Update on paediatric antiretrovirals
Polly Clayden, HIV i-Base
Updates on the paediatric development of rilpivirine and the single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate were shown at the 6th International Workshop on HIV Paediatrics. Presentations at the workshop also included an overview of raltegravir – now approved in the US for infants 4 weeks and above – and tenofovir data for adolescents.
Rilpivirine is approved for treatment of 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 naive adolescents aged 12 to 18 years.
Part 1 of this trial was to find a rilpivirine dose providing comparable exposure to that in adults. Data from part 1 were shown last year. Based on PK, tolerability and efficacy data up to week 4, 25mg once daily was selected. This dose was effective and generally well tolerated, in combination with 2 NRTIs, over 24 weeks for the treatment of ART-naive adolescents, with viral load ≤100,000 copies/mL. [1,2]
Safety and efficacy in the 24-week primary analysis of Part 2 were shown. 
Participants were recruited from sites in India, Thailand, Uganda, South Africa and the USA. Part 1b and 2 recruited only participants with viral load <100,000 copies/mL (following the adult phase 3 results); 8/11 participants from part 1a had viral load >100,000 copies/mL.
Participants received 25mg rilpivirine once daily, taken with a meal with two NRTIs: 67% tenofovir disoproxil fumarate(TDF)/ emtricitabine (FTC), 22% TDF/lamivudine (3TC) and 11% zidovudine (AZT)/3TC. The primary endpoint was the proportion of participants with viral load <50 copies/mL at 24 weeks.
Of 36 participants in Part 2, 20 (56%) were girls and 32 (89%) black or African American, the majority was from South Africa (56%) and Uganda (31%).
By intent to treat analysis (ITT-TLOVR), 75% (27/36) of participants had viral load <50 copies/mL at week 24. This proportion was 86% (24/28) in those with baseline VL ≤100,000 copies/mL but only 38% (3/8) in participants with viral load >100,000 copies/mL.
At 24 weeks, 9 participants (25%) had discontinued treatment: 7 for virologic failure, 1 due to adverse pulmonary tuberculosis and 1 for other reasons. The median increase in CD4 count from baseline (non completer=failure) was 165 cells/mm3 (range -210 to 530).
Thirteen participants (36%) reported an adverse event (any grade) that the investigators considered could have been related to rilpivirine. Most common were: 5 (14%), somnolence, 2 (6%) rash and 2 (6%) nausea. Most adverse events were grade 1 or 2. Grade 3 or 4 adverse events were: 2 malaria, 1 decreased blood phosphorus, 1 pancreatitis, and 1 depression, suicidal ideation and suicide attempt. There was 1 serious drug hypersensitivity (with hospitalisation), possibly related to rilpivirine.
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
The Stribild single-tablet regimen is approved for adults and contains elvitegravir (EVG) 150 mg, cobicistat (COBI) 150 mg, FTC 200 mg and TDF 300 mg (E/C/F/TDF). Safety, efficacy, and PK of E/C/F/TDF at 24 weeks in adolescents in the initial Part A of a prospective, 48-week, single-arm, open-label trial, were presented. 
Thirty-three (Part A n=14/Part B n=17) treatment-naive participants 12 to <18 years of age with viral load > 1000 copies/mL, CD4 count > 200 cells/mm3 and eGFR >90 mL/min were enrolled and received E/C/F/TDF once daily.
The participants were a median age of 16 years (range 12 to 17), 30% girls, 79% black, 21% Asian and 3% white. At baseline, median CD4 count was 407 cells/mm3 (range 133 to 664), mean viral load 4.71 log10 copies/mL and median eGFR 143 mL/min/1.73m2 (range 102 to 198).
There were no deaths, serious adverse events or adverse events leading to discontinuation of study regimen. Six of 33 (18.2%) participants experienced 11 adverse events the investigators considered to be related to E/C/F/TDF: 6/11 were gastrointestinal (vomiting, nausea, abdominal pain and diarrheoa) and 5/11 were CNS events (headache and dizziness). All were mild and none resulted in change of treatment.
The median change in eGFR from baseline at 24 weeks was -18 mL/min/1.73m2.
At 24 weeks 18/21 (85.7%) participants had viral load <50 copies/mL. Two participants had low level viraemia at this time point; 51 and 54 copies/mL and one discontinued due to pregnancy before 24 weeks.
None of the participants had virologic failure with emergent resistance. The antiretroviral steady state exposures of the component agents in E/C/F/TDF were comparable to adults.
In collaboration with the IMPAACT network, the originator company Merck has an ongoing programme for paediatric development of raltegravir, with chewable tablet and granules for oral suspension formulations.
In December 2013 the FDA changed the label to include babies 4 weeks to less than 2 years, weighing at least 3 kg to less than 20 kg receiving the granules – this formulation is expected to be commercially available in the US the third quarter of 2014.  The CHMP of the EMA gave the granule suspension a favourable opinion in June 2014 and approval by the EMA is expected soon.
The company provided a summary of the development programme to date, and ongoing studies in neonates below 4 weeks of age. 
IMPAACT P1097 was conducted to establish the washout PK of raltegravir in neonates born to mothers receiving raltegravir in late pregnancy, before starting a direct active dosing study. [7,8] P1097 enrolled 22 mother-infant pairs, confirmed good transplacental transfer (median cord:maternal blood concentration ratio 1.48), and showed variable and prolonged elimination of raltegravir in the first days of life compared with older infants and children: t1/2 26.6 hours (range 9.3-184).
P1097 is now assessing washout PK in a cohort of low birth weight (including preterm) infants.
IMPAACT P1110 is an ongoing two-part PK and safety study of raltegravir in term neonates at high risk of vertical HIV infection, and was informed by P1097 results.  Part 1 will collect intensive PK and safety data from two single raltegravir doses (at birth and 7 to 10 days) in approximately 12 neonates to estimate raltegravir clearance in the first two weeks of life.
Modelling and simulation will be used to inform multiple dosing in Part 2 to provide treatment from birth to 6 weeks in 20 additional infants. Raltegravir can be continued beyond 6 weeks if HIV is confirmed.
Completion of this programme should provide data for approval of raltegravir for the entire paediatric age range from birth onwards.
Tenofovir disoproxil fumarate
TDF was approved for adolescent use in the US in 2008 and the EU in 2012. The final results of GS-US-104-031 (Study 321) in treatment-experienced adolescents 12 to less than 18 years of age were shown at the workshop.
Study 321 was a 48-week randomised, phase 3, double-blind placebo controlled study with genotype-guided optimised background therapy. Participants received 300 mg TDF or placebo. The primary endpoint was time-weighted mean change in viral load at week 48.
No difference was observed between arms at this timepoint: -1.580 log10 TDF vs -1.549 placebo, p=0.55. Participants with baseline GSS < 1, viral load decrease was -0.57 log10 greater in the TDF vs placebo arm.
TDF open label extension followed the 48-week phase in participants expected to derive benefit from continued TDF up to 336 weeks. To look at efficacy the analysis stratified participants by subgroups: baseline viral load >1000 copies/mL initially randomised to TDF (TDF subgroup); randomised to placebo and failed with viral load >1000 copies/mL and switched to TDF (placebo/TDF >1000 subgroup); and placebo with viral load <1000 copies/mL switched to TDF (placebo/TDF <1000 subgroup).
A total of 81 participants received TDF in the open label extensions (all TDF group): 43.2% male, 53.1% white, 29.6% black, median age 14 years, mean CD4 422 cells/mm3.
At TDF baseline, 61 had viral load >1000 c/mL (44 in TDF/TDF, 17 in placebo/TDF >1000) and 18 had HIV-1 RNA <1000 copies/mL (placebo/TDF<1000).
At 288 weeks, only 1/1 participant in the placebo/TDF <1000 subgroup had viral load <50 copies/mL (missing= excluded).
Of 57 participants analysed for resistance, additional mutations from TDF baseline were identified in 20: 1 K65R, TAMS in 11/20 and M184V in 5/20.
There were no deaths. Most frequent adverse events were: sinusitis (32%), cough (30%) and vomiting (26%). Grade 3 or 4 lab abnormalities occurred in 25/81 participants: neutropenia in 15 (14 taking AZT) and hyperbilirubinaemia in 7 (6 taking atazanavir with chronic HCV infection). Median height and weight increased.
Median change in eGFR from baseline in the all TDF group at week 144 was -38.1 mL/min/1.73 m2 (n=25); p<0.001) – this is consistent with normal changes during adolescence.
There was 1 acute renal failure during the open label extension after amphotericin B therapy for cryptococcosis; as well as 1 real colic and 2 proteinuria. One participant had signs of phosphoribosyltransferase (decreasing eGFR, hypouricemia, proteinuria, and glycosuria) prior to taking an overdose of TDF as a suicide attempt: eGFR increased following TDF overdose; other abnormalities resolved/improved while TDF maintained. No fractures were reported. Median spine and total body bone mineral density increased over time.
The i-Base/TAG 2014 Pipeline Report includes an update on paediatric antiretroviral drug development:
Unless indicated otherwise, references are to the programme and abstracts of the 6th International Workshop on HIV Paediatrics, 18-19 July 2014, Melbourne, Australia.
- Crauwels H et al. Rilpivirine pharmacokinetics in HIV-1-infected adolescents: A substudy of PAINT (phase II trial). 21st Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2014, Boston. Poster abstract 900.
- Clayden P. Paediatric pipeline: CROI 2014 update on new antiretrovirals for children. HTB 24 March 2014.
- Lombaard J et al. Safety and efficacy of a rilpivirine-based regimen in HIV-infected treatment-naive adolescents: week 24 primary analysis of the PAINT phase II trial. Oral abstract O_05.
- Chokephaibulkit K et al. Safety, efficacy and pharmacokinetics of the integrase inhibitor-based Stribild single-tablet regimen in HIV-infected treatment-naïve adolescents through 24 weeks. Oral abstract O_06.
- FDA press release. New Isentress (raltegravir) dosage form: oral suspension. 20 December 2013.
- Teppler H et al. Raltegravir paediatric development: new options for treating the youngest children with HIV. Poster abstract P_10.
- Clarke D et al. Raltegravir pharmacokinetics and safety in neonates (IMPAACT P1097). 20th CROI, 3-6 March 2013, Atlanta, GA, USA. Poster abstract 974.
- Clayden P. Safety of transplacental raltegravir in neonates and washout pharmacokinetics. HTB 1 April 2013.
- Clinicaltrials.gov. Evaluating the safety and pharmacokinetics of raltegravir in infants.
- Clinicaltrials.gov. Safety and pharmacokinetics of raltegravir in HIV-1-exposed newborn infants at high risk of acquiring HIV-1 infection.
- Della Negra M et al. Tenofovir DF (TDF) plus an optimised background regimen (OBR) in HIV-1 infected adolescents failing a regimen: study GS-US-104- 0321 final results. Oral abstract O-09.