Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age

Abstract

Objective: To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age. Design: Phase I/II, open-label, multicenter, dose-finding study. Methods: Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7–18 days after starting ETR. Participants with ETR AUC 12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics. Results: Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC 12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC 12 h less than 2350 ng h/ml and underwent a dose increase. ETR AUC 12 h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued. Conclusion: ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.

Outcomes of etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living with HIV in Europe and Thailand

“…A Spanish observational cohort ( N =23) of treatment-experienced children/adolescents reported similar findings; 78% had VL<50 copies/mL at a median of 48 weeks [ 10 ]. The recent P1090 trial on ETR in treatment-experienced children aged 1–6 years reported that among children on the final dose, 75% of those aged 2–6 years and 33.3% of those aged 1–2 years had VL<400 copies or ≥2 log reduction from baseline at week 48 [ 14 ].…”

“…Clinical outcome data for ETR in treatment-experienced children and adolescents are limited to single-arm trials and observational studies with <50 patients. These reported 33%-78% viral suppression <50 copies/mL at 48 weeks [9][10][11][12][13][14]. Common adverse reactions included gastrointestinal disorders and rashes.…”

Antiviral drugs

“…In a recent Phase I/II multicenter study including 26 children (46.2% girls) aged 1 year to < 6 years from South Africa, Brazil, and the United States, approximately 20% experienced adverse effects which included rash, cough, nasal congestion, rhinorrhea, pharyngitis, diarrhea, and vomiting. Two children experienced elevated lipase levels, which is a rare adverse effect of ETR use, and resulted in one leaving the study ( MacBrayne et al, 2021 ) [M]. Another study aimed to determine the long-term effects of ETR on the reproductive system, liver, kidneys, and bones in mature 8-week-old male Wistar rats.…”

The role of HIV-1 polymorphism in the pathogenesis of the disease

“…Этравирин (ETR) -ненуклеоиздный ингибитор обратной транскриптазы второго поколения, эффективность и безопасность применения которого при лечении ВИЧ-инфицированных детей от года до шести лет продемонстрировали недавние зарубежные исследования [38]. Учитывая, что список препаратов, разрешенных для лечения ВИЧинфицированных детей младшего возраста, крайне ограничен, применение этравирина для лечения ВИЧ-инфекции у детей в будущем представляется перспективным [39].…”