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

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

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

The History of Pineapple Improvement

Man has been directing the genome of pineapple for a very long time. There is some evidence to suggest the domestication process started around 6000 years ago. The methods for breeding have of course changed considerably from the earliest times of pineapple domestication, but we still are seeking much the same goals. So much so that one of the cultivars to emerge from that early domestication, ‘Smooth Cayenne’, is still the predominant processing pineapple worldwide. The most modern pineapple genotypes today are only about eight generations removed from the early pre-Columbian village cultivars. These early pre-Columbian cultivars have in fact been the source of genetics for most pineapple breeding programs. There has been little effort to incorporate wild genetics into modern pineapple. There is in fact little need given the substantial level of heterozygosity that domestic pineapple exhibits. The high level of heterozygosity in pineapple has both been a great source of diversity for breeders and also a major bottleneck in progress. Almost all modern approaches to genome manipulation or breeding have been attempted in pineapple to overcome the problems associated with high heterozygosity including inbreeding, ploidy manipulation, mutation breeding and gene modification. Only gene editing and marker-assisted breeding have yet to make their impact in pineapple. This chapter looks at the history of pineapple breeding, the approaches used and lessons learnt in the hope we build on their successes to provide the world with more examples of the great diversity in pineapple