Interim IMPAACT Results Show Raltegravir (Isentress) Is Safe and Effective for Children and Adolescents with HIV

By Liz Highleyman

Raltegravir (Isentress)

Raltegravir (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.

IMPAACT

Andrew 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 or higher.

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.

Results

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% < 400 copies/mL;

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.

Based 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."

Enrollment in the study is continuing, and researchers are developing a chewable formulation of raltegravir for children under age 12.

French Expanded Access Program

In 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.

Patients 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 (Intelence).

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.

3/06/09

References

A 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. Abstract 874.

I Thuret, C Tamalet, V Reliquet, and others. Raltegravir in Children and Adolescents: The French Expanded Access Program. CROI 2009. Abstract 873.