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Response to Etravirine Regimen in Experienced Children and Adolescents
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
Virologic response to an etravirine-based rescue regimen was better in antiretroviral-experienced children than adolescents in the open-label PIANO trial [1]. The overall 56% response rate in an intention-to-treat analysis was close to the 61% rate in treatment-experienced adults in the pooled DUET trial analysis [2].
In the United States etravirine is licensed for use by antiretroviral-experienced adults and youngsters at least 6 years old. But data on use of this nonnucleoside in children and adolescents is limited. To address this lack, researchers planned the 48-week PIANO trial, an open-label phase 2 study of etravirine plus an optimized background regimen in children (6 to under 12 years old) and adolescents (12 to under 18 years old). These youngsters live in Argentina, Canada, South Africa, Thailand, the United States, and the United Kingdom. (PIANO stands for Pediatric study of Intelence as An Nnrti Option.)
Study participants received etravirine at a dose of 5.2 mg/kg twice daily to a maximum dose of 200 mg twice daily, which is the adult dose. They also started a ritonavir-boosted protease inhibitor, and nucleosides. A few also began enfuvirtide or raltegravir. All study participants had at least 2 active antiretrovirals in their background regimen, and all had a viral load above 500 copies when entering the trial.
PIANO included 41 children and 60 adolescents with respective median starting viral loads of 3.6 and 4.0 log10 copies/mL (4000 and 10,000 copies) and median CD4 counts of 443 and 356. Only 34% of children and 18% of adolescents had no nonnucleoside experience when they entered the trial. Almost two thirds of study participants (63%) were girls, and 49% were white.
Of the 101 enrollees, 76 (75%) completed the trial. Most dropouts were caused by adverse events (8%) or noncompliance with the trial protocol (8%). There were 2 virologic failures (5%) among children and 2 (3%) among adolescents. Overall 88% of study participants had any adverse event, 0 children and 8% of adolescents had a serious adverse event, and 15% of children and 13% of adolescents had a grade 3 or 4 event.
The most common events were upper respiratory tract infection (24% of children and 28% of adolescents) and rash (15% of children and 28% of adolescents). The investigators at least possibly attributed any grade 2 or worse rash to etravirine in 7% of children and 17% of adolescents. Overall 4% of youngsters dropped out because of rash. Three adolescents (5%) had diarrhea at least possibly related to etravirine. Rates of any grade 2 to 4 events at least possibly attributed to etravirine were 15% for children and 25% for adolescents.
At study week 48, two thirds of children and adolescents (65%) were adherent to their antiretrovirals according to the PENTA adherence questionnaire. Pill count indicated that only 46% of children and 35% of adolescents were more than 95% adherent, but 70% overall were more than 80% adherent.
Average CD4-cell gains through 48 weeks were 178 in children, 141 in adolescents, and 156 overall.
A week-48 noncompleter-equals-failure analysis determined that 28 children (68%) and 29 adolescents (48%) had a viral load below 50 copies, for an overall response rate of 56%. Proportions with a 48-week viral load below 400 copies were 76% for children, 62% for adolescents, and 67% overall. A time-to-loss-of-virologic response analysis determined sub-50-copy response rates of 68% in children, 43% in adolescents, and 53% overall. Median time to viral load below 50 copies was 16 weeks in children and 24 weeks in adolescents.
PIANO investigators classified 41 trial participants as having virologic failure, including 29 nonresponders and 12 rebounders. Among 30 youngsters with genotypic data after failure, 18 (60%) had nonnucleoside-related mutations, including Y181C in 8, E138A in 3, L100I in 3, and V90I in 3.
The researchers concluded that efficacy, safety, and resistance profiles of etravirine at these doses in antiretroviral-experienced children and adolescents were comparable to those seen in treatment-experienced adults in the DUET trials [2]. They suggested that responses were probably better in children than adolescents because children had less advanced disease, better adherence, and less nonnucleoside experience. The PIANO team stressed, however, that the trial was not designed to compare responses between children and adolescents.
References
1. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents: PIANO 48-week results. XIX International AIDS Conference. July 22-27, 2012. Abstract TUAB0204.
2. Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS. 2009;23:2289-2300.
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