Articles
Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial

https://doi.org/10.1016/S2352-4642(21)00165-6Get rights and content

Summary

Background

Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV.

Methods

In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per μL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320.

Findings

Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0–93·0] for AUCtau and 65·4% [58·3–73·3] for Ctau in adolescents; GLSM 125% [90% CI 117–134] for AUCtau and 88·9% [80·6–98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance.

Interpretation

In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population.

Funding

Gilead Sciences.

Introduction

The aim of antiretroviral therapy (ART) in children and adolescents with HIV is to optimise immunological outcomes via virological suppression while maintaining overall wellbeing. Children and adolescents receiving ART with high treatment tolerance are the most likely to achieve these goals. Integrase strand-transfer inhibitors (INSTIs) have demonstrated few off-target effects and are recommended first-line agents in the USA and European Union for adolescents and children.1, 2, 3

Research in context

Evidence before this study

Integrase strand-transfer inhibitors (INSTIs) are the preferred third agents within a complete antiviral regimen for treatment of HIV in children globally. Coformulated emtricitabine and tenofovir alafenamide is a preferred component in antiretroviral regimens for children in the USA and the European Union. Data in adult populations support the use of fixed-dose combinations for the treatment of HIV; single-tablet regimens are recommended for enhancement of adherence and are also considered optimum for children. Many fixed-dose combinations recommended for adults are also recommended for adolescents, but not for children (especially those with bodyweight <25 kg) due to weight restrictions. Approval for these fixed-dose combinations have mainly been based on data derived from use of the individual components in participants included in paediatric studies rather than from the fixed-dose product itself. We searched PubMed for articles published between Jan 1, 1997, and Sept 30, 2020, using each of the search terms “tenofovir alafenamide” or “bictegravir”, “children”, “adolescent” or “pediatric”, “trial” or “study”, limited to English language articles. The search yielded two articles on the safety, efficacy, and pharmacokinetics of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide: one study in 50 treatment-naive adolescents with HIV (aged 12 to <18 years) at week 48 and another study in 23 virologically suppressed children (aged 6 to <12 years) at week 24. Results of these studies showed that this single-tablet regimen was safe, well tolerated, and maintained high rates of virological efficacy in children and adolescents. Our search identified no articles of the fixed-dose combination containing bictegravir, emtricitabine, and tenofovir alafenamide in children and adolescents.

Added value of this study

This is the first report of pharmacokinetic, safety, and efficacy data for the single-tablet regimen containing bictegravir coformulated with emtricitabine and tenofovir alafenamide, given once daily for 48 weeks in paediatric participants (aged 6 to <18 years) with a bodyweight of at least 25 kg. In our study, population pharmacokinetic modelling showed that the area under the curve at the end of the dosing interval (AUCtau) and maximum plasma concentration (Cmax) of bictegravir in adolescents were similar to that in adults, and bictegravir concentrations at the end of the dosing interval [Ctau]) were slightly lower than adults, but were markedly higher than the half-maximal inhibitory concentration. In children (aged 6 to <12 years), bictegravir AUCtau and Cmax values were modestly higher than those of adults and Ctau levels were similar to those of adults. Adherence was high and consistent with the acceptability of the tablet.

Implications of all the available evidence

The pharmacokinetics, safety, and tolerability of coformulated bictegravir, emtricitabine, and tenofovir alafenamide given as a single-tablet regimen in children and adolescents with HIV (aged 6 to <18 years with bodyweight ≥25 kg) informed the US Food and Drug Administration approval for this group in the USA. The findings of this study support ongoing paediatric drug development of this treatment regimen at lower doses for younger children.

Bictegravir is an INSTI with a high genetic barrier to resistance and low potential for drug–drug interactions.4, 5 Bictegravir is associated with few drug–drug interactions with one notable exception: administration with rifampin decreases bictegravir concentrations, which are occassionally reduced below levels known to be efficacious.6 Bictegravir 50 mg is coformulated with emtricitabine 200 mg and tenofovir alafenamide 25 mg as a single-tablet regimen. Tenofovir alafenamide has a favourable bone and renal safety profile when compared with tenofovir disoproxil fumarate,7, 8 which is important in growing children. In adults, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen results in high virological suppression rates with a favourable safety profile,9, 10, 11, 12 and is currently approved in multiple regions for adults, and in the USA and Brazil for adolescents and children (aged 6 to <18 years with bodyweight ≥25 kg).13, 14 The regimen is recommended by key European and US HIV Treatment Guidelines as the preferred single-tablet regimen for adults and adolescents.2, 15, 16 The approved tablet of bictegravir, emtricitabine, and tenofovir alafenamide is small in size (15 mm × 8 mm). Comparatively, larger tablet sizes are reported for abacavir, emtricitabine, and dolutegravir (22 mm × 11 mm) and elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (19 mm × 9 mm).

Fixed-dose combinations are considered optimum for paediatric ART worldwide and are associated with improved adherence.17, 18, 19, 20, 21, 22 Optimising adherence to sustain virological control is crucial for children who require lifelong therapy. Adolescents with HIV also greatly benefit from regimen simplification using fixed-dose combination ART whether infected perinatally or later in life, since adherence challenges are numerous during this stage of life.23, 24

Pharmacokinetic parameters can be used to predict the efficacy of an antiretroviral in a paediatric population with HIV on the basis of the drug's efficacy in adults. Similar exposures (within a given bioequivalence range) to particular efficacy-associated analytes in both populations suggest that efficacy is likely to be similar. Thus, pharmacokinetic parameters are often used as primary endpoints in paediatric studies of antiretrovirals.

We report the 48-week pharmacokinetic, safety, and efficacy data for the coformulated bictegravir, emtricitabine, and tenofovir alafenamide combination in children and adolescents (aged 6 to <18 years).

Section snippets

Study design and participants

GS-US-380-1474 is an open-label, single-arm, two-part trial done at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. This study was designed as a phase 2/3 trial since bictegravir, emtricitabine, and tenofovir alafenamide was being assessed in a novel population (ie, paediatric) and the study follows phase 3 results from four adult studies comprising 2414 participants.13, 14 Eligible participants were children and adolescents (aged 6 to <18 years), had a bodyweight of at

Results

Between Sept 29, 2016, and Feb 16, 2018, 102 participants were enrolled, of whom 100 received at least one dose of study drug and thus were included in the full analysis set (figure). This analysis includes data collected up to June 21, 2019. At the time of data cutoff for this analysis, 100 participants had been treated with bictegravir, emtricitabine, and tenofovir alafenamide and 99 had completed the 48-week main phase. One participant discontinued study drug due to adverse events. Median

Discussion

Week-48 results of this ongoing, single-arm, open-label trial showed that the single-tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated and highly effective in maintaining virological suppression in adolescents and children with HIV.

Exposure-related adverse events have not been identified in adults receiving bictegravir, emtricitabine, and tenofovir alafenamide using a pharmacokinetic–pharmacodynamic evaluation for the most commonly reported adverse

Data sharing

Gilead shares anonymised individual patient data upon request or as required by law or regulation with qualified external researchers. Approval of such requests is at Gilead's discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to [email protected].

Declaration of interests

AHG reports that his institution holds a Clinical Trials Agreement with Gilead to support the clinical trials sponsored by Gilead, including those that contributed to data shared in this manuscript; no direct payment was made to AHG. CAR has received research grant support and payment for attending scientific meetings from Gilead. KC reports research support from Gilead. HMax, PW, DP, SM, MSY, HG, HMar, DMB, and CP are or were employees of Gilead at the time of this analysis and report and hold

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