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Raltegravir Formulations Effective for ART-Experienced Teens and Children
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
Two formulations of the integrase inhibitor raltegravir proved generally safe and effective through 48 weeks in antiretroviral-experienced youngsters [1]. The FDA used results of this trial to license raltegravir for HIV-positive children and adolescents from 2 to 18 years old.
IMPAACT P1066 is an ongoing international phase 2/3 open-label trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of three raltegravir formulations in treatment-experienced children and adolescents. At the International AIDS Conference, P1066 investigators presented results of formulations tested in 6- to 18-year-olds and 2- to 12-year-olds. Granules for suspension are being tested in infants and toddlers from 4 weeks to 2 years old. The study began with a pharmacokinetic stage to establish appropriate and safe test doses with each formulation. Then investigators enrolled additional children to asses selected doses of each formulation.
Study participants from the United States, South Africa, Botswana, Brazil, and Argentina had a viral load above 1000 copies after failure of at least one antiretroviral regimen. All participants received an optimized background regimen in addition to raltegravir.
Two groups (12- to 18-year-olds and 6- to under-12-year-olds weighing at least 25 kg) took adult film-coated tablets at a dose of 400 mg twice daily. And two groups (6- to under-12-year-olds and 2- to under-6-year-olds) took chewable tablets with weight-based dosing of about 6 mg/kg (75 to 300 mg) twice daily. Study participants were almost equally divided between boys and girls, and 59% were black. Viral load at study entry averaged 20,000 copies, and median CD4 count stood at 481. More than three quarters of study participants had already taken a protease inhibitor and a nonnucleoside, and 59% had CDC category B or C HIV disease.
Fifteen youngsters had grade 3 or 4 clinical adverse events, including 1 with drug-related psychomotor hyperactivity, abnormal behavior, and insomnia. Fourteen had serious clinical adverse events, including one drug-related rash. Sixteen participants had grade 3 or 4 lab abnormalities, including one drug-related liver enzyme elevation. Two had serious lab abnormalities, including one with drug-related transaminase elevations. No one discontinued study drugs because of adverse events, and no one died.
Proportions of youngsters who achieved a viral load below 50 copies at week 48 in the primary analysis were 57.1% and 50.0% of the older and younger age groups taking the adult tablet and 54.5% and 57.9% of the older and younger age groups taking chewable tablets. The overall sub-50-copy response rate was 56.7%. Overall, 79.8% of participants reached a week-48 viral load below 400 copies or had at least a 10-fold drop in viral load. CD4 counts rose by an average 156 cells through week 48.
For comparison, at week 16 and week 48 of the BENCHMRK trials of raltegravir in adults with triple-class drug resistance, 62% at both points had a viral load below 50 copies in a noncompletion-equals-failure analysis [2].
The FDA licensed the 400-mg film-coated adult tablet twice daily for 12- to 18-year-olds and for 6- to under-12-year-olds weighing at least 25 kg. The agency licensed the chewable tablet for weight-based twice-daily dosing for children 2- to under 12-year-olds weighing at least 10 kg.
References
1. Nachman S, Acosta E, Zheng N, et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through week 48. XIX International AIDS Conference. July 22-27, 2012. Abstract TUAB0205.
2. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-354.
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