IMPAACT Results Show Raltegravir (Isentress) Is Safe and Effective for Children
and Adolescents with HIV
(Isentress), Merck's first-in-class HIV integrase inhibitor, was approved
in October 2007 for use as part of combination
antiretroviral therapy for treatment-experienced patients.
As is the
usual procedure, testing of the drug in children began after its safety and effectiveness
was established in adults. At the 16th Conference on Retroviruses
and Opportunistic Infections (CROI 2009) last month in Montreal, researchers
reported some of the first data on raltegravir in pediatric patients.
Wiznia from Albert Einstein College of Medicine and colleagues presented interim
findings from the ongoing IMPAACT study (ACTG P1066), a prospective, non-randomized,
open-label dose-finding trial of raltegravir plus optimized background therapy
(OBT) in treatment-experienced children and adolescents.
At the time of
the analysis, the researchers had enrolled 22 adolescents between 12 and 19 years
of age (Cohort I) and 14 children aged 6 to 12 years (Cohort II). Study participants
were about evenly divided between boys and girls. Two-thirds were black and one-quarter
were white. In both cohorts, the median baseline HIV RNA level was 4.4 log10 copies/mL
and the median CD4 percentage was 22% (range 0% to 42%). Viral load was 1000 copies/mL
In stage 1 of the study, raltegravir poloxamer film tablets
were added to participants' current stable failing antiretroviral regimen. Pharmacokinetic
analysis was done on days 5-12, then regimens were optimized with additional drugs.
Participants were initially given 6 or 8 mg/kg twice-daily raltegravir, with a
maximum dose of 600 mg. After early pharmacokinetic data was analyzed, the 8 mg/kg
dose was selected. In stage 2, raltegravir was started and the rest of the regimen
was optimized at the same time.
In an intent-to-treat (missing = failure) analysis of participants who received
8 mg/kg raltegravir by December 2008:
After 8 weeks, 50% of patients achieved viral load < 50 copies/mL and 77% <
After 12 weeks, 63% had HIV RNA < 50 copies/mL and 88% < 400 copies/mL.
Among 11 participants who reached 24 weeks, 54% had viral load < 50 copies/mL
and 64% < 400 copies/mL.
Median CD4 percentage increased to 25% at weeks 8 and 27% at week 12.
Raltegravir in pediatric patients aged 6 to 18 years was generally well tolerated.
No deaths occurred during the study period.
4 patients withdrew from the study, 3 of them due to poor adherence.
In both cohorts combined, 6 participants had grade 3 or worse adverse events:
5 neutropenia, 1 increased blood lipids, 1 elevated GGT liver enzyme, and 1 increased
creatinine (a potential indicator of kidney problems).
However, only 1 case of grade 4 neutropenia and the grade 3 GGT elevation were
judged to be possibly related to raltegravir.
on these findings, the investigators concluded, "Preliminary, short-term
and partial data from IMPAACT P1066 suggests that raltegravir plus OBT in children
ages 6 to 18 was generally safe, well tolerated and effective."
in the study is continuing, and researchers are developing a chewable formulation
of raltegravir for children under age 12.
Expanded Access Program
a related poster presentation, Isabelle Thuret and colleagues described outcomes
among 23 vertically infected adolescents (age 12 to 17) taking raltegravir through
the French Expanded Access Program between December 2006 and December 2007.
were highly treatment-experienced with nucleoside/nucleotide reverse transcriptase
inhibitor (NRTI), NNRTI, and protease inhibitor (PI) drugs; 13 had taken the fusion
inhibitor enfuvirtide (T-20; Fuzeon).
In addition to raltegravir, 13 started 2 other drugs also on expanded access at
the time: the new PI darunavir
(Prezista) and the next-generation NNRTI etravirine
At the last follow-up visit, after a median 9 months,
68% had HIV RNA < 50 copies/mL and 86% < 400 copies/mL -- similar to the
rates observed in IMPAACT. Only 1 patient discontinued therapy, due to headache.
There were no other moderate-to-severe clinical side effects and no grade 3-4
laboratory abnormalities. The median CD4 cell count increased progressively from
194 cells/mm3 at baseline to 402 cells/mm3 at 6 month. Patients who combined raltegravir
with darunavir and/or etravirine experienced a potent antiretroviral effect with
a good safety profile.
"Despite very long periods of viral replication
on previous ART and large spectra of resistance, virological success was obtained
for most patients at the last follow-up," the investigators concluded.
Wiznia, P Samson, E Acosta, and others. Safety and Efficacy of Raltegravir in
Pediatric HIV Infection. Preliminary Analysis from the International Maternal
Pediatric Adolescent AIDS Clinical Trials Group, P1066. 16th Conference on Retroviruses
and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009.
I Thuret, C Tamalet, V Reliquet, and others. Raltegravir
in Children and Adolescents: The French Expanded Access Program. CROI 2009. Abstract