Paediatric pipeline: CROI 2014 update on new antiretrovirals for children
Polly Clayden, HIV i-Base
Several posters at CROI 2014 reported data on antiretrovirals in the paediatric pipeline. These included the new integrase inhibitor class – which might be a useful option for children in the future.
Rilpivirine is an NNRTI, approved for treatment adults 18 years old and above with viral load less than 100,000 copies/mL. PAINT (Pediatric study in Adolescents Investigating a New NNRTI TMC278), is an ongoing, open label, 48-week phase 2 trial looking at rilpivirine pharmacokinetics (PK), safety and efficacy in treatment naïve adolescents aged 12 to 18 years. 
Part one of this trial aimed to find a rilpivirine dose providing comparable exposure to that in adults. Part two is assessing safety and efficacy at 12 and 24 weeks (with an extension of up to 240 weeks) and will be reported at a later date. Rilpivirine steady-state PK plus preliminary four-week safety and efficacy data (with a 25 mg once daily dose) from part one were shown.
Participants (n=25) were enrolled from sites in India, Thailand, Uganda and South Africa. All were treated with rilpivirine in combination with two NRTIs, taken with a meal.
They were a median age of 15 years (range 13 to 17); 56% were girls; 48% were aged 12 to 15 years and 52% were 15 to 18. The majority (84%) were black African and the remainder Asian. Their viral load was a median of 4.9 log copies/mL (range 3.3 to 5.8). In 72% of participants viral load was <100,000 copies/mL, 20% 100,000 to 500,000 copies/mL and 8% > 500,000 copies/mL.
Samples were collected predose, 2, 4, 5, 6, 9, 12 and 24 hours after an observed rilpivirine dose, between 2 and 4 weeks of treatment. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry with a lower limit of quantification of 1.0 ng/mL.
PK data were available for 23 participants. Geometric mean AUC24h, C0h and Cmax were 1750 (range 887-3573) ng*h/mL, 70.6 (range 20.03-191.0) ng/mL and 102.3 (range 48.5-182.0) ng/mL, respectively. Geometric mean PK parameter ratios adolescents:adults (pooled phase 3 ECHO/THRIVE PK substudy) were respectively 0.98, 1.21 and 0.88. Ratio of >0.80 and <1.25 had been predetermined to demonstrate comparability in rilpivirine PK parameters between adults and adolescents.
The investigators observed no apparent relationship between rilpivirine PK parameters and weight, age or between sexes.
At 4 weeks, all but two participants (92%) had >1 log drop in viral load from baseline. The mean decrease in viral load from baseline was 2.3 log copies/mL (n=24). For participants with a baseline viral load <100,000 copies/mL or >100,000 copies/mL, the mean decrease in viral load was 2.6 (n=17) and 2.2 (n=7) log copies/mL, respectively. The mean increase in CD4 count from baseline was 105 cells/mm3 (n=21).
None of the participants discontinued the study drugs due to adverse events (AEs) by week 4. AEs were similar to those reported in adults.
Dolutegravir is an integrase inhibitor approved for treatment naïve and experienced adults and adolescents 12 years old and above.
It is being evaluated for children in IMPAACT 1093 – an ongoing, phase 1/2, open label PK, safety and efficacy study in children and adolescents in age de-escalated cohorts. Preliminary data in children aged 12 to 18 years were included with the adult regulatory submissions for dolutegravir leading to the recent FDA and EMA approval.
Twenty-four week data were shown for children aged 6 to 12 years and 48-week data for children and adolescents aged 12 to 18 years.
In the first study, 11 treatment experienced but integrase inhibitor naïve children with viral load > 1000 copies/mL were enrolled in an intensive PK evaluation. Participants received dolutegravir tablets (10, 25, 50mg) dosed at 1 mg/kg once daily (based on weight bands) added to a stable, failing ART regimen, with optimised background therapy added after the PK evaluation, which was performed between days 5 and10. 
Children were a median age of 10 years (IQR 8 to 11); 36.4% girls; 36% African American, 27% white, 18% Asian and 36% Latino. Their median baseline viral load was 5.0 log10 copies/mL (IQR 3.5 to 5.3) and median CD4 645 cells/mm3 (IQR 325 to 732). They had received prior ART for a median duration of 9.3 years and just over half were triple class experienced.
PK targets were AUC0-24 37 to 67 ug*h/ mL and C24 0.77 to 2.26 ug/mL.
Five children (>40 kg) received 50 mg, 2 (30 to < 40 kg) received 35 mg and 4 (20 to <30 kg) received 25 mg dolutegravir once daily. This achieved adequate dolutegravir geometric mean AUC(0-24) and C24 of 50.46 (63%) ug*h/mL and 0.92 (89%) ug/ mL respectively.
In ITT analysis 82% achieved virological suppression <400 copies/mL and 64% <50 copies at 24 weeks. There were no discontinuations due to AEs. Adolescents, aged 12 to 18, had also previously achieved PK comparable to those in adults with the paediatric weight band dose of 1 mg/kg once a day.
The second study from IMPAACT 1093 showed safety and efficacy in 23 adolescents at 48-weeks. 
This group were a median age of 15 years (IQR 12 to 16); 78% female; 52% African American, 35% white and 26% Latino. Median baseline viral load was 4.3 log copies/mL (IQR 3.9 to 4.6) and CD4 was 466 cells/mm3 (IQR 297 to 771). About a third were triple class experience and two participants had previously used T-20. Nineteen participants (> 40 kg) received 50 mg dolutegravir once daily and four (30 to <40kg) received 35 mg.
At 48 weeks, 74% of participants achieved virologic suppression <400 copies/mL and 61% <50 copies/mL. There were no Grade 4 AEs, serious AEs or discontinuations due to AEs.
Elvitegravir is an integrase inhibitor approved by the EMA (for use with a boosted protease inhibitor) and in regulatory review with the FDA for adults. It is given with a booster and mostly used in the fixed dose combination (FDC) elvitegravir/cobicistat/FTC/TDF.
Two paediatric formulations are in development – a 50 mg tablet and a 5 mg/mL suspension. Data from a single dose PK evaluation of the two formulations boosted compared to the 150 mg adult formulation (all boosted by ritonavir) in healthy volunteers were presented at CROI 2104. 
The study design was prospective, open-label, crossover, randomised with multiple cohorts in healthy adults. Cohort 1 (n=30) compared the paediatric tablets (3 X 50 mg) to the adult tablet (reference). Cohort 2 (n=26) compared the paediatric suspension (30 mL) to the reference. Cohort 3 (n=18) evaluated multiple dose PK of both formulations. All formulations of elvitegravir were given with 100 mg ritonavir within 5 minutes of a standard meal.
Intensive PK sampling was performed over 48 hours post dose. Bioequivalence was assessed in cohorts 1 and 2 using standard definition: geometric mean ratios and 90% confidence interval of 80% to 125% (>85% power). Only descriptive PK was assessed in cohort 3.
In cohorts 1 and 2, elvitegravir exposures were within the defined bioequivalence bounds for both the pediatric tablet and suspension formulations vs reference. For the tablet GMR% of adult tablets for AUCinf ng*h/mL, AUC48h ng*h/mL and Cmax ng/mL were respectively: 100 (90% CI 93.8 to 107), 99.6 (90% CI 93.2 to 106) and 100 (90% CI 93.1 to 107). For the suspension these values were: 109 (90% CI 102 to 118), 111 (90% CI 103 to 120) and 108 (90% CI 98.7 to 118).
In cohort 3, ritonavir boosted elvitegravir PK after multiple doses was comparable between the paediatric tablet and suspension formulations and with historical steady state data, including mean trough concentrations (elvitegravir Ctau) ~8.5 and 9.2-fold, respectively, above the IC95 (44.5 ng/mL).
These formulations will be evaluated in children in an ongoing phase 2/3 study.
Cobicistat is a CYP3A inhibitor with no antiretroviral activity that is approved for adults as a booster of atazanavir 300 mg or darunavir 800 mg by the EMA. It is also a component of the FDC elvitegravir/cobicistat/FTC/TDF.
A 50 mg pediatric immediate release tablet and as a 20 mg pediatric dispersible tablet are in development. Both were compared to the 150 mg adult tablet formulation (reference) in healthy volunteers.
The PK study was designed in the same way as the previous elvitegravir one for cohorts 1 and 2, with the same predefined bioequivalence bounds. Cohort 1 (n=32) evaluated the paediatric immediate release tablets (3 X 50 mg) and cohort 2 (n=30) the paediatric dispersible tablet (7.5 X 20 mg – tablet divided using a pill cutter) vs reference. 
In cohorts 1 and 2, cobicistat exposures were within the defined bioequivalence bounds for both the paediatric immediate release and dispersible tablets. For the immediate release tablet GMR% of adult tablets for AUCinf ng*h/mL, AUC48h ng*h/mL and Cmax ng/mL were respectively: 95.0 (90% CI 88.9 to 101), 95.0 (90% CI 88.9 to 101) and 100 (90% CI 92.8 to 108). For the dispersible tablet these values were: 96.6 (90% CI 90.1 to 104), 96.6 (90% CI 90.0 to 104) and 108 (90% CI 86.8 to 97.4).
Both formulations will also be evaluated in an ongoing phase 2/3 study.
Elvitegravir and cobicistat were also evaluated in treatment naïve adolescents aged 12 to 18 years as components of the adult FDC or single tablet regimen (STR) containing elvitegravir 150 mg, cobicistat 150 mg, FTC 200 mg and TDF 300 mg (E/C/F/TDF).
In this study, 14 adolescents weighing >35 kg with viral load >1000 copies/mL, CD4 counts >100 cells/mm3 and eGFR >90 mL/min received one E/C/F/TDF tablet once daily.
The participants were from the United States, Thailand and South Africa and had a mean age of 16 years (range 13 to 17). Their mean baseline viral load was 4.83 log copies/mL (71% were < 100,000 copies/mL) and CD4 count was 441.5 cells/mm3.
Intensive PK was performed at steady state (day 10). Samples were collected predose, 2, 4, 4.5, 5, 8 and 12 hours post dose. The primary endpoint was EVG AUCtau. Exposures were compared to population PK-based exposures in adults from E/C/F/TDF Phase 2 and 3 trials (ANOVA). Viral load, AEs and routine laboratory tests were evaluated through week 12.
At Day 10 this revealed elvitegravir geometric least squares mean (GLSM) AUCtau 130% (90% CI 105 to 162) of the adult level and GLSM Cmax of 142% (90% CI 116-173%). The GLSM Ctau was 410 ng/mL, 106% of the adult level (90% CI 70.0 to 160), which is 9.2 times the protein-adjusted IC95 of 44.5 ng/mL. The investigators reported cobicistat, TDF and FTC exposures that were similar to those observed in adults. At 12 weeks, 100% of participants had viral load < 400 copies/mL and 64.3% <50 copeis/mL, and median CD4 count was 627 cells/mm3.
Median serum creatinine increased 0.06 mg/dL by week 12, similar to that seen in adults and consistent with cobicistat’s inhibition of tubular creatine secretion. There were no discontinuations due to AEs.
Study of E/C/F/TDF in adolescents and children continues.
Unless indicated otherwise, all references are to the Programme and Abstracts of the 21st Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2014, Boston.
- Crauwels H et al. Rilpivirine pharmacokinetics in HIV-1-infected adolescents: A substudy of PAINT (phase II trial). Poster abstract 900.
- Viani RM et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children. Poster abstract 901.
- Viani RM et al. Safety and efficacy of dolutegravir in HIV treatment-experienced adolescents: 48-week results. Poster abstract 906LB.
- Custodio JM et al. Bioequivalence of two paediatric formulations vs adult tablet formulation of elvitegravir. Poster abstract 902.
- Custodio JM et al. Bioequivalence of two paediatric formulations vs adult tablet formulation of cobisistat. Poster abstract 908.
- Gaur A et al. Pharmacokinetics, efficacy, and safety of an integrase inhibitor STR in HIV-infected adolescents. Poster abstract 909.