Although several antiretroviral drugs are approved for the treatment of HIV-1-infection in children who are naive to treatment, there remains a lack of options for treatment-experienced, HIV-1-infected children . Guidelines for the second-line treatment of HIV-1 infection in children recommend the use of three fully active agents wherever possible. This usually consists of two nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] and either a boosted HIV protease inhibitor or a non-NRTI (NNRTI), depending on whether failure occurred after NNRTI-based or protease inhibitor-based therapy, respectively [2–5].
The NNRTI etravirine is approved in combination with other antiretroviral drugs for the treatment of HIV-1-infected, treatment-experienced adults. Two phase III, randomized, double-blind, placebo-controlled trials (DUET-1 and DUET-2) demonstrated the efficacy and safety of an etravirine-containing regimen in HIV-1-infected adults with documented resistance to first-line NNRTIs for up to 96 weeks [6–9]. There was no apparent relationship between the pharmacokinetics of etravirine and efficacy or safety in the DUET trials . The antiviral activity and generally favorable safety profile of etravirine in HIV-1-infected adults suggests a potential to explore the use of this drug in treatment-experienced, HIV-1-infected children.
Although data with antiretroviral agents in treatment-experienced children are sparse, some clinical data are available and several clinical trials are currently in progress. Salazar et al.  showed that after 48 weeks of ritonavir-boosted tipranavir, approximately 35% of HIV-1-infected children and adolescents achieved HIV-1 RNA viral load less than 50 copies/ml, with an acceptable tolerability profile. Furthermore, with the boosted protease inhibitor darunavir, approximately 50% of treatment-experienced children and adolescents achieved HIV-1 RNA viral load less than 50 copies/ml after 48 weeks of treatment . Other trials in treatment-experienced children and adolescents are currently underway, including with darunavir (dArunavir in tReatment experIenced pEdiatric population, ARIEL, NCT00919854); etravirine (Pediatric trial with Intelence as an Active NNRTI Option, PIANO, NCT00665847); maraviroc (NCT00791700); and raltegravir (International Maternal Pediatric Adolescent AIDS Clinical Trials P1066, NCT00485264).
Nonetheless, treatment of HIV-1-infected children who have failed prior treatment remains a difficult challenge. Drug resistance is common, particularly with the first-generation NNRTIs (efavirenz and nevirapine); reasons for failure were considered to be a low genetic barrier for developing resistance, underdosing, low drug levels and suboptimal adherence [13,14]. Indeed, dose optimization of antiretrovirals remains problematic, as children often require higher weight-based dosing of antiretroviral drugs than adults due to differences in drug absorption, body composition and metabolic activity . Furthermore, the population of treatment-experienced children requiring second-line regimens is likely to increase with time, a particular challenge in resource-limited countries where the need for effective, affordable options will be acute.
The aim of this study was therefore to determine a weight-based dose of etravirine that achieves comparable pharmacokinetic exposures in HIV-infected children and adolescents aged at least 6 years to 17 years or less and weighing at least 20 kg as HIV-infected adults receiving 200 mg twice daily (b.i.d.). A secondary objective was to assess the short-term safety and tolerability of etravirine.
Participants and methods
The trial protocol and subsequent amendments were approved by Independent Ethics Committees and/or Institutional Review Boards. The study was conducted in accordance with the principles of Good Clinical Practice and the revised Declaration of Helsinki. Risks were minimized as much as possible given that participation in the study had no direct benefits for the participants ; however, it was not expected that the exposure to current antiretroviral drugs would change upon addition of etravirine. Children (≥6 to <12 years) agreed to participate in the study and their parent(s)/legal guardian(s) provided written consent prior to any study-related procedure. Adolescents (≥12 to ≤17 years) and their parent(s)/legal guardian(s) provided written consent prior to any study-related procedure.
Treatment-experienced, HIV-1-infected children and adolescents between the ages of 6 and 17 years inclusive, weighing at least 20 kg, but below the 90th percentile for weight  were recruited. Participants were required to be on a stable regimen of at least two NRTIs and lopinavir/ritonavir, with or without enfuvirtide (at approved pediatric doses) for at least 2 months, with a HIV-1 RNA viral load less than 50 copies/ml on two consecutive determinations, and were not expected to change their regimen in the next 15 days.
Main exclusion criteria were a life expectancy of less than 6 months (as assessed by the investigator), a currently active AIDS-defining illness, hepatitis A, B or C infection at screening and any grade 3 or 4 toxicity . The use of investigational drugs (except tenofovir disoproxil fumarate, which was allowed) was prohibited from 30 days prior to the first intake of study medication until the last follow-up visit. Study discontinuation was mandatory in the event of any grade 3 or 4 adverse event, at least grade 2 rash (but not after the last dose of etravirine in the case of grade 2 rash), clinical hepatitis or persisting grade 2 nausea at least, pregnancy or at the investigator's discretion.
Study design and treatment
This was a phase I, open-label, nonrandomized trial in which etravirine was administered for 8 days in addition to the existing antiretroviral therapy including lopinavir/ritonavir. The trial was structured in two sequential stages (stages I and II), each with a 28-day screening period and a 1-month, posttreatment, follow-up period. For each stage, 20 patients were to be enrolled; 10 into each cohort (children aged ≥6 to <12 years and adolescents aged ≥12 to ≤17 years). The first 20 patients were enrolled in stage I (etravirine 4 mg/kg b.i.d.), with 20 patients subsequently enrolled in stage II (etravirine 5.2 mg/kg b.i.d.).
On completion of stage I, an interim analysis of the pharmacokinetic and safety data was performed. Patients enrolled in stage I were able to continue in stage II if they remained eligible; additional patients were recruited to achieve a target enrollment of 20. Patients participating in both stages had a 1-month follow-up period after stage I prior to starting stage II.
Dose selection and administration
The dose of etravirine in stage I was based on allometric scaling of the adult dose . For stage II, the dose was arbitrarily set 30% higher than stage I. Only 25 and 100-mg tablets of etravirine were available; the relative oral bioavailability of the compositionally proportional 25-mg tablet is similar to the 100-mg tablet .
Etravirine was to be taken orally, swallowed whole (25 and 100-mg tablets) and taken within 10 min of a meal, every 12 h together with the rest of the antiretroviral regimen.
Blood sampling and nonpharmacokinetic assessments
Plasma viral load (Roche Amplicor HIV-1 Monitor 1.5 UltraSensitive assay; Roche Diagnostics, Mannheim, Germany) was assessed in a central laboratory at screening and on day 8 of each stage. Adverse events were monitored regularly throughout the study and up to 30 days postdose. Blood and urine were collected at screening, on days 1, 5 and 8 of each stage, and at the follow-up visit for evaluation of biochemistry/hematology and urinalysis, respectively. Blood collection was minimized as much as possible and was not to exceed 3 ml/kg in an 8-week period. Blood coagulation and thyroid function were also assessed at screening, on day 8 of each stage, and at follow-up, as coagulation and thyroid disturbances have been observed in nonclinical studies of etravirine . Other safety assessments included physical examination, vital signs and 12-lead ECG.
Twelve-hour pharmacokinetic sampling was performed on day 8 of treatment, with samples taken predose and 1, 2, 3, 4, 6, 8, 10 and 12-h postdose. Plasma concentrations of etravirine were determined using a validated liquid chromatographic-mass spectrometry/mass spectrometry method (lower limit of quantification: 2.00 ng/ml) . Pharmacokinetic analyses were performed using WinNonlin Professional software (version 4.1; Pharsight Corporation, Mountain View, California, USA), applying a noncompartmental approach with extravascular input (i.e. drug exposure was estimated from the plasma concentration–time curves produced after oral dosing, rather than being based on a model). The minimum and maximum plasma concentrations (C min and C max, respectively) and time-to-reach C max (t max) were obtained by inspection of the plasma concentration–time profiles. C min was the lowest plasma concentration observed within a dosing interval. Area under the plasma concentration–time curve from time of administration to 12 h after dosing (AUC12h) was determined using the linear trapezoidal rule.
The decision to recruit at least 10 patients into each age subgroup and dose stage was based on established AUC12h and C min values in HIV-1-infected adults. A simulation of 1000 trials showed that recruitment of at least 10 patients into each age subgroup and dose stage would provide an 80% probability that the mean data of the primary pharmacokinetic parameters would be the same as the corresponding parameters in adults (i.e. would provide equal exposure), assuming equal variability (SD).
The efficacy and pharmacokinetic analyses were performed on the intent-to-treat population, with an as-treated analysis performed for the safety parameters. Descriptive statistics are presented for the plasma concentrations of etravirine and the derived pharmacokinetic parameters. Least square mean (LSM) ratios and 90% confidence intervals (CIs) for AUC12h and C min were determined.
Comparison of etravirine AUC12h and C min data were performed using the pediatric population as test and historic steady-state (day 8) AUC12h and C min values from 27 treatment-experienced, HIV-1-infected adults receiving etravirine 200 mg b.i.d. (while on a stable predominantly lopinavir/ritonavir-containing background regimen) as reference . Treatments were declared comparable if the LSM ratios of the primary pharmacokinetic parameters were within 80–125% of the corresponding parameters in adults. Pharmacokinetic parameters were also compared with population pharmacokinetic results from a post-hoc analysis from the DUET-1 and DUET-2 trials; in these trials, the pooled mean (SD) AUC12h and predose plasma concentration (C 0h) were 5501 ng h/ml (4544) and 393 ng/ml (378), respectively .
In the safety analyses, the type and frequency of adverse events (coded using the Medical Dictionary for Regulatory Activities) and laboratory abnormalities (classified according to the Division of AIDS grading scale) were tabulated; the severity and relatedness of adverse events to etravirine was also described.
The study was conducted at 13 sites across Europe and the United States between September 2006 and February 2008. Twenty-nine patients were screened for stage I. Of these, 21 eligible patients started treatment: 10 in the at least 6 years to less than 12 years subgroup and 11 in the at least 12 years to 17 years or less subgroup. One patient aged at least 12 years to 17 years or less subsequently discontinued stage I prematurely after first etravirine intake due to an adverse event [grade 3 increased creatinine (168 μmol/l, normal range 23–83 μmol/l)] on day 1, reported prior to first intake of etravirine (Figure 1a).
An interim analysis conducted after 17 patients had completed stage I revealed pharmacokinetic exposure to 4-mg/kg etravirine b.i.d. was comparable with that seen in HIV-1-infected adults . However, the expected 90% CIs were not met and stage II was, therefore, initiated.
Twenty-six children and adolescents were screened for stage II, of whom 21 were eligible. Twelve patients started treatment in the at least 6 years to less than 12 years subgroup and nine in the at least 12 years to 17 years or less subgroup; all patients completed stage II (Figure 1b). In total, 41 patients completed stage I or II, and seven patients (three aged ≥6 to <12 years and four aged ≥12 to ≤17 years) participated in both stages of the trial.
Baseline characteristics were similar between the two stages of the trial (Table 1). Comparison of the two age subgroups (≥6 to <12 years and ≥12 to ≤17 years) within each stage also showed no significant differences. In stages I and II, the most commonly used NRTIs were lamivudine (62% in each stage), abacavir (33 and 29%, respectively), zidovudine (33% in each stage) and didanosine (29% in each stage).
Pharmacokinetic data were available for 19 and 20 patients in stage I and II, respectively. Three patients (one from stage I and two from stage II) were reported with a major protocol violation (increased dose of etravirine, treatment with a disallowed antiretroviral and failure to carry out a pregnancy test at screening, respectively); only the protocol violation of failure to carry out a pregnancy test at screening was included in the pharmacokinetic analysis.
Median t max was similar in both stages (Table 2) [10,23]. Mean C min, C max and AUC12h were higher with the etravirine 5.2 mg/kg b.i.d. dose (stage II) than with the 4 mg/kg b.i.d. dose (stage I). The pharmakokinetic profile for the 12h dosing interval is shown in Figure 2 for both stages.
Comparison of data from children and adolescents with adult reference
Comparison of systemic exposure between children and adolescents dosed with 4 mg/kg b.i.d. showed both the C min and AUC12h were similar to adults (LSM ratio 99 and 102%, respectively, Table 2), although interindividual variability was high. In contrast to the 4 mg/kg b.i.d. dose, when dosed at 5.2 mg/kg b.i.d. (stage II), systemic exposure to etravirine (C min and AUC12h) was increased by 58% versus adults (Table 2).
Comparison of at least 6 years to less than 12 years and at least 12 years to 17 years age subgroups with adult reference
In stage I, based on LSM ratios, C min and AUC12h following etravirine 4 mg/kg b.i.d. were similar between the two age subgroups and the adult reference: at least 6 years to less than 12 years subgroup, 93 (90% CI 54–161) and 108% (90% CI 67–174), respectively; at least 12 years to 17 years or less subgroup, 104 (90% CI 67–161) and 97% (90% CI 67–140), respectively. However, in both cases, the 90% CIs of the LSM ratios of C min and AUC12h fell outside the predetermined limits of 80–125%.
The age-stratified analysis of patients dosed at 5.2 mg/kg b.i.d. (stage II) showed that exposure was higher in children than in adolescents, although the variability was large in both age groups. LSM ratios for the comparison of C min and AUC12h (5.2 mg/kg b.i.d. versus adult dose) were 183 (90% CI 114–294) and 190% (90% CI 129–282), respectively, in the at least 6 years to less than 12 years subgroup versus 131 (90% CI 82–210) and 126% (90% CI 86–185), respectively, in the at least 12 years to 17 years or less subgroup.
Plasma viral load remained undetectable (HIV-1 RNA <50 copies/ml) throughout the trial in all patients.
Safety and tolerability
No deaths or serious adverse events were reported during the two treatment stages; however, one serious adverse event not related to the study drug (grade 1 influenza leading to hospitalization) was reported during the follow-up period of stage I in a child aged at least 6 years to less than 12 years.
The higher etravirine dose was not linked to an increased risk of adverse events. Overall, 14 patients (67%) in stage I (seven in each age group) and nine patients (43%) in stage II (three aged ≥6 to <12 years and six aged ≥12 to ≤17 years) reported at least one adverse event. The most frequently reported adverse events were headache (three patients in each stage; one aged ≥6 to <12 years and two aged ≥12 to ≤17 years) and rhinitis (two patients in each stage and one in each age group).
All adverse events were grade 1 or 2 in severity with the exception of one grade 3 adverse event [stage I, increased creatinine (not related; patient withdrawn from trial), predose on day 1] and one grade 4 adverse event (stage II, increased triglycerides, detected on day 8, namely after the last intake of drug, considered probably related to etravirine and possibly related to the background regimen). Adverse events considered to be at least possibly related to etravirine were reported in five patients (24%) in stage I and six patients (29%) in stage II; treatment-related adverse events of severity of at least grade 2 are shown in Table 3.
Apart from the patient mentioned above, there were no other discontinuations due to adverse events reported during the two treatment stages. Three patients reported skin events of interest: grade 2 maculopapular rash (on day 8 of stage I, very likely related to etravirine); grade 1 rash (on day 8 of stage I, probably related to etravirine) and grade 1 erythema (on day 1 of stage II, not related to etravirine). Both cases of rash resolved with continued treatment (hydroxyzine and dimetindene maleate, respectively) within a few days.
The most common treatment-emergent laboratory abnormalities in stages I and II were increases in total cholesterol (30 versus 24%), low-density lipoprotein (LDL) cholesterol (45 versus 10%) and glucose (15 versus 5%). All treatment-emergent graded laboratory abnormalities were grade 1 or 2, except for a grade 3 increase in LDL cholesterol and total cholesterol, each observed in one patient. With two exceptions, there were no consistent or clinically relevant changes from baseline in any laboratory parameter reported in either stage, with the exception of one patient in stage I who was reported with a grade 3 increase in creatinine in the predose sample on day 1 and was withdrawn from the study after the first dose of etravirine, and one patient in stage II who developed a grade 4 increased triglyceride level after the intake of 5.2 mg/kg (200 mg) etravirine on day 8; at the follow-up visit on day 36, this had decreased to grade 2. No clinically relevant changes from baseline in vital signs or ECG parameters were reported.
Appropriate management of HIV-infected pediatric patients is particularly important, especially given the requirement for treatment during critical phases of growth and development, as well as the lifelong need for therapy. In addition, the challenge of developing suitable pediatric formulations and the limited number of antiretroviral agents registered for children limit the therapeutic options for the pediatric population. Etravirine retains antiretroviral activity in the presence of mutations that would normally confer resistance to first-generation NNRTIs [24,25] and, thus, may provide potential benefits for HIV-1-infected, treatment-experienced pediatric patients.
This study was designed to evaluate the pharmacokinetics of etravirine in children and adolescents aged at least 6 years to 17 years or less. In the present study, mean exposures achieved with the 4 mg/kg b.i.d. dose of etravirine were largely comparable with those seen in treatment-experienced adults receiving etravirine 200 mg b.i.d. (with lopinavir/ritonavir and at least one NRTI, with or without enfuvirtide) over the same 8-day dosing period , according to the prespecified criteria for comparability. However, the 90% CIs were outside the 80–125% limits for both C min and AUC12h. As no major safety or tolerability concerns were identified in the interim analysis and, in light of the concerns regarding general underdosing in children, stage II was, therefore, initiated with an etravirine dose of 5.2 mg/kg b.i.d.
Exposures achieved with the 5.2 mg/kg b.i.d. dose of etravirine were higher than those seen in the adult reference trial , and both the LSM ratios and upper limits of the 90% CIs were outside 80–125% threshold for comparability for C min and AUC12h.
The exposure of etravirine when administered as 4 or as 5.2 mg/kg b.i.d. was higher in children (≥6 to <12 years) compared with adolescents (≥12 to ≤17 years). This result was mainly due to one patient in the younger age group who participated in both stages and who had consistently high exposures to etravirine at both doses; it is, therefore, unlikely to be clinically relevant.
As commonly observed in pediatric antiretroviral pharmacokinetic studies, the interindividual variability in the pharmacokinetic parameters was high [15,26]. This probably reflects individual differences in absorption, distribution, metabolism and excretion, a common condition in pediatric patients . The fact that the lower limits of the 90% CIs fell within the 80–125% threshold for comparability with adults for C min and AUC12h suggests that the 5.2 mg/kg b.i.d. dose is unlikely to lead to underdosing in children. As expected, viral load remained undetectable in all patients throughout the trial.
Both doses of etravirine were shown to be generally safe and well tolerated, with no serious adverse events or discontinuations due to adverse events reported during treatment. The short-term safety and tolerability profile of etravirine in children and adolescents was very similar to that reported in the adult reference study , with the caveat that the results are based on 1 week of treatment.
The main objective of the trial was to determine the optimal dose of etravirine in children and adolescents, and not the efficacy or long-term safety. Therefore, the study was primarily designed to reduce the risk of underdosing and the possibility of selecting for resistant strains. For this reason, we believe that adding a new antiretroviral agent to an existing effective antiretroviral regimen is a viable option for studies aiming to determine the optimal dose of investigational drugs. The sample size in each age-stratified subgroup was small, but enough to determine an appropriate dose, even given the high interindividual variability.
In summary, etravirine administered at both 4 and 5.2 mg/kg b.i.d. to HIV-1-infected children and adolescents (aged ≥6 to ≤17 years) provides exposures similar to etravirine 200 mg b.i.d. in treatment-experienced, HIV-1-infected adults. Etravirine 5.2 mg/kg was well tolerated in this study and, based on the general concern for underdosing of antiretroviral drugs in children [15,26,31–33] and given the overall favorable safety and tolerability profile of the higher dose, etravirine 5.2 mg/kg b.i.d. was selected as the dose for further investigation in the PIANO study.
R.R. passed away during the development of this manuscript. The author reviewed the outline and first draft in detail for clinical accuracy and intellectual content.
The authors would like to thank the patients and their parents/legal guardians for their participation in the study, study center staff, particularly Irene Picciolli, Caterina Sabatini and Margherita Semino, Richard Linde and Kai Beuckmann, and Tibotec study personnel for their support during the trial. They also acknowledge David Anderson, Benny Baeten, Goedele De Smedt, Eric Lefebvre, Steven Nijs, Frank Tomaka and Katrien Janssen for their important contributions to the manuscript. In addition, the authors would like to acknowledge Karen Pilgram (Senior Medical Writer at Gardiner-Caldwell Communications, Macclesfield, UK) for assistance in drafting the manuscript and collating author contributions.
Support for medical writing services, carried out by Gardiner-Caldwell Communications, was provided by Tibotec Pharmaceuticals.
Conflicts of interest
This study was sponsored by Tibotec Pharmaceuticals.
All study investigators received research funding from Tibotec to support their patients’ participation in this trial. C.K. has received research funding for clinical trials from Abbott, Bristol Meyers Squibb, Boehringer Ingelheim and Tibotec. C.V. has received grant money from Tibotec and Janssen and has acted as a board member, consultant and speaker for Pfizer, Gilead Sciences, Merck, Astellas and Schering-Plough. S.E. has received grant money from Tibotec. C.F.-S. has received grant money and support for travel to meetings from Tibotec. T.N.K., M.P., I.P., R.S., R.M. and K.B. are all full-time employees of the trial sponsor, Tibotec. R.L. is a full-time employee of Johnson & Johnson Pharmaceutical Research and Development.
C.G. and R.R. declare no further conflict of interest.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
children; etravirine; HIV-1; pediatric; pharmacokinetics; phase I