PIANO was a phase II, open-label, single-arm trial of etravirine in combination with an investigator-selected optimized background regimen (OBR) in HIV-1-infected, treatment-experienced children (aged ≥ 6 to < 12 years) and adolescents (aged ≥ 12 to < 18 years). The study consisted of a 6-week (maximum) screening period, 48-week treatment period and 4-week follow-up (with optional extension), involving 41 centres from 13 countries.
The primary objective of the trial was to evaluate the safety and tolerability of etravirine over 24 weeks in children and adolescents aged 6 to < 18 years. Secondary objectives included evaluation of long-term safety and tolerability of etravirine over 48 weeks, in addition to antiviral activity, pharmacokinetic parameters of etravirine, immunological effect, and changes in viral genotype and phenotype.
Eligible patients received etravirine according to predefined weight bands and corresponding doses (range 16 to < 20 kg: 100 mg bid; range 20 to < 25 kg: 125 mg bid; range 25 to < 30 kg: 150 mg bid; and ≥ 30 kg: 200 mg bid), based on the 5.2 mg/kg bid dose from previous results. Etravirine was provided in two different tablet strengths, containing 25 mg (formulation F066) or 100 mg (formulation F060) of etravirine. The OBR, selected by the investigator based on the medical history, consisted of at least two active antiretrovirals and included a ritonavir-boosted HIV protease inhibitor (PI) in combination with nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs]. Acceptable ritonavir-boosted PIs included lopinavir, darunavir, atazanavir and saquinavir. Inclusion of enfuvirtide or raltegravir was permitted if paediatric dosing information was available.
Written informed consent was obtained from all patients or their parent/legal guardian prior to any study-related procedures. The study protocol was approved by the appropriate committees and authorities and was conducted in accordance with the Declaration of Helsinki and the European Union Trials Committee.
The main inclusion criteria were: age between 6 and < 18 years, body weight ≥ 16 kg, HIV-1 plasma VL > 500 copies/mL (at screening visit) and current treatment with a stable antiretroviral for ≥ 8 weeks, continued until baseline (of this study). Exclusion criteria included: evidence of resistance to etravirine (based on the Virco®TYPE HIV-1 resistance test at screening; Janssen Diagnostics BVBA, Beerse, Belgium; formerly Virco BVBA), and the presence of any AIDS-defining illness (except stable Kaposi's sarcoma or HIV wasting syndrome).
Safety was monitored throughout the trial by an independent safety review panel. Adverse events (AEs) were classified and graded using the Medical Dictionary for Regulatory Activities (MedDRA version 11.1) and the National Institutes of Health's Division of Acquired Immune Deficiency Syndrome scales, respectively. Type (system organ class and preferred term) and incidence of AEs and HIV-related events were tabulated accordingly. The MedDRA system organ class describes grouped disorders, while preferred term describes a single medical disorder. Using the treatment emergent principle, events were recorded within the study period during which they emerged, and not in any subsequent study periods, even if the event continued to be present.
Efficacy and Virology Evaluations
Antiviral activity was assessed by measuring plasma VL (COBAS Taqman™ HIV-1 test; Roche Molecular Systems, Inc., Branchburg, NJ, USA) and CD4 cell counts at baseline and weeks 2, 4, 8, 12, 16, 24, 32, 40 and 48.
Viral phenotypic and genotypic assays were performed at Janssen Diagnostics BVBA (Beerse, Belgium), using Antivirogram® and Virco®TYPE HIV-1 assays, respectively.
The etravirine weighted genotypic score was determined in all patients. A weighted genotypic score of 0–2 predicts the highest (i.e. susceptible) response to etravirine, a score of 2.5–3.5 predicts an intermediate response and a score ≥ 4 predicts a reduced response (i.e. resistant).[25,26]
Adherence and Pharmacokinetic Evaluations
Adherence was assessed (1) by pill count and (2) using specific questions from the Paediatric European Network for the Treatment of AIDS (PENTA) self-reported adherence questionnaire. Pill counts were conducted at each visit and questionnaires were completed at weeks 2, 8, 16, 24, 32, 40 and 48.
At weeks 4, 8, 12, 24 and 48, blood samples were taken to determine etravirine and, optionally, PI plasma concentrations. A paediatric population pharmacokinetic model for etravirine was developed from previous adult modeling,[28,29] in addition to rich and sparsely sampled pharmacokinetic data from the present study and from study TMC125-C126. The paediatric model and Bayesian estimation were used to derive the etravirine area under the plasma concentration–time curve over 12 h (AUC0–12h) and trough plasma concentration (C 0h). The etravirine maximum plasma concentration (C max) was approximated for each patient using the median value of plasma etravirine concentrations measured 5–6 h post-dose.
Target enrolment for PIANO was 100 treatment-experienced, HIV-1-infected patients currently on stable, but virologically failing, treatment regimens.
The primary population was the intent-to-treat (ITT) population of all enrolled patients who had taken at least one dose of etravirine. The final analysis was performed after all patients had completed the study (including follow-up) or discontinued earlier. Analyses were performed by study period and by age group (overall; ≥ 6 to < 12 years; ≥ 12 to < 18 years); however, the study was not powered to make statistical comparisons between the two age groups. Statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC).
An ad hoc multivariate logistic regression model was used to explore potential independent prognostic factors for the development of rash. However, given the limitations of the exploratory analysis model (especially the small sample sizes and that it was not designed to verify the effect of age on risk of rash development), an additional multivariate analysis was performed including adult data from the phase III trials [Demonstrate Undetectable viral load in patients Experienced with antiretroviral Therapy (DUET)-1 and -2].[19,20,22,23]
The primary efficacy parameter was virological response according to the noncompleter equals failure (NC=F) imputation method. Time to loss of virological response (TLOVR) and non-VF censored TLOVR algorithms and a snapshot analysis for weeks 24 and 48 were also performed. Virological responses and their 95% confidence intervals (CIs) were calculated for all response parameters. An exploratory multivariate logistic regression model was used to investigate prognostic factors for virological response (TLOVR) at week 48.
VF was defined using the TLOVR non-VF censored algorithm.
The effects on etravirine pharmacokinetic parameters (log10-transformed) of sex, race, boosted PI use (darunavir/ritonavir, lopinavir/ritonavir or other), tenofovir disoproxil fumarate (TDF) use, weight (as a continuous variable), age (as a continuous variable) and adherence to etravirine based on pill count (as a continuous variable) were determined using a multivariate analysis of covariance approach.
HIV Medicine. 2014;15(9):513-524. © 2014 Blackwell Publishing