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

Abstract

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 . 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, Nation...

Update on Adverse Effects of HIV Integrase Inhibitors

“…One patient had a transient liver function enzyme elevation that was possibly related to treatment and resolved without study’s drug discontinuation. Two participants (1%) had a drug-related allergic rash: one of them was grade 3 at day 7, and had to discontinue the study because of an adverse event [ 75 ].…”

Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study

“…Emergent INSTI resistance has been previously reported among pediatric patients aged 4 weeks to <19 years who had virologic failure after treatment with the first-generation INSTI raltegravir in the P1066 study. Raltegravir resistance-associated substitutions developed in 15 of 40 participants with virologic failure by week 48 and in 19 of 60 by week 240 ( 3 , 20 , 21 ).…”

“…Adolescents and children with HIV-1 face multiple barriers to antiretroviral therapy (ART) adherence, including logistical challenges related to drug access and age-related factors, as well as issues with formulations, dosing frequency, pill or volume burden, toxicity, side effects, and others ( 1 – 3 ). As a result, there is a critical need to develop simple, safe, potent, and acceptable ART medications for adolescents and children with HIV-1.…”

High levels of resistance to nucleoside/nucleotide reverse transcriptase inhibitors in newly diagnosed antiretroviral treatment-naive children in sub-Saharan Africa

“…raltegravir in infants <4 weeks of age and dolutegravir in children weighing >20 kg) [13]. As raltegravir has a low genetic barrier for resistance [14], its use in neonates with NRTI resistance may lead to emergence of resistance, potentially compromising future use of dolutegravir [15,16]. There is limited evidence to support the use of dolutegravir in infants with NRTI resistance.…”