Abstract and Introduction
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 5.2 mg/kg (maximum dose 200 mg) 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<50 copies/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 (C 0h). 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 12 h (AUC0–12h; 5216 ng h/mL) and C 0h (346 ng/mL) were comparable to adult target values.
Conclusions Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients.
Paediatric populations infected with HIV-1 present a sizeable treatment challenge. Barriers to effective antiretroviral treatment include: suboptimal treatment adherence (particularly in adolescents); differences in transmission and pharmacokinetics compared with adults; fewer available antiretroviral drugs and age-appropriate formulations licensed for paediatric use.[1–4]
As with adults, treatment guidelines for treatment-naïve and -experienced HIV-1-infected children and adolescents recommend a combination of three antiretrovirals, from at least two classes. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) continue to be extensively used in the treatment of HIV-1 infection in children, especially as first-line therapy agents. Efavirenz is the preferred NNRTI for treatment-naïve children over 3 years of age, having shown comparable results to those in adults when administered as combination therapy to HIV-1-infected children.[5–7] However, efavirenz is associated with neuropsychiatric side effects,[8,9] rash (more common in children than adults)[10–12] and potential teratogenicity during the first trimester of pregnancy – efavirenz is not recommended for use in adolescent female patients, unless contraception can be ensured. Nevirapine is approved as an alternative NNRTI agent in HIV-1-infected children, showing good antiretroviral efficacy in several different combination regimens.[13–15] It is also the preferred NNRTI option for children under 3 years of age. However, nevirapine is associated with a risk of hepatic toxicity, rash (including, rarely, significant hypersensitivity reactions), and a possible increased risk of virological failure (VF) compared with efavirenz.[4,16,17]
The pharmacokinetics and safety of etravirine, a second-generation NNRTI, have previously been evaluated in virologically suppressed children between 6 and < 18 years on a stable lopinavir/ritonavir-containing regimen. Based on the results of this study (TMC125-C126), etravirine dosed at 5.2 mg/kg twice daily (bid) was selected for further study. The study described here [Paediatric study of Intelence As an NNRTI Option (PIANO); TMC125-C213; ClinicalTrials.gov Identifier NCT00665847] aimed to evaluate safety and tolerability as well as antiviral activity and pharmacokinetics over 48 weeks. Week 24 primary endpoint data from PIANO have shown that etravirine 5.2 mg/kg (up to a maximum dose of 200 mg) bid demonstrated a good safety profile in paediatric patients, with a comparable proportion of patients achieving plasma viral load (VL) < 50 HIV-1 RNA copies/mL (virological response) (52%) to that observed in HIV-1-infected, treatment-experienced adults receiving etravirine 200 mg bid as part of highly active antiretroviral therapy.[19–23] Here we present the final week 48 safety and efficacy analysis of PIANO.
HIV Medicine. 2014;15(9):513-524. © 2014 Blackwell Publishing