perinatally HIV-infected Thai Adolescents.

BACKGROUND: Persistent renal dysfunction (PRD) has been reported in up to 22% of perinatally HIV-infected adolescents (PHAs) in the United States and Europe. There are limited data available on PRD among PHAs in resource-limited settings regarding access to antiretroviral therapy (ART) at more advanced HIV stages. METHODS: We retrospectively described the prevalence of PRD and associated factors in a Thai PHA cohort. Inclusion criteria were current age ≥10 years old and at least 2 serum creatinine (Cr) measurements after ART initiation. Cr and urine examination were performed every 6-12 months. PRD was defined as having ≥2 measurements of low estimated glomerular filtration rate (eGFR); either <60 mL/min/1.73 m2 or elevated Cr for age and eGFR 60-89 mL/min/1.73 m2, or proteinuria (dipstick proteinuria ≥1+). Factors associated with PRD were analyzed using a multivariate logistic regression analysis. RESULTS: This study included 255 PHAs with median (interquartile range) age of 16.7 (14.5-18.8) and ART duration of 10.3 (7.1-12.4) years. Fifty-six percentage used boosted protease inhibitor (bPI)-based regimens, and 63% used tenofovir disoproxil fumarate (TDF). The overall PRD prevalence was 14.1% [95% confidence interval (CI): 10.1-19.0]; low eGFR 6.7%, proteinuria 3.5% and both 3.9%. Among 109 users of TDF with bPI, 22.9% had PRD and 2.8% discontinued/adjusted dosing of TDF because of nephrotoxicity. Factors associated with PRD were age 10-15 years old (adjusted odd ratio (aOR): 10.1, 95% CI: 4.1-25.2), male (aOR: 3.2, 95% CI: 1.4-7.7), CD4 nadir <150 cells/mm (aOR: 2.6, 95% CI: 1.1-6.1) and use of TDF with bPI (aOR: 9.6, 95% CI: 3.2-28.9). CONCLUSIONS: PRD is common among PHAs. Almost one-fifth of adolescents using TDF with bPI had PRD. These adolescents should be a priority group for renal monitoring.

Cultural Adaptation of an Evidence-Informed Psychosocial Intervention to Address the Needs of PHIV+ Youth in Thailand.

Globally, pediatric HIV has largely become an adolescent epidemic. Thailand has the highest HIV prevalence in Asia (1.2%), with more than 14,000 children living with HIV. There is growing demand for evidence-based psychosocial interventions for this population that include health and mental health support and sexual risk reduction, which can be integrated into HIV care systems. To address this need, a multidisciplinary team of Thai and US researchers adapted an existing evidence-informed, family-based intervention, The Collaborative HIV Prevention and Adolescent Mental Health Program + (CHAMP+), which has been tested in multiple global trials. Using community-based participatory research methods, changes to the intervention curriculum were made to address language, culture, and Thai family life. Involvement of families, youth, and stakeholders in the adaptation process allowed for identification of salient issues and of program delivery methods that would increase engagement. Participants endorsed using a cartoon-based curriculum format for fostering discussion (as in CHAMP+ South Africa) given stigma around discussing HIV in the Thai context. The Thai version of CHAMP+ retained much of the curriculum content incorporating culturally appropriate metaphors and story line. Sessions focus on family communication, coping, disclosure, stigma, social support, and HIV education. This paper explores lessons learned through the adaption process of CHAMP+ Thailand that are applicable to other interventions and settings. It discusses how culturally informed adaptations can be made to interventions while maintaining core program components.

Multicentre analysis of second-line antiretroviral treatment in HIV-infected children: adolescents at high risk of failure.

INTRODUCTION: The number of HIV-infected children and adolescents requiring second-line antiretroviral treatment (ART) is increasing in low- and middle-income countries (LMIC). However, the effectiveness of paediatric second-line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second-line ART outcomes for children and assessed the need for paediatric third-line ART. METHODS: We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second-line ART in LMIC, contacting the corresponding study groups and including patient-level data on virologic and clinical outcomes. Kaplan-Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second-line treatment. RESULTS: We included 12 cohorts representing 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9-19.4) of children experienced virologic failure. Adolescents (10-18 years) had failure rates of 14.5 (95% CI 11.9-17.6) per 100 person-years compared to 4.5 (95% CI 3.4-5.8) for younger children (3-9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first-line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24-48 months and >48 months, respectively, compared to <24 months). CONCLUSIONS: In LMIC, paediatric PI-based second-line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI-based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.