Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Environmental arsenic exposure and risk of diabetes type 2 in Ron Phibun subdistrict, Nakhon Si Thammarat Province, Thailand: unmatched and matched case&ndash;control studies

Kwanyuen Sripaoraya,1,2 Wattasit Siriwong,1 Sumol Pavittranon,2 Robert S Chapman1 1College of Public Health Sciences, Chulalongkorn University, Bangkok, 2Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand Background: There are inconsistent findings on associations between low-to-moderate level of arsenic in water and diabetes risk from previous epidemiological reports. In Ron Phibun subdistrict, Nakhon Si Thammarat Province, Thailand, a low level of arsenic exposure among population was observed and increased diabetes mellitus (DM) rate was identified.Objectives: We aimed to investigate the association between determinants (including low-level water arsenic exposure) of DM type 2 risk among residents of three villages of Ron Phibun subdistrict, Nakhon Si Thammarat Province.Materials and methods: Secondary data from two previous community based-studies, conducted in 2000 and 2008, were utilized. Data on independent variables relating to arsenic exposure and sociodemographic characteristics were taken from questionnaires and worksheets for health-risk screening. Water samples collected during household visit were sent for analysis of arsenic level at certified laboratories. Diabetes cases (N=185) were those who had been diagnosed with DM type 2. Two groups of controls, one unmatched to cases (n=200) and one pair matched on age and gender (n=200), were selected for analysis as unmatched and matched case&ndash;control studies, respectively. A multiple imputation technique was used to impute missing values of independent variables. Multivariable logistic regression models, with independent variables for arsenic exposure and sociodemographic characteristics, were constructed. The unmatched and matched data sets were analyzed using unconditional and conditional logistic analyses, respectively.Results: Older age, body mass index (BMI), having a history of illness in siblings and parents, and drinking were associated with increased DM type 2 risk. We found no convincing association between DM type 2 risk and water arsenic concentration in either study.Conclusion: We did not observe meaningful association between diabetes risk and the low-to-moderate arsenic levels observed in this study. Further research is needed to confirm this finding in the study area and elsewhere in Thailand. Keywords: diabetes, arsenic exposure, case&ndash;control, Ron Phibun subdistrict, Thailan