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Dolutegravir Effective at 24 Weeks in Adolescents Replacing Failing Regimen
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IDWeek, October 2-6, 2013, San Francisco
Mark Mascolini
More than 80% of adolescents taking a failing antiretroviral regimen attained a viral load below 400 copies 24 weeks after starting the integrase inhibitor dolutegravir plus other antiretrovirals, according to results of an ongoing phase 1/2 dose-finding trial [1]. No one stopped study drugs because of adverse events, and no grade 4 or serious adverse events developed in 24 weeks.
Dolutegravir has emerged as a potent antiretroviral for treatment-naive or experienced adults with or without previous exposure to integrase inhibitors. To determine the efficacy, safety, and appropriate dose of dolutegravir in children and adolescents, US researchers are conducting the phase 1/2 open-label P1093 trial in youngsters switching from a failing regimen.
Study participants were 12 to under 18 years old and (1) taking an unchanged failing regimen (viral load above 1000 copies) for at least 8 weeks or (2) treatment experienced but off therapy for at least 4 weeks. No one had taken an integrase inhibitor, and everyone had at least one fully active antiretroviral available for an optimized background regimen.
Stage 1 of the trial involves 10 children in a pharmacokinetic (PK) analysis in which they added dolutegravir to a failing regimen or took dolutegravir alone for 5 to 10 days. At that point, after intensive PK analysis, they optimized therapy by adding a tailored background regimen. Treatment will continue for 48 weeks, with a planned efficacy and safety analysis at week 24. Stage 2, an extended follow-up on dolutegravir and an optimized background regimen, involves 13 children.
The 23 study participants had a median age of 15 years (interquartile range [IQR] 12 to 16). Twelve children (52%) were African American, 8 (35%) white, and 3 (13%) Asian. Eighteen study participants (78%) were girls. Median baseline viral load stood at 4.3 log10 copies (about 20,000 copies), median CD4 count at 466, and median CD4 percent at 22%.
These children had taken antiretrovirals for a median 12.5 years (IQR 10.8 to 14.0). Eighteen children (78%) had taken a protease inhibitor, 12 (52%) had taken a nonnucleoside, and 8 (35%) had triple-class experience. The most frequently prescribed background regimen was tenofovir/emtricitabine (TDF/FTC) plus darunavir/ritonavir (30%). Three children (13%) took darunavir/ritonavir with abacavir/lamivudine, 3 took lopinavir/ritonavir with TDF/FTC, and 3 took efavirenz with TDF/FTC.
Nineteen children weighing 40 kg or more took 50 mg of dolutegravir daily and 4 weighing 30 to under 40 kg took 35 mg daily. Pediatric weight-band dosing of approximately 1 mg/kg once daily achieved dolutegravir levels comparable to those achieved with 50 mg once daily in adults.
No children stopped study drugs because of adverse events. There were no drug-related clinical adverse events, no grade 3 or 4 clinical events, and no serious adverse events. Two children had grade 3 lab abnormalities--bilirubin elevation in 1 child taking atazanavir and lipase elevation judged unrelated to study drugs.
Nineteen of 23 children (82.6%, 95% confidence interval [CI] 61.2% to 95%) had a viral load below 400 copies at week 24 by snapshot analysis. Sixteen children (69.6%, 95% CI 47.1% to 86.8%) had a viral load below 50 copies at week 24. Median CD4 gain through 24 weeks stood at 63 (IQR -56 to 180) and median CD4 percent gain at 4.9% (IQR 1% to 8%).
The investigators proposed that their findings support FDA labeling of dolutegravir for adolescents 12 to under 18 years old.
Reference
1. Viani RM, Zheng N, Alvero C, et al. Safety and efficacy of dolutegravir (DTG; GSK1349572) in treatment-experienced HIV-1 infected adolescents: 24-week results from IMPAACT P1093. IDWeek 2013. October 2-6, 2013. San Francisco. Abstract 172.
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