Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial

Summary

Background

Raltegravir is an integrase inhibitor approved for use in adults and children with HIV-1 infection, but there are no data on the long-term use of this medication in children. We aimed to assess the long-term safety, tolerability, pharmacokinetics, and efficacy of multiple raltegravir formulations in children aged 4 weeks to 18 years with HIV-1 infection.

Methods

In this phase 1/2 open-label multicentre trial (IMPAACT P1066), done in 43 IMPAACT network sites in the USA, South Africa, Brazil, Botswana, and Argentina, eligible participants were children aged 4 weeks to 18 years with HIV-1 infection who had previously received antiretroviral therapy (ART), had HIV-1 RNA higher than 1000 copies per mL, and no exposure to integrase inhibitors. Participants were separated into five age groups and enrolled in six cohorts. Three formulations of open-label raltegravir—adult tablets, chewable tablets, and granules for oral suspension—were added to individualised optimised background therapy, according to the age and weight of participants. The primary outcome at 48 weeks has been previously reported. In the 240-week follow-up, outcomes of interest included graded clinical and laboratory safety of raltegravir formulations during the study and virological efficacy (with virological success defined as HIV-1 RNA reduction of >1 log₁₀ from baseline or HIV-1 RNA <400 copies per mL) at week 240. The primary analysis group for safety and efficacy comprised patients treated only with the final selected dose of raltegravir. This trial is registered with ClinicalTrials.gov, number NCT00485264.

Findings

Between August, 2007, and December, 2012, 220 patients were assessed for eligibility, and 153 were enrolled and treated. Of these patients, 122 received only the final selected dose of raltegravir (63 received adult tablets, 33 chewable tablets, and 26 oral granules), and one was not treated. There were few serious clinical or laboratory safety events noted, with two patients having a drug-related adverse event (skin rash), which led one patient to discontinue the study treatment. The addition of raltegravir to an individually optimised ART regimen resulted in virological success at week 240 in 19 (44·2%, 95% CI 29·1–60·1) of 43 patients receiving 400 mg tablets, 24 (77·4%, 58·9–90·4) of 31 patients receiving the chewable tablets, and 13 (86·7%, 59·5–98·3) of 15 patients receiving oral granules. Among patients with virological failure, raltegravir resistance was noted in 19 (38%) of 50 patients who had virological rebound after initial suppression and had samples at virological failure available for testing.

Interpretation

Our study suggests that raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who had previous extensive antiretroviral therapy.

Funding

National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, and Merck.

Introduction

Raltegravir was the first integrase inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in adults with HIV-1 infection. The addition of raltegravir to optimised antiretroviral therapy (ART) has shown high virological success rates, with 72·3% (332 of 459 participants) success at 48 weeks among highly treatment-experienced adults¹ and 86·1% (241 of 280) success at 48 weeks among treatment-naive adults.² Raltegravir, as part of an optimised background therapy, had a 42% (193 of 462) success rate at 240 weeks in treatment-experienced adults³ and 71% (198 of 279) success among treatment-naive adults.⁴

On the basis of 24-week and 48-week pharmacokinetic, safety, and efficacy data, three formulations of raltegravir have now been licensed and approved for use in children younger than 18 years: a 400 mg tablet, for twice-daily use in children who weigh 25 kg or more; and chewable tablets (100 mg and 25 mg) and granules for suspension (100 mg sachet), for twice-daily weight-based dosing in children older than 4 weeks. In 2017, raltegravir in granules for suspension was approved for use in neonates. This IMPAACT P1066 trial was designed to assess the pharmacokinetics and both short-term (24 weeks and 48 weeks) and long-term (240 weeks) safety and efficacy of these different formulations. Data on intensive pharmacokinetics and 48-week safety and efficacy have been previously published.5, 6, 7 This report focuses on the long-term safety and efficacy of three formulations of raltegravir added to an optimised ART in patients after 240 weeks of follow-up.

Research in context

Evidence before this study

The treatment of people younger than 18 years with HIV-1 infection is evolving. Few data exist on the short-term use of integrase inhibitors in all children and no data exist regarding their long-term use. We searched PubMed for studies published from Jan 1, 2010, to Dec 30, 2017, with the search terms “integrase inhibitors”, “children”, “youth”, “adolescents and infants”, and “long term”, but restricted studies to those published in the English language. We found no indication that such data had been published to date.

Added value of this study

This long-term follow-up study of 122 young patients (aged 4 weeks to 18 years) with HIV-1 infection receiving three different, age-appropriate, formulations of raltegravir showed that this integrase inhibitor was well tolerated and had favourable virological outcomes. Older children, who were often highly treatment experienced, had lower proportions of virological success than did children younger than 12 years.

Implications of all the available evidence

Our study suggests that raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who have had previous extensive antiretroviral therapy.