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

A Mobile Phone App to Support Adherence to Daily HIV Pre-exposure Prophylaxis Engagement Among Young Men Who Have Sex With Men and Transgender Women Aged 15 to 19 Years in Thailand: Pilot Randomized Controlled Trial

BackgroundWidespread smartphone use provides opportunities for mobile health HIV prevention strategies among at-risk populations. ObjectiveThis study aims to investigate engagement in a theory-based (information–motivation–behavioral skills model) mobile phone app developed to support HIV pre-exposure prophylaxis (PrEP) adherence among Thai young men who have sex with men (YMSM) and young transgender women (YTGW) in Bangkok, Thailand. MethodsA randomized controlled trial was conducted among HIV-negative YMSM and YTGW aged 15-19 years initiating daily oral PrEP. Participants were randomized to receive either youth-friendly PrEP services (YFS) for 6 months, including monthly contact with site staff (clinic visits or telephone follow-up) and staff consultation access, or YFS plus use of a PrEP adherence support app (YFS+APP). The target population focus group discussion findings and the information–motivation–behavioral skills model informed app development. App features were based on the 3Rs—risk assessment of self-HIV acquisition risk, reminders to take PrEP, and rewards as redeemable points. Dried blood spots quantifying of tenofovir diphosphate were collected at months 3 and 6 to assess PrEP adherence. Tenofovir diphosphate ≥350-699 fmol/punch was classified as fair adherence and ≥700 fmol/punch as good adherence. Data analysis on app use paradata and exit interviews were conducted on the YFS+APP arm after 6 months of follow-up. ResultsBetween March 2018 and June 2019, 200 participants with a median age of 18 (IQR 17-19) years were enrolled. Overall, 74% (148/200) were YMSM; 87% (87/100) of participants who received YFS+APP logged in to the app and performed weekly HIV acquisition risk assessments (log-in and risk assessment [LRA]). The median duration between the first and last log-in was 3.5 (IQR 1.6-5.6) months, with a median frequency of 6 LRAs (IQR 2-10). Moreover, 22% (22/100) of the participants in the YFS+APP arm were frequent users (LRA≥10) during the 6-month follow-up period. YMSM were 9.3 (95% CI 1.2-74.3) times more likely to be frequent app users than YTGW (P=.04). Frequent app users had higher proportions (12%-16%) of PrEP adherence at both months 3 and 6 compared with infrequent users (LRA<10) and the YFS arm, although this did not reach statistical significance. Of the 100 participants in the YFS+APP arm, 23 (23%) were interviewed. The risk assessment function is perceived as the most useful app feature. Further aesthetic adaptations and a more comprehensive rewards system were suggested by the interviewees. ConclusionsHigher rates of PrEP adherence among frequent app users were observed; however, this was not statistically significant. A short app use duration of 3 months suggests that they may be useful in establishing habits in taking daily PrEP, but not long-term adherence. Further studies on the specific mechanisms of mobile phone apps that influence health behaviors are needed. Trial RegistrationClinicalTrials.gov NCT03778892; https://clinicaltrials.gov/ct2/show/NCT0377889

Adaptation of a Theory-Based Social Networking and Gamified App-Based Intervention to Improve Pre-Exposure Prophylaxis Adherence Among Young Men Who Have Sex With Men in Bangkok, Thailand: Qualitative Study

BackgroundHIV disproportionately affects young Thai men who have sex with men (YMSM). Recent studies report a high incidence and prevalence of HIV among Thai YMSM. The Thai national guidelines have recommended pre-exposure prophylaxis (PrEP) since 2014 for key populations; free PrEP has been piloted since 2019. Smartphone-based mobile health (mHealth) interventions provide an optimal platform for innovative PrEP adherence interventions for Thai YMSM. ObjectiveThis study aims to adapt the P3 (Prepared, Protected, emPowered) app, developed with YMSM and transwomen in the United States to improve PrEP adherence and persistence for YMSM in Thailand. The app aims to provide daily adherence support and addresses gaps in staff available for large-scale PrEP rollout needed to see population-level effects of HIV prevention. MethodsWe conducted focus group discussions (FGDs) with YMSM and key informant interviews (KIIs) with PrEP care providers in Bangkok, Thailand, to investigate PrEP adherence facilitators and barriers, preferences for functions and features in mHealth apps among YMSM, and how to best adapt the P3 app to the Thai context. We conducted four FGDs with 4-8 participants per group and 15 KIIs. ResultsFor FGDs, 23 YMSM participated with a mean age of 20 years (range 18-21), 96% (22/23) enrolled in full-time education, and all owned smartphones. The mean age of KII participants was 40 (range 26-60) years; most were state health service providers, with the majority being counselors (6/15, 40%) and physicians (6/15, 40%). Overall, the facilitators and barriers for PrEP adherence identified were similar to those of MSM and YMSM globally including the United States. Key themes included general recommendations for improving mHealth apps in Thailand, such as presenting reliable information in an appealing format, minimizing privacy risks, and addressing connectivity challenges. Additional themes focused on P3 Thailand adaptations and were related to cultural and stylistic preferences, engagement strategies, and recommendations for new functions. To develop the adapted app, P3 Thailand, these findings were balanced with resource limitations resulting in the prioritization of minor modifications: changes in app esthetics (color scheme, iconography, and imagery) and changes in the presentation of information in two of the app’s features. FGDs identified similar PrEP adherence facilitators and barriers to those already addressed within the app. ConclusionsThe core elements of the P3 app address major PrEP facilitators and barriers for Thai YMSM; however, changes to the app features, including stylistic presentation, were needed to appropriately customize the app to the Thai context. Given the similarities of facilitators and barriers for PrEP adherence globally, adapting existing PrEP mHealth solutions based on input from end users and key informants provides a promising approach. However, partnerships with local app designers and developers can improve the adaptation process and final product. Trial RegistrationClinicalTrials.gov NCT04413708; http://clinicaltrials.gov/ct2/show/NCT0441370

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