Elvitegravir in children and adolescents

Polly Clayden, HIV i-Base

Three posters at CROI 2015 showed new paediatric elvitegravir (EVG) data. The posters described preliminary safety in the 6 to 12 year old age group, and safety, efficacy, pharmacokinetics (PK) and resistance in 12 to 18 year olds receiving EVG in fixed dose combinations (FDCs). [1, 2, 3]

EVG 150 mg is approved for adults as a component of the once-daily FDC containing cobicistat (COBI, C), emtricitabine (F) and tenofovir disoproxil fumarate (TDF), or when co-administered with a ritonavir-boosted protease inhibitor.

EVG has also been co-formulated with tenofovir alafenamide fumarate (TAF) in E/C/F/TAF, the FDC that is currently under regulatory review in the US and EU.

EVG 85 mg is used in combination with ritonavir-boosted atazanavir or lopinavir because of increased EVG plasma concentrations due to UGT enzyme inhibition. Previous studies have confirmed use of the ritonavir or COBI-boosted adult dose in 12 to 18 year olds. [4]

Elvitegravir in children aged six to less than 12 years

GS-US-183-0160 is an ongoing, phase 2/3 open label, study with an age de-escalation design (oldest to youngest) evaluating the safety and PK of EVG in treatment experienced infants, children and adolescents 4 weeks to <18 years of age.

PK and preliminary safety data from 6 to <12 year olds (Cohort 2) were presented.

Sixteen participants were enrolled: median age 9 years (range 6 – 11); 14 had viral load <50 copies and 2 >1000 copies mL and baseline, their mean CD4 count was 811 cells/mm3.

Participants received EVG (adult or paediatric formulation) once daily added to their background regimen including either lopinavir/r or atazanavir/r. Data were available for 14 (57% male, 14% Asian, 71% black and 14% white).

Participants weighing >30 kg received the adult EVG 85 mg dose (n=6) and those weighing 17 to <30 kg received 50 mg (n=8).

The investigators compared PK parameters to exposures in adults from EVG plus boosted protease inhibitor phase 3 trials.

This comparison revealed geometric mean ratios (GMR) of 136%, 147%, and 129% vs adult exposure for AUCtau, Cmax and Ctrough respectively.

Mean EVG Ctrough was approximately 11-fold above the in vitro protein-binding adjusted IC95 (44.5 ng/mL); all participants’ Ctroughs were above the IC95.

These data are consistent with the range of exposures seen in the 12 to <18 years age group.

The investigators suggested that EVG appeared to be safe and well tolerated, based on limited data in a small number of participants.

E/C/F/TAF PK in adolescents

Treatment-naive 12 to 18 year olds (n=50), with viral load >1000 copies/mL, CD4 >100 cells/mm3 and eGFR >90 mL/min/1.73m2 received E/C/F/TAF once daily, in a phase 2/3, single arm, open label, two part trial.

Steady-state PK parameters of EVG, COBI, FTC, TAF and tenofovir (TFV) were compared to adult exposures by GMR with equivalence boundary of 70% to 143% for the 90% confidence interval. The trial evaluated adverse events, laboratory tests, and the proportion of subjects with viral load <400 and <50 copies/mL.

There were 48 participants (24 Part A/24 Part B) with a median age of 15 years (range 12 – 17), median weight of 52 kg, 58% female, 88% Black and 12% Asian; 21% with viral load >100,000 copies/mL, median CD4 count 452 cells/mm3, and median eGFR 158 mL/min/1.73m2.

The investigators found TAF, TFV, EVG, COBI, and FTC PK parameters in adolescents consistent with those associated with safety and efficacy in adults. TFV exposure by AUCtau was >90% lower from E/C/F/TAF than E/C/F/TDF as is seen in adult PK. All participants had EVG Ctau above the protein binding adjusted IC95 of 44.5 ng/mL.

Lack of resistance in adolescents on EVG-based FDCs at 24 week

Data from week 24 interim analyses that included 21 treatment-naive adolescents on E/C/F/TDF and 23 on E/C/F/TAF – from two ongoing single-arm studies of these FDCs, conducted in the US, Thailand, Uganda and South Africa – was also shown.

Most participants receiving the TDF FDC had HIV subtype C (47.6%, 10/21) or B (38.1%, 8/21) and the remainder had subtype AE (14.3%, 3/21). Most of the group receiving the TAF FDC had subtype A1 (56.5%, 13/23) and smaller proportions had subtype AE (17.4%, 4/23), B (17.4%, 4/23), D (4.3%, 1/23), or complex mixtures (4.3%, 1/23). The investigators noted that distribution of subtypes reflected geography: A1, Uganda; AE, Thailand; B, USA; C, South Africa.

The majority of adolescents receiving both FDCs had viral load <50 copies at 24 weeks: 85.7% (18/21) on E/C/F/TDF and 91.3% (21/23) on E/C/F/TAF.

Genotyping was performed at baseline in all participants at study entry to confirm sensitivity to FTC and tenofovir; screening genotyping to confirm sensitivity to EVG was only done in those receiving the TAF.

At baseline 14.3% of the participants receiving the TDF FDC had NNRTI-associated resistance mutations and 95.2% had secondary PI-associated mutations. Of those receiving the TAF FDC, 17.4% had NRTI-associated, 21.7% had secondary INSTI-associated, 8.7% had NNRTI-associated, and 100% had secondary PI-associated resistance mutations.

There was no correlation between pre-existing NNRTI, NRTI, secondary PI and secondary INSTI resistance mutations and virologic success at 24 weeks. No emergent resistance was detected in participants receiving E/C/F/TDF of E/C/F/TAF in these interim analyses.

References:

Unless otherwise stated, all references to the programme and abstracts to the 22nd Conference on Retroviruses and Opportunistic Infections, 23-26 February 2015, Seattle.

Custodio JM et al. Safety and pharmacokinetics of elvitegravir in HIV-1 infected pediatric subjects. Poster abstract 951.
http://www.croiconference.org/sessions/safety-and-pharmacokinetics-elvitegravir-hiv-1-infected-pediatric-subjects
Kizito H et al. Week-24 data from a phase 3 clinical trial of E/C/F/TAF in HIV-infected adolescents. Poster abstract 953.
http://www.croiconference.org/sessions/week-24-data-phase-3-clinical-trial-ecftaf-hiv-infected-adolescents
Porter DP et al. Lack of emergent resistance in HIV-1-infected adolescents on elvitegravir-based STRs. Poster abstract 952.
http://www.croiconference.org/sessions/lack-emergent-resistance-hiv-1-infected-adolescents-elvitegravir-based-strs