Etravirine in treatment-experienced, HIV-1-infected children and adolescents : 48-week safety, efficacy and resistance analysis of the phase II PIANO study

Objectives: PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥6 to <12 years) and adolescents (≥12 to <18 years) over 48 weeks. Methods: In a phase II, open-label, single-arm study, 101 treatment-experienced patients (41 children; 60 adolescents) with screening viral load (VL) ≥500 HIV-1 RNA copies/mL received etravirine 5.2mg/kg (maximum dose 200mg) twice a day (bid) plus OBR. Results: Sixty-seven per cent of patients had previously used efavirenz or nevirapine. At week 48, the most common treatment-related grade ≥2 adverse event (AE) was rash (13%); 12% experienced grade 3 AEs. Only two grade 4 AEs occurred (both thrombocytopaenia, not etravirine related). At week 48, 56% of patients (68% children; 48% adolescents) achieved a virological response (VL<50copies/mL; intent-to-treat, noncompleter=failure). Factors predictive of response were adherence >95%, male sex, low baseline etravirine weighted genotypic score and high etravirine trough concentration (C0h). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were >95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration-time curve over 12h (AUC0-12h; 5216ng h/mL) and C0h (346ng/mL) were comparable to adult target values. Conclusions: Results with etravirine 5.2mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients.