D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.

Beliefs about antiretroviral therapy and their association with adherence in young people living with perinatal HIV in England: a cross-sectional analysis.

This cross-sectional analysis aimed to describe beliefs about antiretroviral therapy (ART) in young people living with perinatal HIV (PHIV) in England, and the association between these beliefs and adherence to ART. The Beliefs About Medicine Questionnaire (Highly Active Antiretroviral Therapy version), was used to measure participants' beliefs in the necessity of ("Necessity score") and concerns regarding ("Concerns score") ART. Participants were classified as having high/low total scores using midpoints of the score scales. Associations between beliefs and being Last Month Adherent (LMA; self-reported not missing more than 2 consecutive ART doses in the month prior to the interview) were analysed using logistic regression, adjusting for sociodemographic, clinical, and psychosocial variables. Of 247 PHIV (median age = 18.6 years), 158 (64%) were LMA. 224 (91%) had a high Necessity score and 54 (22%) a high Concerns score. There was no association between high Necessity score and LMA in multivariable analysis (adjusted odds ratio (aOR) = 1.34, 95% confidence interval (CI) = 0.34-5.28, p = 0.679); however, high Concerns score was independently associated with a reduced odds of being LMA (aOR = 0.19, CI = 0.07-0.47, p < 0.001). Interventions to address the concerns young people living with PHIV have about ART should be explored as a strategy to improve their adherence.